Abstracts of Poster Presentations
259 31.01.01 PHARMACOTHERAPY, PSYCHOTHERAPY, AND PSYCHOEDUCATIONAL INTERVENTIONS: EFFICACY IN RECURRENT DEPRESSION POSTER E. Frank, and D. J. Kupfer We are currently engaged in a study of maintenance treatments for PRESENTATION recurrent unipolar depression which compares the efficacy of psychotherapy, pharmacotherapy and their combination. Rather 31.01 than focusing exclusively on the number of recurrences in each of the experimental conditions, we have also been concerned with the quality of patients' lives between episodes and with the !ength of the symptom-free interval. The three-year maintenance phase of our study is still in progress; therefore, final results will not be available for another 18 months to 2 years. We can, however, discuss the information available on Basic and Clinical Aspects those 62 patients who have already experienced a recurrence of illness and for whom the blind has been broken. While the majority of Depression of recurrences have been experienced by patients in the non- medication conditions, it would appear that, with or without medication, psychotherapy has had a significant effect in delaying the onset of a new episode. At this point in time, however, we have little evidence that continued psychotherapy adds to the generally good quality of patients' social functioning in symptom-free interval. A full understanding of the additive and interactive effects of pharmacotherapy and psychotherapy in the treatment of recurrent depression must await the completion of this study ",,,'here analyses which indicate both the recurrences and the survivors will be possible,
University of Pittsburgh, School of Medicine, Department of Psychiatry and Psychology, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213
31.01.02 31.01.03
CHARACTERISATIOt; OF DEPRESSIVE SUSGROUPS ON THE THE THERAPY 3F ORGANIC DEPRESSION
BASIS OF PSYCHOPATHOLOGICAL,PSYCHOPHYSIOLOGICAL, Marko Munjlza NEUROENDOCRINOLOGICAL AND CLI!;IC~L PARAMETERS IN THE COURSE OF ~EPRESSION According to the recent reports ]ssued by WHO the prevalence rate of E.M.STEINHEYER,A.CZERNIK depression is from 3 to 5 per cent for the whole population. The greater comparat~an-aqysls Is presented of symptoma- incidence of ~3r~ous psychogeriatric disorders with depressive symptoma- tological,phychophysiological,neuroendocrinolo- tology, as well as numerous somatic and neurologic disorders: appears to gical,diagnosisspecific,and course-specific pa- be the sign o'~ an inCreasingly large number of somatogenic depression and rameters of 38 =emale impatients durina the de- depressive syndrome on the whole. pressive phase of and after relief from depres- Since the aet~olugy of somatogenic depression has within itself somatic, sion.We studied the state or trait dependence of neurologic, b;olugic, social and other factors, the author explores the specific reaction patterns of operationalized application of combined therapy with vasoactive substances and antide- depressive subgroups.The extent to which the pa- pressants. Data were collected prospectively on 190 patients, both genders tients can be subdividet into distinguishable (86 males and 1C4 females), in age from 45 tO 75 years, over a six weeks groups during the depressive phase and after re- period. Throughout the study, the patients received Pentoxyfilin (Trental) covery from depression,and the specific diffe- and antidepres.~nts according to the form of depressive reaction --inhibited rences between the possible subgroups are shown. or agitated picture. The results of the cluster-,discriminant-,and In addition to tee statistical analysis, particular attention is paid to the factor-analyses demonstrate a very high dominan- clinical evalu~ior of applied therapy inthe most frequent symptoms of ce of biochemical and neuroendocrinoloqical na- somatogenic depression. During the clinical evaluation different scales rameters for the determination of depression- were used in accordance with symptomatology. The combination of specific reaction patterns durin 9 depression.A PentoxyfiIin ar=:l antidepressants at all these scales appears to offer more greater coherence,i.e.,a lower indeeence of the advantages tl-en any other method improving the existing state~ of individual psychoautonomic,co9nitive,and psycho- depressive mood, depressive inhibition, symptoms of fear and SOmatic physiological systems was confirmed,which sug- manifestations. This satisfactory outcome of combined therapy also gests a narrowina and a reduction of the "de- provides improvement in the sphere of concentration and memory, grees of freedom~(HEIMANN) in the depressive producing willir~jress for social contacts and interest in work and activity. phase.After recovery from depression,psycholoni- The satifying effect of combined therapy with regard to the therapy with cal and cognitive parameters have more relevan- antidepressants only, especially in depressive, somatic and neurasthenic ce and show a high discriminant validity between difficulties, is iliu~rated most obviously by statistical analysis Where the neurotic and endogenous depressive subgroups. significant difference was obtained already at level below 0.05 for the Abtl. Psychiatrie der Medizinischen Einrichtun- benefit of Pentoxyfilin in combination with antidepressants. gender Rheinisch-Westf~lischen Technischen Hochschule Aachen,Pauwelsstr.,51&~cnen INSTITUTE FOR MENTAL HEALTH, Palmoticeva 37, 11000 Belgrade YUGOSLAVIA Belgrade University Medical ghool
260 31.01.04 31.01.05 RELATIONAL DEPRESSION RATING SCALE AND CLINICAL PATTERNS OF COGN I T I VE AND PSYCHOMOTOR ASSESSMENT OF MAPROTILINE D I STURBANCES I N DEPRESSED PAT I ENTS UNDER Y, Poinso, M. Ohayon SEDATIVE AND ACTIVATING ANTIDEPRESSIVE THERAPY Reliable rating scales are needed in multicentric trials of psychoactive drugs. The C.R. Vieira, M. Paes de Sousa~ M.L. Figueira, L.C. author presents a new depression rating scale (RDRS) stressing the Psychiatrist- Pestana, M. Feio Patient relationship during a non*directive clinical interview, our basic hypothe- Since previous studies showed that activating sis being that the clinician evaluates the severity of the depression more upon ant idepressive therapy improves cognitive and this relation than upon the seeking of the classical depressive symptoms. There- psychomotor performances of depressive patients, the fore, RDRS scans the relational elements of the interindividual communication question remained if the same effect was achieved (ie. 1) non-verbal communication tokens: features' and body's mobility, look, clo- with sedative antideoressive drugs. thes, 2) verbal communication: voice, topics, adaptability, 3) emotional display: In matched samples of depressive patients submitted effective need, anguish during the interview, aggressivity and irritability, self- to activating (Amineptine) and sedative (Dothiepine aggressivity). The 12m item is a global estimation of the quality of the and Trazodone) antidepressive treatments, , tests of psychiatrist-patient interaction. central nervous arousal (CFF), attention, Short-term RDRS performs a reliable estimation of depression, with a perfect correlation with other classical rating scales such as MADRS, as demonstrated by the statis- and iconic visual and verbal memory and choice tical assessment reaction time (CRT), were performed before and Its main interests are: 1) easy rating, even by generalists. 2) Monofactorial struc- after four weeks of treatment. The data obtained ture, all the items being closely correlated or:ly with the intensity of depression. were statistically (means, standard deviations and 3) steady logarithmic decrement of RDRS sco;es under trealmenL ANOVA) compared among themselves and also with 4) good inter-observer reliability. the data obtained with the same battery of test_-- in As an instance, the author presents the results of a mult~=ntric trial of Maprotiline a sample of normal subjects. The results were using RDRS together with other rating scales. The scale was welcomed by the analysed and discussed. clinicians, owing to the fact t~at it needs no change in their own way of interview, Dept. of Psychiatry. Faculty of Medicine of Lisbon. Its results are quite similar to those of the other rating scales used, showing no Hospital St a Maria. Av. Prof. Egas Moniz. P-1600 gross discrepancy. This study confirms the value of RDRS as a rating tool for de- Lisbon. Portugal. pression. Laboratoire de Traltemant des Connaissances, CHU Sainte-Marguerite, 270, Boulevard de Ste-Marguerite, 13009-Marseille (FRANCE)
31.01.06 31.01.07 THE INFLUENCE OF SOME PSYCHO-SOC IAL AND TAIL SUSPENSION TEST : STRAIN DIFFt~RENCES AND THE'EFFECTS PATHOLOGICAL CHARACTERISTICS OF DEPRESSIVE OF THREE ANTIDEPRESSANTS PATIENTS ON THE SYNDROMATIC EVOLUTION UNDER ANTIDEPRESSIVE THERAPY A. Len~m'c. I. AvriL L Stdru and R.D. Porsolt M. Paes de Sousa, M. L. Figueir a 424 depressive patients treated with several Mice when suspended by the tail will alternate between periods of vigorous antidepressant drugs (Clomipramine, Doxepine, activity (searching) and immobility (waiting). Immobility, like that measured in the Dibenzepine, Tandamine, Nomifensine, Amineptine, "behavioural despair" test, is reduced by a wide variety of antidepressants. The Amitrityline, Nortriptilyne and Minaprine) were procedure has been automated (ITEMATIC-TST) and permits the objective described and assessed before and after 1-2 months measurement of two parameters, immobility and the power of movements. The of treatment with the AMDP system. A principal present experiments compared the behaviour of 5 strains of mice (C57BL10, components analysis on the basis of the AMDP-4 C57BL6, DBA/2, Balb/C, NMRI) on the two parameters and examined the Scale items, was made before and after the effects of three antidepressants with different mechanisms of action : imipramine, treatment. The first analysis enabled to isolate nomifensine, dtalopram. three factors (depression/inhibition, anxiety/ agita- tion and self-distortion) and the second analysis The results showed dear differencesin base-line bchavlour : Balb/C showed enabled to isolate two factors (depression/inhibition twice as much immobility as NMRI with similar po~ver of movements whereas and anxiety/agitation). Taking into consideration DBA/2 mice showed similar immobility to NMRI but increased power of each one of these factors, an analysis of variance movements. The different strains also reacted differently to drugs. NMRI showed ~sas performed among some psycho-social and clear decreases in immobility with all drags whereas DBA/2 were particularly psychiatric history variables of the subjects of the sensitive to nomifensine and dtalopram. BALB/C responded only to dtalopram.. sample. The variables studied were: sex, age, marital status, education, social-economical status, These results suggest that choice of strain might be a significant factor for body type D personality, patients psychiatric history, dete.cfing antidepressants with particular mechanisms of action. depressive diagnostic, depression modality~ in or outpatients and antidepressive drug. Significant differences were obtained for some variables. Whenever there was more then two possibilities for I.T.E.M.-Labo, 93 Avenue de Fontainebleau, 94270 Kremlin-Bic2tre - France one single variable, the Bonferroni t test was applied to discriminate the sens of the significance. The differences considered significant were analysed and discussed. Dept. of Psychiatry. Faculty of Medicine of Lisbon. Hospital St -a Maria. Av. Prof. Egas Moniz. P-1600 Lisbon. Portugal.
261 31.01.08 31.01.09 EFFECT OF NIFEDIPINE ON THE SHUTTLEBOX ESCAPE DEFICIT ANTIDE~NT-LI~ ACTION OF 8-[]H 0OAT, A D-HTIA ;~I~QIST, IN l)E INDUCED BY INESCAPABLE SHOCK IN THE RAT L~ ~S~ESS PARADIGM : PFE- OR POST-~TIC NE[}P.NI~I ? M. Geoffrey, E. Mogilnicka, M. Nielsen and P_z_-F~rtin, Ru ~[, O. Maesol, ~ .~rte, S. E1 Mestika~ O. J. Rafaelsen P. Soubri~, M. Has,n*, A.O. Puesh. The behavioural ~ffeet of subchronic treatment ~ith calcium channel antagonists (nifedipine, verapamil) amd A recent rt~.ie~ suggested the potential indication of buspiroce in with imipramine ~as assessed in rats subjected to ines- anxious patients suffering frcm depression and an qcen trial reported capable shock. Furthermore, the effect of subchronic its utility in the treatment of non melaroholie depressed patients. In treatment with nifedipine and imipramine on specific animal models of depression, the S-HTIA aganists, B-hydroxy-2-(di-n- 3H-nitrendipine (SH-NDP) binding was investigated in propylamino) tetralin (8-O4-DPAT), bJspirone, gepirone and ips~irone frontal cortex of naive rats and in rats given acbCnistered i.p. mimicked the b~havioral effects of antidepressants. inescapable shock and later tested in a shuttlebox For instax~, in the learned helplessness p~c[s these ck'uga rever- escape paradigm. sed the escape deficit ~ by prior ingle shocks (60 inesca- The test was carried out in a twe-wa~ shuttlebox and pable ~'~d
31.01.10 31.01.11 URINARY 24 HOteLS FREE SULFATE AND GLUCU~ONIDE ~ VALUES INTEREST OF IV ADMINISTRATION OF CLOMIPRAMINE IN RAT FOR fIN ENDOGENOUS %~RSUS NON ENDOGENOUS DEPRESSED PATIENTS THE STUDY OF THE 5-HT PHARMACOLOGICAL EFFECTS OF THIS DRUG :Ph. LESIEUR~ P. PENINQUE, J.P. GARNIER, J.PIRON, J.P. LEPINE D.Varoquaux,P.Lesieur,D.Morin,M.Pays,C.Advenier,W.Z.Potter and M. PETIT C]omipramine is known to be a potent and specific serotonir Method : seventeen depressed patients, dru~-free for at (5-HT) reuptake inhibitor whereas its demethylatedmetabo- least 15 days were hospitalised. All subjects met the DSM3 lite (DMC) is considered as a noradrenaline reuptake inhi- criteria for r.ajor affective (n=12) or dysthymic(n:5) disor. iter (Carlsson and al.,1969;Horn,1976;for review Mass,1979 ders. Severity of depression was assessed usingMADRS (range l yttel,1982). 28 to 46). The Newcastle Diagnostic Index was used to clas The aim of this study was to compare plasma levels of CMI sify the patients as endogenous (n=12) and as non- with those of its metabolites after an IV injection of CMI endogenous (n=5) in rat. Before and 30 days after a treatment by metapramine (300 Two days prior to experiment an indwelling catheter was to 600 mg/day), we measured tha 24 hours urinary excretion implanted to the tail artery (Chiueh and Kopin,1978). This of free, glucuro and sulfate MHPG. preparation allowed us a systemic clomipramine (5 mg.kg-l) Results : At baseline, the individuals scores on the MADRS injection and 10 blood samples collection over a 24 hours are negatively correlated to both total and sulfate MHPG period in the same conscious and unrestrained rat (n=8). (r= -.516 p<.05 and r = -.611 p<. 01 respectively); the Clomipramine (CMI) and its 8-hydroxy (8-OHCMI),demethyl endogenous group havinB the lowest values on this scale : (DMC),8-hydroxydemethyl (8-OHDMC) and didemethyle (DDMC) 37.9 + 4.1 vs 31.8 + 3.1 p<.01 . metabolites were determined on a 100 ~l plasma sample by More [nterestingly,-the 24 urinary excretion of total sul- Bn HPLC-EC method (O.Spreux-Varoquauxand a~.,J.of Chromat. fate and glueuro MHPG are significantly lower in tha en- 1987,416,311-319). dogenous group : 5.82 + 2.97 vs 11.72 + 3.84 ~moI/24 H Tmax(h) were I~0.2 for 8-OHCMI and 0.08 +0.02 for DMC. For p<.01, 1.08 + .8 vs 3.26 + 1.2 p<.001 and 2.21 + 1.78 vs CMI,B-OHCMI and DMC, Cmax(Bg.l-I) were 27802+3005, 6.5+0.6 ~.46 + p <.0[ respectively. and 51+5 respectively, tl/pB(h) (ti/2 apparent for metabo- Aftar-30 days of treatment the measures were completed in lites)'were 2.9+0.4, I0.1%~.8 and 3L5+0.5 respectively, 8 out of 12 endogenous patients, Only the sulfate form AUC (Ng.l'1.h) were 10725-+ 1865,87.5~ 7.2 and 49.9 6.5 increases significantly : 1.04 + 95 vs 3.10 + 2.14 p<.05. r~spectively, and MRT (h) were 2.8~0.7,15.1~I.3 and 4.2,0.5 Conclusion : These data point-out the relevance of tha Neweastla Diaanostie Index as a clinical tool able to dis- ~espectively. The plasma AUC CMI/metabolite ratio is 214.9 criminate depressed patients with high and low ~4 urinary for DMC and 122.5 for 8-OHCMI. The 8-OHDMC and DDMC were MHPG excretion mever detectable below 200 pg and 10 pg in 100 ul plasma ~ample respectiyely. Because of the very few a~ounts of CMI metabolites and since CMI is known to be a selective 5-HT reuptake inhibi- %or, these data suggest IV administration of CMI to be a ~eliable tool to study the pharmacological effect of CMI on 5-HT system. Centre Hospitaiier du Rouvray - 4 rue Paul Eluard B.P.A5 D~partement de Biochimie et Pharmacologie,Centre Hospita- 76301SOTTEVILLE LES ROUEN - FRANCE lier de Versailles,HBpital A.Mignot,F-78 157 Le Chesnay.
262 31.01.12 31.01.13 PLASMA SEROTONIN LEVELS IN RELATION TO HYPO- STIMULATION WITH DL-FENFLURAMINE IN ACUTE THALAMIC-PITUITARY-ADRENAL FUNCTION IN DEPRESSION AND REMITTED PATIENTS WITH MAJOR DEPRESSION C. Rupprecht, A. Barocka, M. Rupprecht, G. Beck, IM. Noder and R. Rupprecht A.Vieira. S.KasDer. R.Schmidt G.VoI1. P Richter. H.Kich Ch Mundt {There is evidence that serotonin precursors and !reuptake inhibitors may exert a stimulatory Abnormalities in central serotonergic function in depression are !effect on the hypothalamic-pituitary-adrenai sys- suggested by CSF, neuroendocrine and postmortem brain studies. 'tam. 5-hydroxytryptophan has been shown to pro- Using dl-fenfluramine (FEN) as a serotonin probe (fenfluramine iduce a greater increase in cortisol levels in de- stimulation test, FFT) we investigated 31 drug-free inpatients pressed patients when compared with normal con- (26 female, 5 male; mean age: 55 + 11 years) with major depression trols. As no data are available on the response by DSM-KI criteria. At baseline and after administration of 60 mg of plasma serotonin during the dexamethasone dl-fenfluramine (FEN) p.o. at 9 a.m. hourly blood samples were suppression test we studied 7 am and 4 pm pre- obtained until 1 p.m and subsequently prolactin, cortisol, TSH, hGH and postdexamethasone cortisol and serotonin and the plasma levels of dl-fenfluramine and its major metabolite levels of 16 patients during depression and after di-norfenfluramine were measured. The test procedure (FFF) was recovery and of 28 healthy controls receiving an performed in the same indi~Sduals (intraindividual comparison) in the oral dose of 1 mg dexamethasone at 11 pm. Dexa- acute stage of the illness with and without application of FEN and methasone had a significant suppressive effect after remission. The peak plasma levels of dl-fenfluramine and its (p Psychiatric Department of the University of Heidelberg, D-6900 HEIDELBERG, Vo/~strage.4, FRG 31.01.14 31.01.15 DST AND THE BLOCKATORS OF NORADRENERGIC AND PsTchopharmacologlcal Aspects of Pineal Function SEROTONERGIC TRANSMISSION IN DEPRESSIVE -V. Srinivasan - PATIENTS Institute of Physiology, }ladurai ~ledical College ~[adurai I. Timoti~ evi6 India. The possibility of Pineal gland involvement as a part The integrative model of affective disorders of neuroendocrine dysfunction in some of the psychiatric considers depression to be the ending of dis- diseases has received attention in recent years. The crders on psychological, biological and empi- significant effects of many psychoactive drugs on the rical level. The basic indicators in the synthesis and secretion of melatonin and the discovery dia~nose and treatment of depression are the of many receptor sites in the pineal gland, beta biological disorders entering the scope of adrenergic, alpha 1 adrenergic, D2-dopaminergic functioning of hypothalamic-hypophysical- S2-serotonergic, muscarinic-cholinergic, GABA ergic, adrenaline axis, and disorders in functioning glutamatergic, benzodiazepinergic and peptidergic receptors of transmitters. (Ebadi & Govitrapon$ 1986) have all suggested that LST is used as a measure of functioning for the study of pineal function and melatonin secretion patients who by precise clinical evaluation provides a valuable model system for psychopharmacologi- have been diagnosed as great depressive dis- cal investigations. Murphy et 1986). Many psychoactive orders (DSM III)? or endogenous, unipolar drugs, namely chlorpromazine, imipramine, lithium, depressions (IC9), and on the basis of these haloperidol, diazepam, nootropil when administered data treated with a~tidepressants of seroto- to animals produces significant increases in pineal nergic reuptake. melatonin and protein concentrations (Srinivasan et The sample consisted of two groups (eight a! !985). Administration of monoamlnc oxidase inhibitor patients in each), of both sexes, age range, antidepressants and tricyelic antidepressants to animals 25 to 56 years. The A group patients were or to patients suffering from depressive illness causes treated with blockators of noradremergic significant increases i n either CSF, Plasma or Urinary transmission and those of B group with sero- melatonin levels (Golden et al 1987, Murph7 et al 1986 tonergic antidepressants. DST was carried out (a) (b), Srinivasan et al 1984, 1986, 1987, "Thompson in both groups before the treatment and 28 et al 1983, 1984). The significant effects of these days after medication. Depression is measured psychoactive drugs on pineal function and melatonin by the score hight on the Hamilton Scale. secretion will be discussed. The results show that all improvements have been achieved disregarding the selective use of antidepressants while DST did not demon- strate sensitivity to the sort of antidepres- sant. DST singled out the patients with cli- nical improvement, but not those with bio- chemical homeostasis which discovers patients in risk of possible decompensation in the case of breaking the continuity of medication. 263 31.01.16 31.01.17 THE TWENTY FOUR HOUR SECRETORY PROFILES OF CINP XVIth Congress Munich, 15th-17th August PROLACTIN IN MA3OR DEPRESSIVE ILLNESS AND h988 AFTER TREATMENT, P. Linkowski, E. Van Cauter, M. Bal6riaux t M. CORTZSOL RESPO~:S~ oF ~POLAR PATiEnTS RECEZVZ~G Kerkhofs, P. Hubain, M. L'Hermite, J. Mendlewicz. AN ANTIGLUCORT!CCID Plasma PRL were measured at 15 rain intervals for 2g hour in 18 male subjects suffering from major endo- Administration of RU 486, a synthetic antagonist genous depressive illness and in 7 age-matched normal of glucocorticos~eroid at the receptor level, men. Eleven of the lg depressed patients were induces in normal subjects a desinhibition of restudied during clinical remission following either the pituitary adrenal axis and antagonizes the electroconvulsive therapy or amitriptyline treatment. ACTH inhibitory effect of Dexamethasone. Durin 8 the acute phase of the illness, the unipolar When the drug is administred at midnight or depressed patients showed an early timing of the I0:00 a.m.. the increase of cortisol, ACTH and nocturnal secretory phase of PRL, which started, on Beta-endorphin plasma levels occurs only during average, two hours earlier than in normal subjects. the early morning ieak. Moreover, the amplitude of the circadian variation of The response of bipolar patients is an increase PRL was reduced in these patients, with decreased PRL of tortisol secretion superior as compared to levels during the midsleep period. This latter abnorma- controls. The best ~ime to discriminate patients lity was also observed in bipolar patients, who had from controls is 5:00p.m. otherwise normal PRL profiles. These lower midsleep This magnif~d reactivity of the glucorcorti- PRL concentrations were associated with a significant costeroid secretion is consistent wich the abnor- increase of the amount of time spent awake during the malities described using dexamethasone suppres- same period. sion test. Antidepressant treatment did not consistently correct the abnormalities in the patterns of PRL release observed during the acute phase of the illness. These results indicate that early timing of nocturnal PRL secretion and damping of the nighttime PRL elevation may be found in patients with endogenous depressive disorders. In contrast to disturbances of the corticotropic and somatotropic axes, these abnormalities of PRL secretion may be still present during clinical remission following antidepressant treatment. Free University of Brussels, grasme Hospital, Depart- ment of Psychiatry, Route de Lennik 808. 5-1070 Brussels. 31.01.18 31.01.19 SEASONAL VARIATION OF CORTISOL LEVELS IN DEPRESSIVES THE EFFECT OF REPEATED ADMINISTRATION OF ANTIDE- A.L.van Bemmel~R.van Diest~ E.H.J.Smeets~P.H.M.van Dongen PRESSANT DRUGS ON THE THYROTROPHIN RELEASING Significantly lower post-dexamethasone (POST-DEX) HORMONE (TRH) CONTENT IN RAT BRAIN STRUCTURES cortisol plasma levels during the four months November to E. Przegali~ski and L. Jaworska February compared to the rest of the year have been reported in depressives (1). This finding was interpreted Several lines of evidence indicate that some as a seasonal variation of the dexamethasone suppression links exist between TRH and depression or anti- test (DST). Significantly less frequent DST non- depressant therapy. For example, repeated treat- suppression in winter than in summer was reported earlier ment with amitriptyline or electroconvulsive in depressives (2). Although of unknown origin, the shock was shown to increase the TRH concentra- seasonal variation of POST-DEX cortisol levels is tion in different regions of the central nervous possibly related to a similar variation in PRE-DEX system (Kubek et al., Life Sci., 36, 315, 1985; cortisol levels. This study is dealing with the question Lighton et al., Neuropharmacology, 24, 401, 1985). whether a seasonal variation in PRE- and POST-DEX cortisol levels in plasma can be found in depressives. The present study investigated the effect of re- Subjects with major depression were selected from two peated treatment with the antidepressant drugs: psychiatric clinics (n=33 and 54 resp.). They were imipramine, amitriptyline, citalopram and mian- hospitalized and tested when depressed. One mg DEX was serin (10 mg/kg p.o., twice daily for 14 days, given at 11 PM and blood samples were collected at 4 PM last dose 4 h before killing) on levels of TRH on the day before and after DEX. A POST-DEX cortisol in several brain structures (cerebral cortex, concentration > 0.14 #mol/1 was defined as non- amygdala + pyriform cortex, hippocampus, nucleus suppression. Variation of PRE- and POST-DEX cortisol accumbens, striatum and hypothalamus) of the rat. levels over all seasons was investigated with simple one- Amitriptyline caused a marked increase in the TRH way ANOVA and the seasonal distribution of the content in the striatum and nucleus accumbens nonsuppression rate with the Chi-square test. These (by 188 and 126%, respectively). Citalopram and analyses did not show significant results. Therefore, mianserin produced a smaller but significant in- the consequence for every day practice of the suggested crease in the peptide content in the striatum seasonality in the DST, whenever it exists, remains only (by 76 and 56%, respectively), while imi- doubtful. pramine did not significantly affect the TRB le- (1)Swade et al.J Affect Disord 13, 9-11, 1987 vel in any of the examined brain structures. (2)Arat6 et al.Arch.Gen.Psychiatry 43, 813, 1986 These results speak against the relationship be- Department of Clinical Psychiatry, State University of tween changes in the brain TRH induced by anti- Limburg, PO Box 616, 6200 MD Maastricht, The Netherlands. depressant drugs and their therapeutic activity. Institute of Pharmacology, Polish Academy of Sciences, Sm~tna Street 12, 32-343 KrakBw, Po- land 264 31.01.20 31.01.21 PITUITARY-ENDORGAN RESPONSES FOLLOWING COMBINED GROWTH NEUROENDOCRINE INTERRELATIONS BETWEEN DEPRESSION HORMONE-(GHRH), THYROTROPIN- (TRH) AND CORTICOTROPIN-RE- AND SEXUAL DYSFUNCTION LEASING HORMONE (CRH) STIMULATION IN DEPRESSED PATIENTS M. Noder, E. Jecht, C. Rupprecht, M, Rupprecht AND CONTROLS. and R. Rupprecht U. MOller, R. Rupprecht, H.M. Schulte, and K.P. Lesch While the hypothalamic-pituitary-gonadal system To explore and to compare hypothalamic-pituitary-somato- has found considerable interest in sexual dys- tropic (HPS), -thyroid (HPT) and-adrenal (HPA) axis func- function, only few data on gonadal hormones are tion in depression, 20 subjects (10 patients with a major available in depression. In order to investigate depressive episode and individually matched controls) re- possible interrelations between psychogenic cieved 50 pg GHRH-44 amide at 9:00 h, 200 pg TRH at 9:00 h sexual dysfunction and depression we studied and lO0 pg human CRH at 18:00 h on consecutive days as an 7 am and 4 pm cortisol, testosterone and LH iv bolus dose. Compared to controls, the depressed pa- levels before and after oral administration of tients showed blunted GH responses to GHRH (p 31.01.22 31.01.23 TYP~IINE CONJL~ATION IN AFFECTIVE DISORDER TWO CASES OF SEASONAL AFFECTIVE DISORDER -- BIOLOGICAL RHYTHM AND LIGHT THERAPY -- H. Standish-Barry, P. Hannah, M. A. Sherman, M.Okawa, T.Nanami, K. Mishima, T.Shimizu, S. me - ' .oee- Iijima, Y. Hishikawa Seasonal affective disorder (SAD) is character- There is some evidence that following ingestion of ized by mild affective symptoms and remarkable an oral load of Tyramine, depressed patients excrete therapuetic effects by bright light. In Japan, significantly less tyramine 0 sulphate compared with SAD has not been reported under the light of controls (Lander et al 1975, Harrison et al 1984). biological-rhythm disorder. Akita is located in Furthermore it seems that this abnormality of the northern part of Japan with less sun light Tyramine conjugation perisits even after recovery in winter. The authors presented two cases of from the depressive episode, suggesting that it severe or mild SAD with results of investigation represents a trait marker for depressive illness on biological rhythms including body temperature (BomhsmCarter et sl 1978 s). The mechanism for this and melatonin. abnormality has not yet been fully elicited. Patient I, a 64-year-old man, visited our hospi- (Bonham Carter et al 1978b, 1980, 1981). Harrison et tal 15 years ago complaining of melancholia, al (1984) have published findings supporting this anorexia, insomnia and fatigue. He had a history view. Hale et al (1986) have produced evidence of repeated depression in autumn and winter, that the Tyramine conjugation test is superior to since he was a high-school boy. Recently, he the dexamethasone suppression test in beth noticed that mood changes became mild with in- sensitivity to and specificity for endogenous creasing age. This winter, depressive symptoms depression. were not manifestied, probably because of fre- quent out-door sun-bathing. Daily changes of The present study looks at the specificity of the rectal temperature in the depressive state show- tyram, ine conjugation test in a group of patients ed a flattening pattern, while that in the neu- suffering from depressive mood disorder. The results tral state showed a circadian rhythm with ad- provide further evidence that the m)Tamine conjugation vanced phase. test is specific for endogenous depression. Patient 2, a 24-years-old female, visited our hospital complaining of mild depressive symptoms in the last 3 winters and her condition was diagnosed as SAD. Photo therapy (3000 Lux light exposure from 0530 to 0700 hr) was applied for 2 weeks. Hamilton scores before and after photo- therapy were 18 and 7 respectively. Cessation of photo-therapy or evening exposure of light exacerbated the symptoms. Circadain rhythm of rectal temperature was preserved both before and after photo-therapy. Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan, 010 265 31.01.24 31.01.25 PLASMA MELATONIN LEVELS IN AFFECTIVE STATES GROWTH HORMONE AS "TRAIT" DISTLqRBANCE IN DEPRESSION P.F. Marriott, I.M. Hc!ntyre, F.K. Oudd, G.D. Burrows, S. C. Risch end R. Hauger T.R. Norman. AbnonTalities of growth hormone secretion have been re- Melatonin is a major endocrine product of the pineal ported in depressed patients including elevations in day- gland. It is produced at night when noradrenaline time p~ concentrations and attenuated responses to cen- acts on beta-adrenergic receptors to stimulate tral provocative challenges %ith insulin-induced hypogly- cemia, clonidine and the tricyclic antidepressant des- enzymes which catalyse the formation of melatonin methylimipramine. The recent availability of the hypothal- from serotonin. Some authors believe that nocturnal melatonin levels reflect beta-receptor function. mic peptide human growth releasing factor (hGRF) allows Because changes in beta-receptor function have been direct testing of pituitary ~ hormone secretory re- implicated in the mechanism of action of somatic spoP~se in depressed patients, re~nitted depressed patients, treatments of depression and in the pathophysiology and age- and sex-matched nozmals. of affective disorders, investigations of melatonin All subjects received a complete history, physical, labor- have been undertaken. We have studied the nocturnal atory examination and Schedule for Affective Disorder and production of melatonin in patients with depression Schizophrenia (SADS) interview. All subjects received and panic disorder, and in control subjects. Mid- hGRF (I ug/kg) and placebo hGRF intravenously on separate night concentrations of melatonin in 22 depressed days one week apart in a double-blind, rendcmized, count- patients were significantly lower than 24 control erbalanced paradigm. Blood samples were obtained every 15 subjects (45.9 • 4.3 pg/ml vs 61.7 • 4 5 pglml; p minutes for 30 minutes prior to and for two hours subse- <0.01). These data support previous reports of quent to the infusions. San~les were subsequently assayed for growd3 hormone and other plasma neurohormones by RIA. reduced melatonYn synthesis in depressive illness. Mean ~han~.es in Log_ growth hormone plasma concentrations In the first report of panic disorders, we showed significantly lower midnight levels of melatonin from baseline to post hGRF timepoints were significantly compared with controls (28.4 • 6.4 pg/ml vs. 51.6 (p=.001, Diagnostic Group x Drug x Time) attenuated in • 4.1 pg/ml, p 31.01.26 NERVE,", GENZODIAZEPIHES IN TIIE TRE/.T;.:E::T OF-. ENDOGENOUS E,EP T.ESSIO;,' E. ~e~ov~ z 3, ~ve. ~kaf k. N,ihunek Some sucnor~ s,-:pposeo tna~ trs::e;iilizer seeh cs T;romazepe.,-., e.nd triszoloUer, zodie.zepi.-:es - elpr,rzolP.m ond adinr.zola~ - ecteC as ~nl;idepres sa:;tc, At UniQersitv Ps~,chiatric Oep~rtzent -I in Srno 59 i.~-pts ~,,&re involved ir an open stu-! dy ~vith :;rosszep~m ~nd 65 pts ~,,ith ,'-Ip~ezolaq. ,..ter pl#ee'o Cnterv~l /2 - I0 days/ the (~)ses were individualized, the minimrl ~r,d m~xi::al averaoe dcilv doses o? bro;ia:eo~m '2celn- s mg and 28 mg ~;:d ~lprazole::, 1,3 resp. 4, S~7 m~. D':rP:;ionrof the treatment w~-s 23 d+ys i~ ~,,,er~e. The ther&peutic effect ~,,as e','al :e~ed ~ccordi.c i:o h[.e F;CD, ~:A;:D, D'/P v,nd .'erc-'sk'-'~ re les. i t e 7lid a {! ::,i::D SCFIcs U'rS e-si~::i- fic~,::t decrease of the ~lo:.el ~core as tell ~s i:, tl;e ;m~oritv of cy:pto::s Plre~-Ev ~2ter 7 rT'v$ O? %reet::~:zt. T'itn ,;romezeons' 2L,II re- /..isrio~ v~ns rchieved in 35,~[ of pts /p~rtiel re:;:issio;, i:: 12,7[/, it ~e,~:;s clinically .~icnl- ciccnt i~prove:uent i:. Ogr~. ',.ith clprc,:_olFn cli:icelly subste~ti~.l ir3provement was echieved in 71y" oF pts /53~ 07 the.n. ~,ere i:-, ?:;II re- F,l.~S.O ,/. ~l(,e e~ ~ ~C~B O, 8UuO,~O,,IC C,,BrSCuer ,'ere of Io~,' i:~ter.zity ~,d frerue~cv. ?atiy'ze ~md r'ro~,sihess war the most Creouent, l,~ bro- n~,zep~ .*tudv or.e hslf o? treeted pts ,ere ph~rT::~coresiste.-,t i;~ 2 or even ~ore previous t:-:errp,, cures,v.ith diCferent entideprers~nte, i'., alprazol,.-~ .~tudy o:~e third of pts,O:-, the bRsis of our prelimi::~rV results ~ve are of the opi:;ion that io~ freeuency and d~ffere-t profile of si~;e effects h~ve clrs.~ifiefi the.~e ~e-~er be~odi:zepines co::siCeri.~q their a. tide..~rres- sire action anong the ar, tidepressr.nts of the ?-;rther ce'.-.er~tlon. University Psychietric Dep~rtuent,JiSlavska Ioo "rno - Pohu-ice G57 15 Czeehoslov~&-{r 266 31.02.01 TREATMENT OF DEPRESSED PATIENTS WITH CLOVOXAMINE FOR UP TO ONE YEAR Richard J Simpson and L DiAnne Bradford* POSTER The long-term safety and efficacy of clovoxamine in depressed patients was studied in an open trial with centres in Austria I PRESENTATION Belgium. France, Germany, Sweden, Switzerland, United Kingdom and Yugoslavia. Patients were treated and monitored 31.02 for up to 12 months, with frequent assessments for efficacy, safely and tolerance, Informed consent was given by the patients for their participation in the study. Two-hundred eighty patients (187 F/93 M, mean age = 52 yrs) entered the study who met the MRC definition for depressive illness and the ICD-9 categories 296.1 or 296.3: pre-treatmenr HAMD was on average 24.7. One-hundred seventy-three (62%) Antidepressants completed one year's treatment: reasons for early termination were: recovery (4.6%). inefficacy (7%), intolerance (9%), (incl. MAO-Inhibitors) suicidetattempt (I.4%) and administrative (non-drug reasons) 13%. Only 4% (I I patients) relapsed between months 2 and 12. There was a significant decrease in the total HAMD scores from week 2 onwards (P<0.002): by month 2, compared with pretreatment, patients had improved on average 64%, this reached 85% by month 12. Nausea (1.5%) was the most frequently reported side effec L anlicholinergic effects were minimal, as were adverse cardiovascular or laboratoD effects, clovoxamine was no| associated with weight gain. The data indicate that clovoxamine was safe and well-tolerated during long-term treatment. Health Centre. Bridge of Allan, Scotland:*Dept. Clinical Research. Duphar BV, PO Box 900, 1381CP Weesp. Holland 31.02.02 31.02.03 TREATMENT OF ELDERLY DEPRESSED PATIENTS WITH TREATMENT OF ELDERLY DEPRESSED PATIENTS FOR UP TO ONE CLOVOXAMINE OR MIANSERIN YEAR WITH CLOVOXA.'v[INE J Vanderdonckt and L DiAnne Bradford A Rundgren and L DiAnne Bradford* The prevalence of depression worldwide is greater than 10% in people over Depression occurs frequently in the elderly, and is even more common in the age of 65 and even higher if physical illness is present (1). The treatmenI those with concomitant illnesses (1). As the number of people over 65 is of depression in the elderly compared with the general population iS steadily increasing worldwide, the treatment of depression in the elderly will complicated by more adverse drug reactions due to polypharmacy and/or provide an increasing burden on the individual, and on social and medical greater intrinsic susceptibility to adverse reactions, physiological changes services, Until recently, tricyclic antidepressants(AD) have been the treatment such as diminished liver and kidney functions which may increase drug of choice in the elderly. However, the side effects which are most commonly effects. associated with tricyclics, namely cardiovascular, anticholinergic and sedative Depressed patients(pts) over the age of 60 yrs who met the DSM-III criteria effects, arc those to which the elderly are most sensitive (l), for major depressive episode, and scored at least 17 on the HAMD prior to The long-term safety, and efficacy of clovoxamine (CLO) in 375 depressed treatment were included in the study. 116 pts (94 F.'22 M) participated, with a patients(pts) has been studied (2,3). The data presented here describes 90 (66 mean age of 72 yrs. Pts gave informed consent to participate in the study. Pts F/24 M) of these pts who were >i 60 years at the beginning of the I yr were randomized to treatment with either clovoxamine(CLO),a new treatment period. Sixty pts (67%) completed treatment for 1 yr; 3% withdrew antidepressant which shows no sedative properties or mlanserin(MIA) which fi'om treatment early because of recovery, 8% for inefficacy. 11% for has been shown to have sedative properties, and has been claimed to be intolerance, 8% for administrative reasons. Only 3% (3 patients) relapsed particularly effective in treating anxiety, associated with depression, as well as between mo 2 and 12. anxiety neurosis (2.3). The mean total HAMD ~ores indicated a good AD response to CLO, with In a week-by-week analysis of the HAMD total scores CLO showed an improvement compared with pretreatment reaching statistical significance equivalent effect to MIA throughout the treatment periods, with both groups (P<0.001) from wk 2 onv.ards. On average, pts improved 68% by wk 8. improving about 55% by wk 8. There was no difference in the treatment Frequent safety assessmen~ indicated that there were no significant changes groups for any of the four factors of the HAMD. in HR; in the early months of treatment, a very small ( 267 31.02.04 31.02.05 CLOVOXAMINE TREATMENT COMPARED WITH LONG-TERM SAFETY OF C1TALOPRAM MAPROTILINE IN ENDOGENOUS DEPRESSED K. Lyby, L. Elsborg, H.E. Hcpfner Petersen and E. Skovlund PATIENTS The selective 5-HT uptake inhibitor CITALOPRAM has been E Radmayr, Chr Schumann* and L DiAnne Bradford* assessed as to long-term safety. This assessment is based on meta-analysis of the results from 325 patients treated Clovoxamine (CLO) comes from a new (non-tricyclic) class of for a period varying between 8 and 296 weeks. Safety was compounds and is equipotent in blocking the re-uptake of both monitored by means of a global assessment of side effects, NA and 5-HT, CLO was compared in a double-blind trial with a side effect check list, laboratory investigations of hema- maprotiline (MAP). a "second generation" tetracvlic tological, hepatic and renal function, cardiovascular control, antidepressant which blocks the reuptake of NA . Patients were and body weight recordings. Compliance was controlled entered in six centers in W.Germany. Austria and Yugoslaxia. by plasma level determinations. and had to meet the diagnostic criteria of DSM-III for major Results: depressive disorder. Informed consent was given by the patients During long-term treatment (i.e. >8 weeks) the side effect for their participation. profile was similar to the profile during short-term treatment, One hundred fifty-nine patients (117 F/42 M, mean age=49 and generally the incidence of side effects was low (4% yrs) entered the study; mean HAMD score at pretreatment was or less). The majority of side effects were mild and caused 27.5. 84% of the patients completed the six-weeks trial; 6 CLO withdrawal in only 5% of the patients. Most frequent side and 5 MAP patients stopped treatment early because of effects were tiredness, sleep disturbances, headache, and recovery; 6 CLO and 4 MAP because of administrative (non- teemor. No adverse effects were observed on the hematol- drug) reasons; and 1 patient in each group because of ogical, hepatic or renal function. No body weight gain was intolerance. recorded. In a few patients with pre-existing low heart rate The drugs could not be differentiated in reducing symptoms as there was a tendency to sinus bradycardia which was not measured by the HAMD total scores;compared with clinically relevant. Otherwise, no electrophysiological or pretreatment, both groups improved by about 70% at the week hemodynamicchanges were observed. 6 assessment. Both compounds had a similar clinical profile on the four factors of the HAMD. Anxiety symptoms were assessed Gone3usion by using the Covi Anxiety Scales in which both dru.gs were Citalopram is a safe and well tolerated drug in long-term shown to equally reduce anxiety associated with depressmn. treatment of depressive disorders. Few patients complained of side effects. The most frequently H. Lundbeck A/S, Ottiliavej 7-9, DK-2500 Copenhagen-Valby reported side effects associated with CLO were nausea and headache while dry mouth and dizziness were most frequently associated with MAP. CLO was associated with little or no effect on cardiovascular measures and anticholinergic effects, nor any adverse effects on laboratory variables. CLO was shown to be safe and well-tolerated, and equally effective as MAP in moderate to severe endogenous depression. Rahnhofplalz, Dornbint. AUT, *Dep! Clinical Research, PO BOX 900, 1381CP 14>esp. NED. 31.02.06 31.02.07 FLUOXETINE (F) AND AMITRIPTYLINE (A) ; SAFETY THE EFFECT OF CITALOPRAM IN DEM~\~IA DISORDERS. A AND WEIGHT IN THE TREATMENT OF MAJOR SCANDINAVIAN MLZTI-CENTER STUDY DEPRESSIVE DISORDER (MDD). A-L. Nyth, C.G. Gottfries, K. Eizen, K. Engedal, A. Harenko, I. Karlsson, T. Koskinen, L. Larsson, H. M. Czarka, C. Rielaert, , P. Linkowski, M. Kerkhofs, Nvgaard, S.M. Samuelsson and A. Yli-Kerttula 3. Mendlewicz The present study was undertaken in order to further study the clinical and pharmacological efficacy of Thirty-four patients suffering from MDD (RDC) were citalopram in patients with dementia. Citalopram has been enrolled randomly in this double blind parallel study. shown to have a specific inhibitory effect on the re- Across the whole study population, there was a moderate uptake of serotonin and it is therefore assumed that the weight gain, though not significant (p=0.1) at the end pharmacological effect is an activation of the serotonin- of the study. For the F group, there was no significant containing neurons. Clinical studies of depressed weight change, however for A, there was a patients have indicated a good antidepressant effect and significant weight gain (p=0.08, mean = 1.33kg.). fewer secondary effects than tricyclic antidepressant No significant differences could be observed between drugs. This is also valid for central anticholinergic as males and females in the overall sample. On the whole, well as cardiovascular secondary effects. The test F was found to be safer than A, less side effects treatment was carried out during a period of 16 weeks. A being reported in the F group (p<0.01). The most frequent double-blind cross-over technique with placebo and side effects reported for Fluoxetine were gastro-intestinal, citalopram was used. The treatment dose varied between lO symptoms (10%) and dry mouth (13%). and 30 mg r or placebo given daily around four o'clock. Ninety-eight patients with a clinical diagnosis Free University of Brussels - Erasme Hospital, Dept. of of moderate dementia of Alzheimer type (AD/SDAT) or Psychiatry, route de Lennik g0g, 1070 Brussels multi-infarct dementia (MID) were included in the trial Belgium. while fifty-nine patients completed the whole treatment test. The results of the clinical assessments indicated significant improvements in emotional lability, motiva- tion, confusion, fear-panic, irritation, reduced mood and restlessness. These improvements were not evident during treatment with placebo. Citalopram appeared to have no effect on the motorial and intellectual functions. Cerebrospinal fluid taps taken (n=15) before treatment start and after twelve weeks showed a significant reduction of 5-HIAA. Both in citalopram and placebo treated patients no or few side effects were recorded. The results in the present study are in agreement with the results of earlier studies. Grteborgs universitet, Department of psychiatry and neurochemistry, St. J~rgen's hospital, S-422 03 Hisings- Backa, Sweden 268 31.02,08 31.02.09 SIDE EFFECT PROFILE AND SAFETY OF CITALOPRAM KINETICS OF THE INTERACTION OF SERTRALINE WITH THE HUMAN H.E. H~pfner Petersen, K. Lyby, L. Elsborg, and E. Skovlund PLATELET PLASMA MEMBRANE 5-HYDROXYTRYPTAMINE CARRIER A survey of the clinical safety of the selective 5-HT uptake O.M. Phillips, K.M. Wood and D.C. Williams inhibitor citalopram is presented. The assessments of safety Sertraline, a new selective 5-HT uptake inhibitor showed are based on meta-analysis of results from more than 1,000 a mixed pattern of inhibition of human platelet 5-HT uptake with a K. value of 2.5nM and K~ value of 25 ruM. patients. i Results: Imipramine and alaproclate were foundlto be fully Side effects were generally mild. The most frequently competitive inhibitors of 5-HT uptake with K. values of 8 recorded were nausea, sweating, headache, reduced salivation, emd 13C nM respectively. Sertraline was ~ fully and tremor. competitive inhibitor of high-affinity [ H]imipramine The frequency of side effects - particularly those of anti- binding to platelet membranes with a K. value of 1.3nM, as was alaproclate and 5-HT with K. values of 170 and cholinergic type - was significantly lower for citalopram 1 than for trieyclie antidepressants (TCAs), whereas there 800 nM respectively. Both sertrallne and imipramine, at was no difference compared with placebo. a concentration o{ 10~M caused a fast monophasic The frequency of recorded side effects in citalopram treated dissociation of [ H]imipramine from platelet membranes patients was higher in TCA-controlled studies than in placebo- in contrast to 5-HT which caused a slow monophasic controlled studies. dissociation. Apart from a slight tendency to sinus bradyeardia in a few These data are consistant with sertraline binding to the patients with pre-existing low heart rate, no adverse effects carrier at a physically-distinct site to that for 5-HT were observed on the electrophysiological and hemodynamic and being a potent and specific 5-HT uptake inhibitor. systems. Department of Biochemistry, Trinity College, Dublin 2, No adverse effects were observed on the hematological, Ireland hepatic or renal systems. Body weight was not changed. Conclusion: The safety profile of citalopram makes it a safe drug of choice in the treatment of depressive disorders. H. Lundbeek A/S, Ottiliavej 7-9, DK-2500 Copenhagen-Valby 31.02.10 31.02.11 DISTRIBUTION AND PHARMACOKINETICS OF THE SELECTIVE TREATMENT AND PROPHYLAXIS OF AFFECTIVE DISORDERS 5-HT UPTAKE BLOCKER SERTRALINE IN MAN, RAT AND DOG. R. A. Ronfeld, G. L. Shaw and L. M. Tremaine BY CARBAMAZEPIN /TEGREToLR/ Sertraline is a highly selective and potent inhibitor of 5-HT uptake (B. Koe et al., J. Pharm. Exp. Ther. N. N. Ilankovie 226:686, 1983) under development for the treatment o--~depression. In man, the average terminal elimination half-life is 26 hours, allowing for once daily adminis- tration. After a single I00 mg dose, Cmax is about The autor present latest discoveries of possi- 20 ng/ml and Tmax occurs at 6 to 8 hours. The distribu- bilities for treatment and prophylaxis of aff- tion/elimination is ofen biphasic with the terminal phase attained 12 to 16 hours post-dose. The terminal ective disturbances (above all MD psychosis , half-life of 26 hours does not change with multiple schizoaffective episodes, atypical psychotic dosing or as a function of dose. Dose proportionality episodes, behavioural disorders). The prominent and linearity of kinetics were demonstrated in a 3-way crossover study of 50, i00 and 200 mg doses. The antimanic effect and "specific" antipsychotic serum protein binding of sertraline is 98.6, 98.9 effect of this drug is stressed, its antidepre- and 97.2% at I00 ng/ml in man, dog and rat, respectively ssive characteristic and the action on regula- and independent of drug concentration over the range of 20 to 2000 ng/ml. Sertraline binds avidly to both tion of consciousness and the awakeness-sleep albumin and al-acid glycoprotein. At a concentration cycles. The authors present their results in exceeding the- usual clinical range, sertraline does treatment and prophylaxis and stress relative- not alter the protein binding of warfarin or prepranolol. ly small risk from toxic side-effects. The psychobiological dimension of stress is dis- A radiolabel study in rats demonstrated that drug cussed too: I. the mechanism of initial OSMOLAR and metabolites distribute extensively into tissues. The volumes of distribution of sertraline in the rat reaction (rolle of VASOPRESSIN/ADH) and 2. the and dog were 23 and 25 i/kg, respectively. In the mechanism of delayed, prolonged reaction - "STE- rat and dog, the elimination half-life of sertraline ROID EXCESS"/hipereortisolemio (Ilankovic,1986)~ is about five hours and plasma clearance is high, estimated at 59 and 49 ml/min/kg, respectively. There Carbamazepin has some vasopressin-like (ADH-re- ls evldenoe of ~irst-pass metabollsm wlth oral admlnls- ceptors agonist) - the possibile mechanisms of tration. Sertraline is not excreted unchanged in action of carbamazepin in affective and cogniti- urine or bile. An initial pathway of metabolism is N-demethylation. The elimination half-life of des- ve disturbances (psychoses). methyl-sertraline is 2 to 3 times longer than that The neurophysiological model of "KINDLING" and of sertraline in man, rat and dog. The metabolite the anti-kindling action of carbamazepin is al- to drug AUC ratio ranged from 0.4 to 3.3 and varied with the species studied, dose and route of sertraline so discussed - these model~ is one of possible administration. In vitro desmethyl-sertraline is mechanism of initiation, modulation and ecolo- i0 times less actl-ve as an inhibitor of 5-HT uptake gical/behavioural sensibilisation in affective than sertraline (B. Koe et al., ibid). The desmethyl metabolite is not thought to contribute to the antide- behaviour and disturbances. pressant activity in vivo. Pfizer Central Res-earch, Eastern Point Rd., Groton, CT, U.S.A. 06340 Psychiatric University Clinic, Center for Clini- cal Neurophysiology & Sleep Disorders, YU-llooo BEOGRAD, Pasterova 2, YUGOSLAVIA 269 31.02.12 31.02.13 BIND;NG OF [3H]SERTRALINE TO BRAIN MEMBRANES SERTRALINE INHIBITS FEEDING AND BODY WEIGHT GAIN IN N G. Bacopoulos, L. A. Lebel , W. M. Welch and B. K. Koe RODENTS Studies from our laboratories demonstrated that sertraline, a new J. A. Nielsen, M. N. Krupp, J. Heym and N. G. BaCODOUlOS antidepressant, is a potent and selective inhibitor of the uptake of A variety of in vitro and in vivo studies demonstrate serotonin in brain (Koe etal., .I. Pharmacol. Exp. Ther. 226, 686, 1983). that sertraline is a highly selective and potent compet- Serotonin (5-HT) uptake occurs via "transport" sites in neuronal itive inhibitor of serotonin uptake (Koe et al., J. membranes. Several laboratories have reported that non-selective uptake Pharn.acol. Exp. Ther. 226, 686, 1983). Animal studies blockers ([3H]imipramine), as well as those more selective for 5-HT have demonstrated that inhibition of serotonin uptake ([3H]paroxetine, [3H]indalpine, [3H]citalopram), bind with high affinity to leads to enhanced serotonergic neurotransmission which sites associated with S-HT uptake. In these studies, binding affinity of may have beneficial effects in depression. Indeed, 5-HT uptake blockers was found to correlate with their potency for clinical trials have shown sertraline to be an effective inhibting 5-HT uptake (Habert etal., Eur. J. Pharmacol. 118, 107, 1985; antidepressant. An extensive literature, however, D'Am,ato et al., J. Pharmacol. Exp. Thor. 242, 364, 1987). Because of the also implicates brain serotonin in the regulation potency and selectivity of sertraline as a 5-HT uptake blocker, of energy balance (Blundell, Neuropharmacology 23, [3H]sertratine (23 Curies/retool) was synthesized and investigated as a 1537, 1984). Therefore, studies have been carried radioligand for high affinity binding to 5-HT uptake sites in brain out to assess the effects of sertraline on feeding membranes. Binding studies with [3H]sertraline were conducted in Tris and body weight in rodents. HCI buffer containing 120 mM NaCi and 5 mM KCI (Mellerup and Plenge, Psychopharmacology 89, 436, 1986). Association experiments with rat Sertraline decreased food intake and body weight in brain membranes indicate that binding was complete in 40 min; bound both normal and genetically obese rodent strains (oh/oh [3H]sertratine was completely dissociated in 20 rain after the addition of mice and fa/fa rats). These effects developed rapidly 150 nM of unlabeled sertraline. Saturation binding experiments indicated after initiation of sertraline treatment and were an ap~arent KD of 0.56 nM and Bmax of 885 fmol/mg protein. Similar maintained during 5-7 days of continued drug administra- binding carried out in the presence of either 5-HT (0.5 pM) or paroxetine tion. Nonspecific disruption of behavior does not (1 nM)increased KD by 101% and 223%, respectively, with little change in accoD_nt for the observed effects on feeding and body Br~ax (+7% and + 10%, respectively). These results suggest that weight since the sertraline treated animals appeared paroxetine and 5-HT are competitive inhlbitors of the binding of healthy and their locomotor behavior was unaffected. [3H]sertraline and that the latter is binding to uptake sites for 5-HT. Thus, these results are in accord with a growing body [3H]Sertraline binding to 5-HT uptake sites in homogenates of different of evidence suggesting that selective serotonin uptake regio~ of marmoset brain was also studied. inhibitors may be clinically useful agents for managing Central Research Division, Pfizer Inc., Groton, CT 06340, USA. some obese patient populations. Pfizer Central Research, Departments of Neuroscience and General Pharmacology, Groton, Connecticut, 06340, U.S.A. 31.02.14 31.02.15 EFFECTS OF SEROTONERGIC AGENTS ON DOWN-REGULATION OF SERY~ALINE, AN ANTIDEPRESSA~N~ ~ICH Ih~IBITS SEROTONIN ~-ADRENOCEPTOR5 BY SERTRALINE UPTAKE, SPECIFICALLY DOWN REGLU_ATES BETA. RECEPTORS B. K. Koe and L A. Lebel J.K. Wamsley, R.T. McCabe, E.J. McConnell, F.W. Byerley Recent studies showed that sertratine, a new 5-HT uptake blocking and B.I. Grosser antidepressant, down-regulates J3-adrenoceptors of cerebral cortex and Chronic exposure to various antidepressant agents has desensitizes the cAMP generating system of limbic forebrain (Koe etal., been shown to cause the do~-regulation of both beta- Eur. J. Pharmacol., 141, 187, 1987; Byerley et al., Brain Res. 421,377, 1987). adrenergie (beta) and serotenergic (5HT) receptors ~ithin Furthermore, these effects of sertraline are facilitated by co-admi nistration the CXS. ~ny antidepressant drugs are mixed 5HT and/or of the 5-HT agonist quipazine (Koe, ibid.). We have extended these studies noradrenalin uptake inhibitors. Some recently developed to other serotonergic drugs to ascertain which 5-HT receptors are involved compounds, however, appear to have the unique ability to in facilitating sertra.line's down-regulation of ~-adrenoreceptors. affect only 5HT uptake. The metabolites of these com~ Experiments consisted of injecting test drug plus sertraline (17.8 or pounds also seem to be specific in this regard. Drug 32 llmol/kg i.p.) to rats b.id. for 4 days and determining K o and Bmax of studies in human patients have shown that one of these [3H]dihydroalprenolol (DHA) binding in anterior cortex one day after agents, sertraline, is quite efficacious in its ability dosing. Test drugs included: 8-hydroxy-2-N,N-dipropylaminotetralin to alleviate the symptoms associated with depression in (8-HO-DPAT, 5-HT1A agonist), 3-trifluoromethylphenylpiperazine (TFMPP, affected individuals. It is still controversial ~ether 5-HT1B agonist), ritanserin (5-HT2 antagonist), methiothepin (5-HT beta or 5HT receptor alteration is important in the eti- releaser) and racemic norfenfluramine (5-HT releaser). Dose of all test ology and treatment of depression. We used the selective drugs was 10 Bmol/kg i.p. except for the latter (20 ]Jmol/kg). Scatchard 5HT uptake inhibitor sertraline to chronically block up- analysis of [3H]DHA binding was determined for each rat brain. The results take in male Sprague-Dawley rats (21 days of treatment). showed that down-regulation of ~-adrenoceptors by sertraline was neither Repeated administration of the non-tricyclic antidepres- facilitated nor blocked by co-administered 8-HO-DPAT, TFMPP or sant caused a down-regulation of beta receptors. These ritanserin. In contrast, methiothepin or nonCenfluramine, in combination findings occurred in microscopic regions of the brain and with 17.Bpmol/kg of sertraline (non-down-regulating dose), elicited a were very closely associated with areas that have been decrease in receptor density (Brnax) without affecting affinity (KD). The shown to have beta-receptor down-regulation after elec- latter results are similar to quipazine's facilitation of sertraline (Koe, ibid.) troconvulsive shock treatment. Moreover, the down regu- and suggest that quipazine, similar to methiothepin and norfenfluramine, lation induced by sertraline occurred exclusively at the may be also acting to enhance 5-HT release. Our findings indicate that beta I receptor subtype. The irony of these findings is only 5-HT itself seems to be effective in inducing down-regulation of that-we have previously demonstrated that low doses of J]-adrenoceptors and that the 5-HT receptors involved in this process may sertraline do not cause a significant alteration in 5HT not be the 5-HT1A, 5-HT18 or 5-HT 2 type. receptors following similar treatment. The betal-rece p- Central Research Division, Pfizer Inc., Groton, CT. 06340, USA. tor alteration, then, is taking place without a concomi- tant alteration in 5HT receptor subtypes. These results support the hypothesis that the common denominator of most antidepressant treat~nts is the down-regulation of beta-adrenergic receptors; including those treatments which only directly affect the 5HT system. Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah 84132, U.S.A. 270 31.02.16 31.02.17 SERTRALINE IN THE PR~"qENTION OF RELAPSE IN MAJOR PD-~OXETINE: A SELECTIVE SEROTONINE REUPTAKE INHIBITOR DEPRESSION TP~T HAS A WEAKER ANTIDLDRESSANT EFFECT THAN CLOMIPRAMIN~ D.P. Doogan and V. Caillard P. KRAGH-SORENSEN, L.F. GRAM, P. 8ECH, P. VESTERGAARD, O. This double-blind placebo-controlled study included 467 J..RAFAELSEN, N. REISBY. patients with major depression. All patients received an In total, 147 hospitalized depressed patients were start- open 8-week period of sertraline 50-200mg/day titrated ed on a one week sengle blind placebo treatment. 118 pa- according to clinical response. At the end of the 8-week tients still fullfilling in~exclusion criteria (Hamilton period patients were selected, based on satisfactory Depression Scale, HDS, 17-item total score X 18) were clinical response, to receive a further 44 weeks double- randomly allocated in a double blind fashion to treatment blind therapy of either sertraline or placebo in a wi=h either paroxetine 30 mg/day (n=62) or clomipramine randomised design in a 2:1 ratio of sertraline:placebo. !50 mg/day (n=56) (fixed, single evening dose). In total, The dose range was also 50-200mg/day. 56 patients on psroxetine and 46 patients on clomipramine The principal efficacy variable was the relapse rate conpleted at least two weeks treatment and were included during the 44-week period. in analyses of therapeutic effect. The two groups were Two hundred and ninety five patients received double- co=parable in terms of age ~225% < 40 years), sex ~70% blind therapy (~85 sertraline and 110 placebo). Over the wo=en) and departmental distribution. The protocolled 44-week period the relapse rate on sertraline was 6.5% =rea~ment period was 6 weeks except that non-responders and on placebo was 39.0%, p < 0.001. This highly (~S) 16) after 4 weeks were terminated. This occurred significant difference was observed consistently with =o 27 patients, 23 on paroxetine and 4 on clomipramine. A Hamilton Rating Scale and Clinical Global Impression. weekly end-point analysis using response categories show- ~ne average dose %~s approximately 100n~ daily during the ed significantly better effect of clomipramine from 2 long-term period. weeks treatment and onwards. At 6 weeks t the percentages The number of patients withdrawing during the long-term of complete (HD8 >16) was 57,30 and 13 respectively in period due to side-effects was minimal, 4.3% on the clomipramine treated and 22,30 and 48 respectively sertraline and 2.7% on placebo. in the paroxetine treated patients. Likewise the group There were no changes of significance in safety variables average score on the HI)S-total at the end of 6 weeks was - vital signs, ECG, laboratory tests. ~bo~t 8 in the clomipramine and about 13 in the paroxeti- Pfizer Central Research, Clinical Research Department, ne group. Analyses of clusters of items on the HDS showed Ramsgate Road, Sandwich, Kent. CTI3 9NJ. U.K. that the difference on the total scale was due to differ- ences on essentially all items covering the major parts of the depressive syndrome. - More patients on clomipra- ~ine dropped out due to side effects (orthostatic hypo- =ension, palpitations etc.) Paroxetine was virtually de- void of autonomic side effects. The present results are in close agreement with our earlier findings with citalo- pram, an other serotonin reuptake inhibitor. Danish University Antidepressant Group, - Odense, Hille- r~, Arhus, Copenhagen, De~ark. 31.02.18 31.02.19 CHANGES IN HUMAN WHOLE BLOOD 5HT DURING TRE~TMSNT WITH EFFECTS OF THE ANTIDEPRESSANT PAROXETINE ON PSYCHOMOTOR PAROXETINE - A SELECTIVE 5HT UFTAKE INHIBITOR FUNCTION QUANTITATIVE EgG (QEEG) AND MOOD IN HEALTHY [, A, Marsden, P, Tyrer, P. Casev and N. Seivewri~ht SUBJECTS The effects of the specific 5-hydroxytrypt~ine (5HT) T.C.G. Tasker~ P. RaDtoDoulos A.M. Johnson, re-uptake i~hib~tor paroxetine on whole blood 5HT and G.R. McClelland the uptake of [ oH]-5HT by platelets was determined in 17 Paroxetine (PAR), a selective 5-hydroxytryptar-ine uptake patients with resistant depression. The biochemical inhibitor (Buss Lassen J. 1978. Psychopharmaeol, 57, par~eters were measured before paroxetine (30 or 151) is an effective antidepressant (Lund Laursen A. et 40 mg/day) treatment, during treatment (6 weeks) and al 1985. Acta Psychiat. Scand., 7!I, 249-255). As part after withdr~al of treatment. Two of the 17 subjects of the phase I evaluation, the effects of a single oral failed to complete the trial; of the remaining subjects 30mg dose of paroxetine on the central nervous system of 12 showed a marked decrease in whole blood SET (~easured 8 healthy subjects was studied using psychomotor using HFLC with electrochemical detection) and [aH]-SHT function tests (McClelland G.R. 1987. Human uptake into platelets. The remaining 3 patients showed Psychopharmacology, 2, 109-119) visual analo~ae scales a variable response both in terms of whole blood 5HT and (VAS) (Bond and Lader, 1974. Br. J. Med Psychol, 47, platelet during paroxetine treatment. A comparison of 211) and QEEG (McClelland and Raptopoulos, 1985, the 15 patients completing the trial showed that Psychopharmacol, 85, 327). paroxetine treatment (36.4_+14 pmols/ml) significantly Whereas amitriptyline (AM/} (75mg) significantly decreased whole blood 5HT compared to the pre-paroxetine impaired (p<0.05) performance in visual choice reaction value (99.7+_30 pmols/ml). At the end of treatment blood time, continuous perfor~nance and tapping rate tasks, pAR 5HT tended to return towards normal although this was did not influence performance (p 271 31.02.20 31.02.21 SELECTIVE REDUCTION OF 5-HT 2 RECEPTORS IN RAT OPEN-LABEL STUDY OF FLUVOXAMINE IN PATIENTS WITH OBSES- BP~.IN AFTER REPEATED ~IINISTRATION OF THE SIVE COMPULSIVE DISORDER ANTIDEPRESSANT, PAROXETI~. B.S. Coleman and K.M. Squillace A.M. Johnson,.D.R. Nelson and D.R. Thomas Patients meetin~ diagnostic criteria for obsessive Paroxetine, an effective ~ntidepressan~ (Lund compulsive disorder who had failed to respond to other Laursen et al, Acta Psy~niat. Scand., 71, 247, therapies, were treated with open-label fluvoxamine, a 1985), is a potent ~nd selective inhibitor of specific serotonin reuptake blocker, under a compassion- 5-HT uptake in rodent brain synaptosomes ate use protocol. Psychiatric outpatients of either (Ki; l.lnM) with no affinity (Ki~ >I~M) for sex, aged 18 years and over, were treated for up to one ~i-, ~2 ~, ~-adrenoceptors, 5-HTl-like or 5-HT2 year with fluvoxamine. After titration, medication was receptors in vitro (_"~omas et a~ Psycho- administered twice daily and maintained at 100-300 m~ pharr~acol., 93, 193, 1987). Magnussen, et al, per day. The efficacy and safety data collected from 1982, (J. Neural Trans. 55, 217) have shown this study will Be presented. that 5-HT uptake inhibition in rodent brain by Kali-Duphar Laboratories, Inc., 20~ Old Wilson BridFe paroxetine is maintained on repeated a~min- Road, Worthington, Ohio 43085 istration for 21 days. It has now been demon- strated that, when administered daily for 21 days, paroxetine, 5mg~g i.p. si@nificantly (p<0.05) reduces the number of [bH]-ket~nserin binding sites (Bmax) in rat brain cortical membranes by 16%, wi~h no change in the affinity of the lig~nd (Kd) for the receptor, 24h after the last dose. However, this treat- ment with paroxetine causes no changes (p>0.05) in the bindinq (Kd or Bma x) of [3H]-dihydro- alprenolol, [3H]-prazosin, [3H]-clonidine, [3H]-5-HT or [3H]-8-hydrcxy-N-N-dipropylar~ino- tetralin indicating that the number of, or affinity of ligands for, 6-, ~I-, ~2-adreno- cepters or 5-HTIA receptor subtypes is not influenced by paroxetine treatment. The above data show therefore that the prolonged 5-HT uptake inhibition by repeated administration of paroxetine leads to the selective down regulation of 5-HT 2 receptors in rat brain. This effect of paroxetine may be relevant to its action as an antidepressant. Beecha/z Pharmaceuticals, Harlow, U.K. C~!19 bAD. 31.02.22 31.02.23 ANTIDEPRESSANT AND ANXIETY LEVOPROTILINE IN COMPARISION TO OTHER ANTIDEPRESSIVE DRUGS A study of fluvoxamine versus diazepam in anxious- depressive patients. NAHUNEK K..~VESTKA J.,RY~KNEK R.,~E~KOVA E. University Psychiatric Dpt ,Brno, ~SSR CHABANNES 3.P.* The authors report an original study conducted in Levoprotiline /CGP 12' 103 A Ciba Geigy/ a R 60 out-patients with anxious and depressive disorders. enantiomer of Oxyprotiline. which lacks the They compared, under double-blind conditions the inhibition of the reuptake of Noradrenaline efficacy of a molecule known for its anxiolytic spectrum : diazepam, and that of a 5-HT reuptake proved in a multiclinical study, on which we inhibitor : fluvoxamine. participated, good antidepressive and The results demonstrate : anxio!ytic effect with rapid onset of the - a much higher efficacy of fluvoxamine in decreasing therapeutic action in 128 patients with depressive disorders, endogenous depression. - a similar efficacy of both drugs on anxiety. The therapeutic effiGacy of Levoprotiline Concerning tolerance, a greater safety of the was studied in an other open study in patients 5-HT reuptake inhibitor fluvoxamine can be noted. with depressive phases and its relations to the In fact, this work sets again the question of the changes of cardiovascular parameters in a true limits between anxiety and depression, therefore conzroled study comparing the results to those between anxiolytics and antidepressants. of other antidepressive drugs. ~e tried to include Levoprotiline in our classification scheme constructed according to the antidepressive index, which reflects the * Dr CHABANNES 3.P. - Clinique du Nivolet - C.H.S. de Bassens - 73011 CHAMBERYCEDEX relation of efficacy in inhibited, anxious and atypical forms of depression in 2187 therapeutic cures with 35 antidepressants and ECT. The influence of the cardiovascular system was evaluated by the changes of the parameters of the electromechanical systole /Blumber~'s quotient/ and compared with other antidepressants /using dosulepine as a referential drug/. 272 31.02.24 31.02.25 DOb~LE-BLIND, PLACEBO CONTROLLED TRIAL OF MINAPRINE IN PHARMACOLOGICAL PROPERTIES OF MIDALCIPRAN MAJOR AFFECTZVE D~SORDER {F 2207), N NOVEL ANTIDEPRESSANT J. Amsterdam~ E. Rickels, L. Goodman, et al. R.MATSUBARA~ T.KOYAMA~ Y.ODNGNKI~ M.NAKNYAMA, Minaprine (MIN} is a putative antidepressant agent which T?INOUE, and I. YAMASHITA antagonizes the symptoms of "inhibitory states" in animal It is known that lon-g-term treatment with most models, and in human beings. Prior studies have shown MIN of antidepressants decreases beta-adrenergic and to be as effective as nomifensine and maprotiline in the 5-HT~ receptor densities, and the time-lag of the antidepressant action has been suggested to treatment of endogenous depression. We performed a multi- be due to this phenomenon. center trial of three fixed doses of MIN (i00, 200, and Midalcipran (F 2207} is a newly developed anti- 400mg) and placebo in 146 outpatients with major depress- depressant in France. An open study involving 27 ion to assess the efficacy and safety profile of this cases of major depressive disorders has shown compound. There were 87 women and 59 men with an age that midalcipran had a significant anti- range from 20 to 69 yrs. After a one week elimination depressant effect within 7 days. period, subjects were randomly assigned to treatment We investigated the pharmacological properties with MIN or placebo for 4 weeks. of midalcipran,especially,the effect of chronic Results demonstrated a significantly greater reduction administration on monoamlne receptors. from baseline in the median Montgomery-Asberg Depression The in vitro studies in synaptosomes of rat Rating Scale (MADRS) scores in the 400mg MIN group com- brain showed that midalcipran was an effective pared to placebo (p 31.02.26 31.02.27 DETERMINING THE THERAPEUTIC DOSE OF MIDALCIPRAN A DOUBLE-BLIND STUDY COMPARING 2 DOSES OF MIDALC!PRAN (F2207) IN THE TREATMENT OF DYSTHYMIA {F2207) TO N!ITRIPTYLINE IN MAJOR DEPRESSIVE DISORDERS S. Bornstein, C. Serre, A. Qu~m~r~, H. Maloux, J.P. Demarez, M. Ansseau, C. Serre, R. Von Frenckell, J.P. Couzlnier Ph. Sutet Midalcipran (M), a non-tricyclic antidepressant We compared 2 daily doses (50 and lOOmg) of Midalcipran (H) which inhibits 5-HT and NE reuptake, has been to 150mg Amitrip~vline (A) in hospitalized patients with evaluated in outpatients presenting signs of major depressive disorders compatible with the RDC defini- dysthymia compatible with the DSM III definition. tion. The investigative intent was to compare the During this double-blind trial, 42 patients received 150mg antidepressant activity of 3 daily doses of M d M. and 44 received lOOmg/d, and 45 received 150mg/d A. administered b.i.d, with that exerted by i00 mg of over a 4-week ~eriod. The population demonstrated a high imipramine (I). degree of endo~enicity. Assessment of the antidepressant The antidepressant activity was assessed by was carried out by means of the following tests~amilton(we-e~. means of the Hamilton and the Montgomery and l~Mont~omerv ~ ~er C, plus CGI,I,-2 and 3 (every 2 weeks) Asberg scales performed weekl~, as well as through A{ dayq4, {he depression scales yielded a noticeably highe~ the use of Beck's inventory which was carried out percentage of lowered scored relatively to initial values twice a month. in the A-group, as compared to the M:group (Hamilton, Of 94 patients treated during 4 weeks, 27 received p=O,O03; MADRS, ~:0,003), which was essentially due to im- 20 mg of M daily, 27 received 50 mg and 23 provment of items such as anxiety and inner tension benefi~ received i00 mg; 22 received I00 mg of I daily. ring from A.'~ sedative effect. This difference was not ap~ The depression scale analysis showed a good parent with CGI I, 2 and 3. correlation between M-dosage and antidepressant At d.21 and d.2~, the antidepressant activity exerted by' potency. At day 14, the scores for the Hamilton 10Dmg M. did not differ significantly from that of 150mgA. scale were lowered relatively to initial values by Both treatments yielded noticeably better results than 50mgl 46% with 20 mg of M., 52% with 50 mg, 62% with 100 The significant difference existing according to the assess~ mg, 54 % with i00 mg of I, respectively. Inasmuch ment scales at d.14 between 100mgM. and 150mgA., although it as no significant difference was noted at day 21 was not found in relation to CGI 3 at the same period of ti~e and day 28 between M 50 or I00 and I I00 mg, we prompted us to consider testing higher dosages (150-200mgM.) propose this dose range in the treatment of in these patients going through an acute, quite endogenomor- dysthymia. The 3 M doses were sufficiently well phic depressive episode (initial score : 36), regardless of tolerated in all instances, in a way little the fact that the difference might originate from delayed different from I with regard to gastrointestinal impregnation {progressive dosing over 5 days due to poor to< side effects. The two drugs differed markedly, lerance frequen=l% encountered at onset of treatment with A.~ however, with respect to anticholinergic-type Nonetheless, we think that the benefit/side effects ratio fe~ symptoms, which only the I-group developed. lOOmgM, is higher than that obtained for A. if one takes intD In this trial, the therapeutic index for M was consideration t~e anticholinergic-type side effects experienL superior when compared to I. ced primarily by oatients treated with this tricyclic anti- D~partemen~ Recherche Ciinique, Centre de depressant. Pecherche Pierre FABRE - 17, Ave. Jean Houlin M. Ansseau - C.~.U. Sart-Tilman - Liege - B 4000 273 31.02.28 31.02.29 BEHAVIORAL EFFECTS OF AIIPAHEZOLE, A SELECTIVE ALPHA-2 GBR 12909: A CLINICAL PHASE I STUDY OF A SELECTIVE ANIAGONIST IN RATS DOP.~INE UPTAKE INHIBITOR R. Lammintausta~ K. Finnes t E. Uyeno, J.G. Csernansky U. Segaard I), J. Michalow I), B. Butler I), A. Lund Laursen I), S.H. In@wersen 2), B.E. Skrumsager 3), Atipamezole, 4-(2-ethyl-2,3-dihydro-lHinden-2-yl)lH-imi- J.O. Rafaelsen 1,4). dazole is a novel selective alpha-2 antagonist which ef- GBR 12909 is a phenyl-substituted piperazine deriva- fectively reverses the alpha-2 agonist sedation in veteri- tive, which selectively blocks dopamine uptake. The nary practice. In rats it has been shown to increase nor- biochemical and pharmacological profiles of GBR 12909 adrenaline turnover at doses of 0.1 mg/kg and above. suggest that it may possess antidepressant activity In the forced swimming teat of rats atipamezole in acute and/or be of value in the treatment of Parkinson's dosing paradigm (26, 18 and 2 hours before testing) was Disease. able to decrease immobility significantly at dose levels The tolerance, the pharmacokinetics and the influence on psychomotor performance of GBR 12909 were investi- of 1.5 and 5.0 mg/kg but not at 0.5 mg/kg i.p. The effect gated in a randomized, placebo-controlled, double- was comparable to that of desipramine. The spontaneous blind study. Four healthy volunteers were orally motility of rats is slightly increased at the dose level administered the single doses of 100, 200 and 300 mg of 5.0 mg/kg i.p. but not at 1.5 mg/kg. GBR 12909 and placebo, and four other volunteers In the approach/avoidance conflict test single doses of received 50, 100 and 150 mg GBR 12909 and placebo once atipamezole 0.5-5 mg/kg i.p. did not change either the daily for seven days. nonpunished or punished drinking response. Yohimbine 2.5 The intermediate and highest single doses resulted in mild-moderate side effects as concentration difficul- ig/kg and pentylenetetrazol 15 mg/kg i.p. decreased the ties, asthenia, feeling of drug influence and palpita- punished drinking suggesting an anxiogenic response. We tions. After multiple dosing side effects were obser- have earlier reported an anxiolytic response for an ved during the 100 and 150 mg dosing periods, all alpha-2 agonist in this test. being milder than observed in single dose study. A After dosing of atipamezole 0.5-5 mg/kg i.p.b.i.d, for dose related effect on ECG was observed with a slight 2-3 weeks the response in forced swimming was not signif- reduction of the T-wave amplitude. No signs of icant, neither could any effect be detected in conflict arrhythmia or incompensation during exercise until exhaustion were observed. Thepsychomotor performance test. A blockade of clonidine sedation could, however, be (measured as CRT) and the alertness (measured as CFPF) demonstrated at 5 hours after the last atipamezole dose. were not affected. Earlier we have shown a persisting forced swimming re- GBR 12909 followed first order kinetics with a termi- sponse after repeated dosing of desipramine. nal elimination half-life of about I-2 days. Steady The Bmax values for pindolol and clonidine binding in the state serum concentrations of GBR 12909 seemed to be cortical brain membranes were not significantly changed reached within one week. From animal studies the the- after atipamezole treatment. rapeutic daily dose has been estimated to 20-100 mg The results suggest an antidepressive but not anxiogenic GBR 12909. Based on results of this study and another human phase I study, the therapeutic doses are expec- effect. The behavioral adaptation to repeated dosing ted to be well-tolerated by patients. needs further clarification. I) Department of Psychiatry, University of Copenhagen, Stanford University, Dept of Psychiatry, and SRI Inter- Rigshospitalet, DK-2100 Copenhagen, Denmark, 2) Phar- national, Palo Alto, CA, USA. Author present address: macokinetic Laboratory, Novo Industri A/S, 3) Clinical Farmos Group Ltd, P 0 Box 425, SF-2OlO1 Turku, Finland Research, F-R&D, Novo Industri A/S, DK-2880 Bagsvaerd, 4~ Deceased Au0ust 1987. 31.02.30 31.02.31 Effect of new antidepressants adinazolam and WEB 1881, A NOVEL ANTIDEPRESSANT, STIMULATES mianserin on intraventricular conduction and NORADRENALINE RELEASE IN VIVO AND IN VITRO cardiac hemodynamics in canine myocardial W.O. Bechtel and 3. Mierau infarction WEB 1881 (A-aminomethyl-l-benzylpyrrolidine-2-one) has M. Nishimoto, H. Hashim_oto, T. Ozaki, $2_. been shown to have antidepressant-like properties in Nagashima, K__~. 0hara, M__t. Nakashima behavioral animal tests (Lehr et al., preliminary re- This study was undertaken to examine and sults presented at the Spring Meeting of the DGPH in compare effects on intraventricular conduction Mainz, FR Germany, March i988). and cardiac function of amitryptyline(AMI), a Studying the mode of action of WEB 1881 concentrations tricyclic antidepressant, mianserin(MIA), a of noradrenaline and dopamine were measured in the rat tetracyclic antidepressant, adinazolam(ADZ), a brain after blockade of catechoiamine synthesis by new benzodiazepine antidepressant, using alpha-methyltyrosine Dretreatment. With high doses of canine myocardial infarction model. WEB 1881 given subcutaneously noradrenaline concentra- Epicardial bipolar ECGs were recorded from the tion was lowered up to ii ~, whereas dopamine concen- normal area in the right ventricle and the tration was not influenced. The finding led to the con- infarcted area in the left ventricle. clusion that WEB 1881 stimulates the release and/or Intraventricular conduction was measured the ~ncreased the turnover of noradrenalime. The antide- excitation induced by a premature stimulation pressant imipramine exerts similar effects on nora- with varying coupling intervals in the normal drenaline concentration in this model. right ventricular area. Left ventricular In vitro ~lth rat brain hippocampal slices, WEB 1881 pressure(LVP), LVPdp/dt, aortic flow, heart caused an dose-dependent enhancement of electrically rate, coronary artery flow(CAF) and peripheral evoked no,adrenaline release. Imipramine showed similar blood pressure(BP) were measured as parameters effects at about a tenth of WEB 1881 concentration. of cardiac hemodynamics. 274 31.02.32 31.02.33 FACILITATION OF SPONTANEOUS ALTERNATION, SIMPLE EFFECTS OF TIANEPTINE ON SLEEP-WAKEFULNESS AND CONCURRENT DISCRIMINATION LEARNING IN MICE CYCLES AND EEG IN MONKEY BY THE ANTIDEPRESSANT DRUG TIANEPTINE E. Moca~r *. D. Lagarde **, E. Balzamo ***, C. Milhaud ** R. Jaffard *, E. Moca~r ,s, D. B~racochSa $1 A. Martghetto * and A. Toumane * It has been previously shown that tianeptine an antidepressant which increases serotonin uptake increased active wakefulness during the first Antidepressants generally impair memory processes. The present study hour after acute administration in rat (2.5 - 10 mg.kg-t i.p.). Tianeptine was designed to investigate the effects of tianeptine, a new repeated administration did not modify the overall distribution of phases antidepressant, on spatial behaviors involving different types of memory. of wakefulness and sleep in the rat. Sequential (6 trials) spontaneous alternation (S.A.} in a T-muse was used The present study was performed in six adult male Rhesus monkeys as an index of working memory. (D. B~racoch6a and R. Jaffard, Behav. (Macaca Mulatta). Tianeptine was administered during 15 days at the Neurosc., 1Ol, 167-197, 1987). Reference memory was tested on two dose of 10mg_kg-1 i.m. twice a day at 9a.m. and 6p.m. Placebo was appeudvely reinforced tasks differing by their complexity, a left-right administered one week before and after tianeptine treatment. The (one pair of arms ; T-maze) and a concurrent (six pairs, automated radial animals were running on a 12 h light - 12 h dark (7 p.m. - 7 a.m.) schedule. maze) discrimination learning task. In all experiments, the drug was Sleep-wakefulness cycles were recorded three times during the placebo administered i.p. 30 minutes before each session. Results showed that at pre-treatment, on days 1, 8, 12, 15 of tianeptine treatment and 48 h after the dose of 10 mg/kg, tianeptine greatly improved S.A. (from 64.0 to treatment withdrawal. Continuous EEG and behaviour (video tape 85.0 %, p < 0.001) and facilitated retention (day 2) of the T-maze recording) were recorded between 6 p.m. and 8 a.m. discrimination learning task (p = 0.013) without changing the speed of The effects of tianeptine on sleep-wakefulness cycles and EEG rhythms initial acquisition (day 1 : trials to criterion : p > 0,30). Finally, animals were analysed during the first hour after administration, during the 12 h treated with tianeptine (10 mg/kg) before each daily session of concurrent of darkness (7 p.m. - 7 a.m.) and between 7 a.m. and 8 a.m. discrimination learning were found to learn faster (p < 0.001) and to Between 7 p.m. and 8 a.m. there is no significant modification of reach higher discrimination performance than controls at the end of wakefulness, sleep stages (1 - 2 - 3 - 4) and REM (duration, episode training (day7:80.1 vs 65.1, p < 0.001}, this facilitative effect was numbers) throughout the treatment. weaker with 5 mg/kg and disappeared with 2.5 mg/kg. The only modifications induced by tianeptine were observed the first hour The present results suggest that tianeptine did not impair this form of after its administration : from day 8 tianeptine induced a significant but memo~" but rather would have facilitating effects on both working and moderate increase of wakefulness and a corresponding decrease of sleep rei'erence memories. The specificity, of these effects are currently being stages 2 and 3 and of total sleep duration ; these modifications can persist studied via a comparison of tianeptine with other classical 48 h after treatment withdrawal. No statistical changes were observed antidepressants (amitriptyline, desipramine, clomipramine} in our when the whole period of recording was considered. behavioral protocol. This study coni'Lrms that tianeptine is devoid of sedative effects and does not globally affect sleep-wakefulness pattern and cortical EEG rhythms * Udiversit~ de Bordeaux I, 33405 TALENCE, France in monkey. ** I.R.I.S., 27 rue du Pont, 92200 NEUILLY sur SEINE, France * I.R.I.S., 27 rue du Pont, 92200 NEUILLY sur SEINE, France ** CERMA, 5 bis avenue de la Porte de S~vres, 75731 PARIS cedex 15, France *** Laboratoire de M~decine Expdrimentale, Facult~ de M6decine, 27 boulevard Jean Moulin, 13385 M.A_RSEILLE cedex 5, France 31.02.34 31.02.35 ACTION OF TL&NEPTINE ON FOCALIZATION" OF ATTENTION METABOLISM OF TIANEPTINE AFTER SINGLE AND IN CAT MULTIPLE DOSING IN MAN P. Delagrange*. J.J. Bouyer*,. M-.F. Montaron*, C. Durand*, I. Bouver *, R. Farinotti *, P. Gel~ **, L. Grislain **. C. Salvadgri** and E. Moca~r ** and A. Rougeul * G. Mahuzier * At variance with the effect of other antidepressant drugs that are known Tianeptine is an original antidepressant characterized by a tricyclic to decrease the level of arousal and vigilance, tianeptine was shown to structure in which median thiazepin ring is substituted with an amino induce a slight arousa' m the rat acid side chain_ Radioisotopically 14C-labelled tianeptine (12.5 mg) was We have noN" analyzed the changes in attentiveness in the cat, through administered orally to 6 healthy volunteers. Tianeptine is rapidly combined behavioral and electrocortieographic methods. The absorbed and extensively metabolized in man. After 7days development of beta rhythms at 36 Hz over the fronto-parietal cortex had approximately 66 % of the dose was eliminated by renal excretion (55 % previously been demonstrated to be a reliable index of behavioral during the first 24hoursL Unchanged molecule contributes in urine, focalized attention ~Bouyer et al., Electroeneeph. Clin. Neurophysiol. 51, 24 hours after administration, for less than 2 % of administered dose. 244, 1981 ) Hydrolysable conjugates represent approximately 20 % of the dose. Tianeptine administered at 5mg/kg was shown here to favour Chromatographic and mass spectral studies on the urinary metabolites attentiveness in our standard paradigm with trains of beta maintained indicate that ~--oxidation is the major route of biotransformation for during 90 minutes of recording correlated with the sustained state of tianeptine in man. 3 major metabolites accounted for 26 % of urinary attentiveness. At 2 mg/kg, the effects were lighter, and depended upon radioactivity are products of ~--oxidation. Two of them are tianeptine the sensitivity'of the subjects, but none of the tianeptine treated animals homologues with C5 and C3 side chain respectively. The third one is a ever developed sleep during the recording sessions. lactam formed by cyclization of C5 metabolite. In plasma, two hours after in order to compare the effects with those of a classical antidepressant administration these three metabolites were present but unchang-d under the same conditions, the same subjects were administered with tianeptine remained the major compound (300 ng.ml'D. amitriptyline. The subjects given similar doses of amitriptyline became Furthermore, in a separate study, tianeptine was given to 12 healthy drowsy after about 10 minutes and slept all through the recording session subjec~ ; the metabolism profile was examined on the urine collected (with no REM sleep, though). during the first 24 hours following the first and the last dose of multiple To sum up, tianeptine increases attentiveness in cat and does not produce dosing (12.5 mg tid for l 0 days). After 10 days of chronic administration drowsiness as other antidepressant substances do. urinary metabolic profile was not modified but some quantitative (supported by IRIS grant 375) difference appeared. The quantities of tianeptine and C5 derivative conjugates decreased of approximately 50 % while the quantity of the C3 Institut des Neurosciences, CNRS-UPMC, 9 quai Saint Bernard, derivative conjugate increased. Thus, the ~-oxidation process seems to be 75005 PARIS, France the rate-limiting step for the conjugation of the C3 metabolite following a * I.R.I.S., 27 rue du Pont, 92200 NEUILLY sur SEINE, France single dose of tianeptine ; this is no more the case at steady-state. * Facult~ des Sciences Pharmaceutiques PARIS XI - Avenue Jean- Baptiste C16ment - 92290 CHATENAY-MALABRY, France ** IR.I.S., 27 rue du Pont. 92200 NEUILLY sur SEINE. France 275 31.02.36 31.02.37 FLE~OBUTE~OL : A NEWANTIDEPRESSANTDRUGP.~ATED TO BETA IITrERACTIONS OF FLEROBUTEROL, A NEW ANTID~SANT DRUG, ADRENERGIC AG~TS. EXPERIMENTAL PROIrILE IN MICE. BETA ADR~K~31~TORS IN RAT CNS. J. Duteil~ F.A. Rambert t A.M. Pointeau, P. Man~iameli R~. Zini~ D. Morin and J.P. Tillement and E. Assous. FLEROBUTEROL (FLERO) has potent antidepressant effects Putative antidepressant effect was demonstrated in mice both in animals and man. As it is chemically related to with isoprenaline, salbutamol and other beta-agonists. beta-adrenergic agonists and as such a mechanism may be Furthermore, therapeutic improvement was demonstrated involved in antidepressant effects, its interactions with with salbutemol in depressive patients. central beta-adrenoceptors were investiEated. Using Potential antidepressant effect of FLEROBUTEROL, radioligand techniques, we determined the inhibition (fluoro-2 phenyl)-i t-butylamino-2 ethanol, (FLERO), a constant (KT) of FLERO and its enantiomers at these new drug related to beta-agonists, was studied using receptors. T~eir affinities3were evaluated by the ability classical psychopharmacolo~ical_~ests in mice. I to inhibit the binding of [ H]-CGP 12177 (Kn = 0.1 nM) in FLERO (-30 min, 0.5-32 mg.kg ~, i.D., 2-16 k~l~ cerebral cortex (mainly beta-I receptors) and in p.o.) completely antaganised apo~r~hine (16 m~ cerebellum (mainly beta-2), The affinity of (• was and partially reversed reserpine- and oxotr~-morine- very close in both tissues (K T = 926 nM for cortex, induced hypothermia and enhanced (16-32 mg.kg , i.p.) K I = 518 nM for cerebellum) which~indicated that the drug the toxic effect of yohimbine. Unlike imipremine (but was not selective of a beta-adrenergic receptor subtype. like other beta agonists), it did not reduce immobility In cerebral cortex, binding inhibition of [~H]-CGP 12177 duration in "hehavioural despair" test. FLERO did not was stereospecific, (-)FLEE0 (KT = 483 nM) being twice enhance 5-HTP-induced head twitches or tremors in MAOI more potent than (• and 7~ fold more potent than pre-treated mice and did not modify l-DOPA-induced motor (+)FLERO (K T = 34 ~M). Moreover (+)FLERO was 7 fold less. activity. As other beta-agonists, FLERO (-30 min, 2-32 active tha~ (+)isoproterenol (KT'-= 140 riM) but 5 fold mg.kg -~, i.p,) induced a decrease in locomotor activity more active than salbutemol (KI --~4600 riM). and did not potentiate the hypnotic effect of barbital. In cortical slices from control rats, the addition of i00 Antagonistic effect of FLERO towards apomorphine-induced ~LM (• resulted in a 135 Z increase in cAMP accumu- hypoth~rmia was prevented by propranolol (-i h, 4-8 lation over basal level (i00 Z or 6.8 pmoles cAMP/mg mg.kg i' i.D.) but not by alpha m p-tyrosine (-3 h, 75 protein/10 min at 37~ This increase was similar to mg.kg" , i.D.). that of i00 ~M salbutamol (129 Z) but much lower than the FLERO did not produce mydriasis and did not prevent stimulation induced by I00 ~M (• (280 Z) or oxotremorine-induced tremors or salivary and lacrymal i00 ~LM (• (402 Z). glands hypes-secretion. It did not reduce reserpine- (• and (• accumulation induced palpebral ptosis and did not induce an increase of cAMP were fully antagonized by i0 mM of (~)atenolol or in toxicity in aggregated mice. 10 ~LM of (~)propranolol. From these results, FLERO appears to demonstrate These results show that FLERO is a central beta- potential antidepressant activity in mice. The ratios of adrenergic agonist with a higher affinity than that of the centrally and peripherally active doses of FLERO and salbutamol. salbutemol are to be evaluated. D~partement de Pharmacologic, Universit~ Paris XII, 8 rue Centre de Recherches du Laboratoire L. LAFON, 19 avenue du G~n~ral Sarrail. F-94010 Cr~teil, France. du Professenr Cadiot. F-94701Maisons-Alfort. France. 31.02.38 31.02.39 ORAL PHARMACOKINETICS OF A NEW SLOW RELEASE AGONIST lq~ROBUTEROL IN RATS : C/IMPARISONWI'r~ SALBI~L FORMULATION OF VILOXAZINE IN DEPRESSED PATIENTS ~.J. Puech(1) t M. Henry(2) t P. Martin(1)~ S. Th~venet(2) 5.8ouquet~S.Guibert r 3.Lavolsy~ 3.B Fourt111an. ~.A. Rembert (2) and J. l)uteil(2). Pnarmacoklnetlc propertzes of viloxazine (V), ~otential antidepressant effect ~as demonstrated in mice were investigated xn twelve Patients with ma3or ith FLEROBUTEROL (fluoro-2 phenyl)-i t-butyl amlno-2 Oepression (DSM III cr~terla)(lO M,2 F),ages ~thanol, (FLERO), a new drug related to beta agonists. ranged from 35 to 52 yrs,wlth score higher than ~he ratios of the centrally and peripherally active doses 2B on the ratlng scale MADRS . Pharmacoklnetlo of FLERO and salbutemol (SALBU) were evaluated after i.p. ~arameters were calculated followlng the ist and I 'administratlon in male Wistar AF rats. 28th administrations of a oally 300 mg oral Oose in the learned helplessness model, FLERO and SALBU were of viloxazine $R. Plasma samples were collected !daily tested on a 30 avoidance trials session in a for 24 h at days: I (I) an~ 28 (ss),respectlvely ishuttle-box, 48, 72 and 96 h after exposure to 60 and at C MIN of days: 7, 14,21. The aepresslon ~ncontrollable an~unpredictable electric shocks. FLERO rating scales were undertaken at ist, 7th, Idth (0.015-0.25 mg.ks -~ b.l.d, for 5 days) stron@ly reduced and,28th days of treatment. Plasma conoentratlon5 were escape I deficits at the minimlmal dose used of 0.015 determined by HPLC and results expressed as (mean~SE). Mean plasma C MAX of (V)reaohed : mg.kg- (-56Z on day 5, 30 - 45 min after injection). In 29275 350 ng/ml (i) and 3824 ~ 536 ng/ml(ss) the same experimental paradigm, SALBU demonstrfted an respectively. The important values of T MAX:5.3 effect at the minimal effective dose of 12 mg.kg- b.l.d. " 0.5 h(1) and 4.8 t 0.4 n(ss) an~ (MRT): Ii.3 • for 5 days (-50Z on day 5). 0.gh (i), 8.7 : 0.4 h(ss), were in accord wltn In conscious rats instrumented with chronic arterial one Oally Oose. ElimlnatIon half-life: T1/2 : catheter, FLERO was idevoid of positive chronotropic 5.6 ~ 0.8 n (1),wa~ higher than the values effect at 0.25 mg.kg-* but increas~ heart rate at the reported by 8.Vandel (3.4 ~ 0.6 h) and P.F.C minimal effective dose of 0.5 mE.ks- (+ 45 beats/min, at 8ayllss (2 to 5 h),after a single admlnzstratlon 30 min, lasting 75 min). In the same conditions, SALBU of 1CO mg standard tablet. The mean values of induced a positive chrono~ropic effect at the lowest dose AUC(ss) 0-24h and AUC(1) 0-~. were 37804 i 5805 studied of 0.325 mg.kg -~ (+ 70 beats/min at 30 min, and 37344 ~ 4795 ng/ml.h, resDectlvelv and mean lasting more than 120 min). Citot reached 163.7 ~ 24.4 I/h (i) and 168.8 Z The ratios of the centrally and peri~erally minimal 21.71/h (Ss)-N~. TheSe results suggest~ t~at active doses were 33 (0.0~5 vs 0.5 mE.ks ~) for FLERO and Dloavailabllity , dl~trlbutlon and ellmlnatlon 0.03 (12 vs 0.325 mE.ks -~) for SALBU. Hence, this ratio of V wer~f~imllari ~during onron~c doslng altn indicates a preferential antidepressant versus cardiac oral SR farm. Helght patients showed a rapld stimulant activity of FLERO as compared to SALBU. clinloa~improvement (Tth ~ay) ,with a ratln9 These results suggest that cardiac stimulation would be ~cale decreased of 60 after 4 weeks of V mini~l in depressed patients treated with FLERO. treatment. NO relatlonshzp was found between (i) D~partement de Pharmacologie, CHU Piti~Salp~tri~re, plasma levels anO clinical response or adverse 91, boulevard de l'Hopital. F-75651 PARIS Cedex 13 effects. (2) Centre de Recherches du Laboratoire L. IdLFON, 19, N~pital la Mil~trie, 8P 577,86021~Poitiers -W. avenue du Professeur Cadiot. F-94701Maisons-Alfort. 276 31,0240 31 0241 DOSULEPIN (DOTH!EPIN) FOR DEPRESSION. ARE THERE INTER- E~CAOY OF ~IANSERIN IN DIFFERENT DEPRESSIVE NATIONAL DIFFERENCES? A REVIEW OF CLINICAL USAGE IN OVER 5,000 PATIENTS FROM THE U.K., GERMANY AND FRANCE. SYNDAO~E S. Donovan S.Loga, l.Oeri6, E.Rustempa~i6 and V.Dane~ Dosulepin (Dothiepin) was administered to 5,386 patients with depressive symptoms ranging between mild and severe, The efficacy and safety of mianserln were compa at a dose generally between 75mg/day and 150mg/day for red with doxepln in 3 independent double-blind four weeks in an open uncontrolled study in 1,965 U.K. patients (i), 1,866 patients in West Germany (2) and controlled studies: (I) in depressive adolesce- 1,555 French patients (3), by a total of 920 investi- nts(5o out-patients), (2) in secondare depres- gators. This is a comparative review of the outcome in the three cohorts. sion of TBC (30 in-patients) and (3) in alcohol Although the assessment rating scales were different in withdrawal syndroms (30 in-patlents). each country, it was evident that a favourable response The patients w~re assessed weekly on HDRSeCGI, occurred in the majority of patients in all three cohorts. Onset of action within one week and maximum DTES(only alc oholics),together with a side-effe rate of improvement during the first two weeks were cts symptoms check-list,physical examination observed in all three groups, although improvement and laboratory assays. continued throughout the four week study period. Premature withdrawal due to lack of efficacy was very During of the 4 week period (alcoholics-2 weeks low in each group and overall, medication was withdrawn the patients were treated with mlanserin (30 - in less than 4% of all patients for this reason. Side effects Were common and although they occurred with 90 mg) or doxepin(25 - 75mg).The total dayly an apparently variable incidence in each group, the dosage was given at bedtime. majority were typical anticholinergic effects, most The results of these 3 studies showed that mi- commonly dryness of mouth in up to one-third of patients. Withdrawal due to adverse events was, however, anserin was as effectiv and as better tolerated low in all three groups, amounting to 5% of the entire than doxepin in milde depression in adolescent9 population studied. There were no serious events secondare depression of TB0 patients and in attributable to study medication. alcohol withdrawal syndrom;morover it seems to The benefit:risk ratio was high in all three cohorts and despite the differences identified in the populations of have more rapid onset of action than doxepin. depressed patients and variations in study methodology in each country, the overall outcome is reassuringly similar UM0 - PsihiJatriJ ska kllnlka,71, ooo SaraJevo, Refs: (1)Rees JA. Marsh BD. Int.Pharmacopsychiat. 1975; M.Pijade 25, Yugoslavia 10:54 57. (2)Karrasch KF. Sehulte RM. Zeit T., Med.Welt. 1987;~8:1453-8 (3)Ades J. Synapse. 1987;36:76-80 The Boots Company PLC, NottinGham, NG2 3AA 31.02.42 31.02.43 COt.~ARISON OF CLINICAL EFICACY OF ALPRAZOLAM, MIANSERIN QSAR STUDY OF MAO-A AND MAO-B INHIBITORY ACTIVITY OF AND IMIPRAMINE IN NEUROTIC DEPRESSION SUBSTITUTED PHENYLALKYLAMINES IN-VITRO. J. S. Relvas, A. S. Vaz-Serra and C. B.'Saraiva Massoud Mahmoudian; It's a common practice the association of benzodiazepi- nes to antidepressants ~n cl~nical management of neuro- Dept. Pharmacology, Firoozgar Institute, Uinv. Med. Sci. =ic depression. Recently, the antidepressant properties Iran, Ali St., Tehran 15934, I RAN. of a new family of benzod~azepines has been stud~ed and many clinical trials uncovered a significant and Quantitative structure activity analysis (Hansch useful clinical effect (Fabre, 1976; Rickels et col., analysis) is app]ied to elucidate the structural require- 1982; Feighner et col., 1983; Rush et col., 1985; Ove- ments for the inhibition of HAO-A and MAO-8 activity by rall et col., 1987). a series of substituted phenylalkylamines. The present clinical trial has been conducted in 47 pati- It has been found that PL~O-A inhibitory activity is ents diagnosed as neurotic depressives ~n a double-blind, achieved best with a compound with a hydrogen acceptor randomized, parallel-groups design. Each group was medi- group at para position of the pheny] ring, a ~ conflgura- cated w~th one of the three drugs during 6 weeks after tion of side chain, with a high hydrophobiclty and a high one week wash-out. inductive constant ('~). However, the bulky substituents Weekly avaliatJons inclued Beck Depression Inventory, are unfavour to the activity, as can be seen from the Zung Self-Rating Auxiety Scale,Evaluation of three goal- negative slope of the sum of molar refractivity of symptoms rated as most disturbing by patients in the substituents on the phenyl ring. first observation, Side-effects Inventory and Laboratory While, the MAO-B inhibitory activity also requires a evolution_ S configuration of the side chain and a high fleld Results showed a significant and sustained antJdepressi- Tnduct|ve constant (~, the other structura] requirements ve effect of alprozolamwJth a rapid onset but of a les- are differ with that of MAO-A inhibitory activity. The ser intensity than other two dTugs I~AO-B inhibitory activity is achieved best with a hydro- Patients medicated with alprazolam presented less side- phobic group at para position of the phenyl ring. Also, -effects in all parameters. while a bulky group at ortho position of the phenyl ring Clfn~ca PsJqui~tr~ea dos Hospitais da UniversJdade de is favoured to the MAO-B inhibitory activity, a bulky Coimbra. H.U.C. 3049 Coimbra. Portugal. group at meta position of the phenyl ring will reduce the activity. From these finding a model for the binding site of MAO-A and MAO-B iso-enzYmes is postulated. 277 31.02.44 31.02.45 ANTIDEPRESSANT ACTIVITY OF RU 41 656 AN OXAERGOLINE~ IN ANTIDEPRESSANT ACTIVITY OF RU 41 656 AN OXAERGOLINE~ 14 BEHAVIOURAL TESTS BEIIAVIOURAL TESTS J.Laurent, M. Guernier~ C. Gieules J.Laurent, H. Guernier~ C. Cieules RU 41 656* a 9-oxaergoline derivative with mixed dopamine RU 41 656* a 9-oxaergoline derivative with mixed dopamine (DA) D2 agonist and DI antagonist activities possesses (DA) D2 agonist and DI antagonist activities possesses antlanoxic and antiischemic properties together with a antianoxic and antiiachemic properties together with a beneficial action on learning behaviour. It is under beneficial action on learning behaviour. It is under development as a potential therapeutic agent for the development as a potential therapeutic agent for the treatment of senescence related disorders. DA has been treatment of senescence related disorders. DA has been implicated in the mechanism of depression and the DA implicated in the mechanism of depression and the DA agonist hromocriptine was found to be clinically effecti- agenist bromocriptine was found to be clinically effectl- ve as an antidepressant (AD). We have therefore looked ve as an antidepressant (AD). We have therefore looked for a potential AD activity of RU 41 656 in comparison for a potential AD activity of RO 41 656 in compariso= with bromocriptine and two AD compounds : nomifensine~ a with bromocriptine and two A]) compounds : nomifensine, a catecholamine (DA + NA) uptake inhibitor and amitriptyli- catecholamiue (DA + NA) uptake inhibitor and amitriptyli- ne a "tricyclic" AD. 3 tests in rats where AD are active ne a "tricyclic" AD. 3 tests in rats where AD are active were used : immobility induced by forced swimming (FS)j were used : immobility induced by forced swimming (FS), muricidal behaviour (MB) and facilitated acquisition of a muricidal behaviour (MB) and facilitated acquisition of a passive avoidance in the bulbectomized rat (BR). The EDS0 passive avoidance in the bulbectomized rat (BR). The ED50 of RU 41 656 in these tests was : FS = 3 mg/kg p.o. ; of RU 41 656 in these tests was : FS = 3 mg/kg p.o. ; MB = 1.5 mg/kg i.p. ; BR = 2.5 mg/kg p.o.. The general MB = 1.5 mglkg i.p. ; BR - 2.5 mglkg p.o.. The general order of potency of the compounds tested was : order of potency of the compounds tested was : nomifensine~ RU 41 656> amitriptyline> hromocriptine. nomifensine~ RU 41 656> amitriptyline> bromocriptine. The efficacy of RU 41 656 was independent of any hyperlo- The efficacy of RU 41 656 was independent of any hyperlo- comotor activity since unlike most DA agonists it reduces comotor activity since unlike most DA agoniats it reduces locomotion. These results might be explained by the locomotion. These results might be explained by the DAergie activity of RU 41 656 although other mechanisms DAergic activity of RU 41 656 although other mechanisms of action cannot be excluded since it also binds to ~2 of action cannot be excluded siuce it also binds to =2 and 5HT2 receptors. Nevertheless a potential AD activity and 5HT2 receptors. Nevertheless a potential AD activity is valuable for the therapeutic use of such a compound is valuable for the therapeutic use of such a compound because depression is often associated with aging. because depression is often associated with aging. * (86)(~) 6-methyl 8-[(methylthio)methyl] 9-oxaergoline * (83)(~) 6-methyl 8-[(methylthio)methyl] 9-oxaergollne chlorhydrate chlorhydrate Centre de Recherches Rouasel Uclaf~ III route de Noisy Centre de Recherches Rouasel Uclaf~ III route de Noisy 93230 Romainville~ France. 93230 Romainville, France. 31.02.46 31.02.47 PRECLINICAL CHARACTERISTICS OF MOCLOBEMIDE, A CSF- AND PLASMA CATECHOLAMINES AND METABOLITES SHORT-ACTING MAO-A INHIBITOR WITH LOW LIABILITY TO UNDER TREATMENT WITH SELECTIVE, REVERSIBLE MAO-A ENHANCE THE TYRAMINE PRESSOR EFFECT INHIBITORS H.H. Keller~ R. Kettler, W.P. Burkard and M. Da Prada The morpholino-ethyl benzamide moc|obemide (MOCLO) belongs E. Sofic, G. Laux, P. Riederer, H. Beckmann to a new generation of reversible MAO inhibitors which prefe- Reversible and selective MAO-A inhibitors are rentially inhibits cerebral MAO-A; it lacks hepatotoxicity and thought to be of therapeutic efficacy in only minimally enhances the tyramine pressor effect ("cheese depression syndrome. Therefore, moclobemide (MO) reaction") (Do Prada et al., J. Neural Transm. Suppl. 26, 33, (Re 11 1163) has been tested (no dietary 1988). Being more active in vivo than in vitro, MOCLO---behaves restriction) vs. maprotiline (MA) in a 28 day as a prodrug. Marked MAO-A inhibition ex vivo in the rat double-blind study in 20 inpatients matched for occurs within 5 rain after oral administration in both liver and sex and age. According to DMS III for major brain, indicating that the MAO-A inhibiting entity is rapidly depressive disorders 15 (MO-group) and 16 (MA- formed by biotransformation, possibly occurring at the MAO group) were unipolar depressions while the other enzyme itself. Accordingly, in vitro MAO-A inhibition is more patients were diagnosed am of the bipolar type. pronounced and non-competitive if the tissue homogenate is Ratings (HRSD, MAMA, CGI, SDS, KUSTA) were done preincubated with MOCLO before adding 5-HT as the substrate, on days 0,3,7,14,21,28. Compliance was checked suggesting a mechanism-based type of inhibition. In contrast, by plasma drug levels of MO. Plasma-(days O, even after a high dose (100 l~moles/kg p.o.), maximum MAO-B 14,28) and occasionally CSF-analyses were per- inhibition occurs only 1 h and 2 h after administration in liver formed for catecholamines and their metabolites and brain, resp.. Peripheral MAO-B inhibition is marked in the by using an HPLC-EC technique. Clinical results:. rat, less pronounced in squirrel monkeys and only moderate in patients responded with HRSD< 50% in 73% (MO) humans (30-50% inhibition in platelets after 200 mg orally). and 60% (MA). There were 3 drop outs with MO Reversibility of MAO-A inhibition after oral MOCLO to rats (deliriumjpsychosis, no effect). Side effects: has been demonstrated by dialysis or simple incubation of the sleep disturbances, pruritus, agitation (MD); tissue homogenates at 37 ~ but not at 13~ strongly suggesting sedation, dry mouth (MA). There were no evidences a conversion of the inhibiting derivative into inactive products. for hypertensive reactions with MO. Biochemical In comparison with other novel MAO-A inhibitors, the accumu- results: CSF (MO in 2 patients only): inconsistent lation of the monoamines and the concomitant decrease of increase o~-f--NA, A and DA; no changes with HVA their metabolites in rat brain induced by MOCLO is short- and 5-HIAA. Plasma: no sign. changes in NA,A,DA, lasting (16 h) even after high doses. More important, MOCLO HVA and 5-HIAA with either MO or MA. Conclusions: has a particularly low liability to enhance tyramine-induced MO shows beneficial therapeutic efficacy, no pressor effects in rats and humans (Korn et al., J. Neural cheese effect and seems to act by increasing the Transm. Suppl. 26, 57, 1988). The present preclinical data indi- central catecholaminergic tonus. cate that MOCL--O meets the prerequisites of a safe drug. In man, MOCLO is well tolerated, produces few undesired effects Clinical Neurochemistry, Dept. Psychiatry, of low intensity while being an effective antidepressant University of WOrzburg, WOrzburg, FRG (Amrein et at., J. Neural Transm. Suppl. 26, 73, 1988). Pharmaceutical Research Department, F. Hoffmann-La Roche & Co., Ltd., CH-4002 Basle, Switzerland 278 31.02.48 31.02.49 STIMULATION OF PROLACTIN SECRETION BY THE EFFECTS OF NOCLOBEMIDE AND MAPROTILINE ON HYPOTHALAMIC-PI- P~EIrERSIBLE M~O-A INHIBITOR, MOCLOBF~MIDE, IN M~N TUITARY-SOMATOTROPIC (HPS) AXIS FUNCTION IN DEPRESSION M. Koulu, M. Scheinin, R. Zin~ner A. Erb, 6. LBUX, K.P. Lesch A. Kaarttinen, J. Kallio and K. Pyykk~ The effects of 4 weeks of treatment with the selective Three different doses of the reversible pre- MAO-A-inhibitor moclobemide vs. the tetracyclic NA re-up- ferential MAO-A inhibitor moclobemide (iOO, take inhibitor maprotiline on HPS function were studied by 200 and 300 mg), matching placebo tablets, clonidine-evoked growth hormone (6H) release in major de- pressive disorder. Growth hormone (6H) responses to 2 NO/ and i0 mg of the irreversible FL~O-B inhibitor kg clonidine were investigated in i0 depressed patients deprenyl were administered to eight male vo- (8 women, 2 men; mean age: 45.8 yrs) before and after lunteers. MAO-B inhibition after moclobemide treatment with 300 mg/day moclobemide (MOC) and in 13 pa- was slight (less than 30%). tients (9 women, 4 men; 48.4 yrs) with a major depressive The secretion of prolactin was powerfully episode before and after treatment with 150 mg/day mapro- and dose-dependently stimulated by moclobemide, tiline (MAP). Compared to individually matched controls as evidenced by increased prolactin levels in the depressed patients showed an attenuation of clonidine- plasma (an average increase from 6.4+2.7 to induced GH responses before treatment with MOC (392 • 111 23.5~7.1 ng/ml at 1 h after intake o~ 300 mg). vs. 95 • 39 ng.min/ml; p<0.01, Mann-Whitney U test) and Prclactin in plasma was slightly reduced after with MAP (534 • 190 vs. 124 • 72 ng.min/ml; p~ 0.001). Af- placebo and deprenyl. Plasma growth hormone ter treatment the mean 21-item Hamilton Rating Scale sco- and cortisol levels were not significantly res were significantly improved in both the MOC (26.4 • affected by moclobemide. 2.2 vs. 10.3 • 1.9; p 31.02.50 31.02.51 NIG~ DOSE TRANYLCYPROMINE FOR REFRACTORY DEPRESSION CLINICAL, KINETIC AND NEUROCHEMICAL FINDINGS WITH THE NEW N.J. Berwish and J.D.Amsterdam. ANTIDEPRESSANTS BROFAROMINE AND ROLIPRAM AS many as 15% of depressed patients may develop a chron- T. Becket, K.P. Lesch, G. KOhne, F.v. Baumgarten, ic, refractory illness. Aggressive treatment with various P. Riederer, 6. Laux, M. Struck, P. Black drug conlbinations, unconventional antidepressants, or ECT Renewed therapeutic interest in MAO inhibitors has fol- has met with only partial success. To this end, we initi- lowed the advent of selective compounds. Brofaromine is a ated an open-label study utilizing high doses of the FL~O reversible, selective MAO-A inhibitor, clinical trials inhibitor, tranylcypromine (TCP] at a range of 90mg to have revealed activating and antidepressant properties. 180mg daily, in seven refractory depressives who had Phosphodiesterase inhibition as shown by rolipram enhances failed to respond to at least three prior treatment regi- second messenger concentration and has been proposed as a mens. new mode of antidepressant action. Rolipram also stimula- All were outpatients with moderate to severe depression. tes noradrenergic transmission presynaptically by increa- Ages ranged from 27 to 64 yrs, with a mean• illness dur- sing noradrenaline synthesis and release. ation of 12• yrs. The number of previous treatment fail- In an open trial n=13 inpatients with a major depressive ures ranged from 3 to 14 with a mean• of 8• episode (4 uni-, 3 bipolar, 6 dysthymic) received brofaro- Four of 7 subjects (57%) had a complete response, and one mine 50 mg t.i.d, for 28 days. 4 patients were withdrawn had a partial response. The mean• maximum TCP dose for due to lack of efficacy and adverse effects (restlessness, the entire patient group was 129• daily while the mean insomnia). ANOVA showed significant reduction of HRSD dose for the "responders" was l12• daily (range 90mg (day 28 vs.O, p .005), but nd~ of Bf-S. No cardiovascular to 130mg). Response was not a function of severity or dur- effects were observed. CSF and plasma kinetics, catechola- ation of present episode, nor was it related to the mines and metabolites after single dose of 100 mg brofare- nllmber Of prior treatment failures. Overall, the side mine were determined. effect profile was favorable, and no "cheese reactions" Furthermore, n=11 inpatients with a major depressive epi- were encountered. Most autonomic side effects occurred sode (5 uni-, 1 bipolar, 5 dysthymic) were given rolipram at low to moderate TCP doses and diminished at high doses. 0,75 mg t.i.d.. Four patients dropped out due to lack of For example, when compared to pretreatment values efficacy and adverse effects (insomnia, restlessness, nau? there was a significant decrease in the mean sitting sys- sea). HRSD showed significant improvement (day 28 vs. O, tolic (p=0.001) and diastolic (p=O.001) blood pressure p .05) Loss of clinical effect was observed in 3 patients and the mean standing systolic (p=0.001) and diastolic plasma levels varied little within and between patients, (p=0.002) blood pressure at moderate TCP doses (67• increase in urinary MHPS wore off over time. Inter-drug Interestingly, there were no difference in blood pressure comparison showed no significant difference regarding measurements from pretreatment values at the maximum TCP efficacy. dosing (129• Psychiatrisohe Universit~tsklinik. F0chsleinstra6e 15. These observations are of clinical significance and sug- 6700 W0rzburg. FR6 gest the need for further controlled studies using high doses of tranylcypromine in refractory depression. Depression Research unit, Department of Psychiatry, Uni- versity of Pennsylvania School of Medicine, Philadelphia, PA. 19104, U.S.A. 279 31.02.52 31.02.53 THE SELECTIVE AND REVERSIBLE MAO-INHIBITOR BROFAR~-IINE BROFAROMINE AND TRA.\~LCYPROMINE IN RESISTANT DEPRESSION (CGP 11.305 A) IN COMPARISON TO TRANYLCYPROMIN W.A. Nolen, J. Haffmans and G.S. Jansen M. ZapletAlek, F. Faltus, K. N~hunek, J. Svestka, Brofaromine (BROF) is a new reversible MAO-inhibitor with a selective effect on MAO-A. In an ongoing double- J. Molcan, U. Binz, G. Wendt blind study BROF (max. 250 mg daily) was compared with Brofaromine is a new selective and reversible MAO- tranylcypromine (TRAN) (~ax. i00 mg daily). Until now 12 inhibitor type A as demonstrated in animal and human patients with a major depression (DSM-III), resistant to pharmacological studies. In comparison to tranylcypro- cyclic antidepressants (given during at least 4 weeks mine it showed a much (about 3 times) smaller tyramine- with "therapeutic" plasma levels), have been studied. potentiating effect and a much shorter pharmacodynamic Clinical effects: One out of 6 patients responded to halflife (1.5 days vs. 2 - 3 weeks). Therefore it is BROF (i.e. Hamilton score dropped at least 50%). The expected to be better tolerated than the classical MAOIs mean scores dropped from 27.7 to 21.5. Two out of 6 especially regarding hypertensive crises. The results patients responded to TRAN and l patient showed a marked of an open study and a double-blind dose-finding study improvement of almost 50%; mean scores 26.5 and 13.8 indicated that brofaromine displays antidepressant respectively. activity with few side effects. Remarkable undesired Side effects: BROF produced fewer side effects, especi- effects were disturbed sleep, weight loss, and nausea. ally no orthostatic hypotension which was observed in 3 of the patients treated with TRAN. The double-blind study vs. tranylcypromine is running Effects on sleep: REM latency was significantly increased in 4 centres with the aim to present the data of 80 in- patients with therapy-resistent depression. Like in the by BROE while the number ofiREM periods, to=el REM and early morning awakening decreased. TRKN completely sup- dose-finding study all patients are on strict diet as pressed REM sleep and stage 4. Assessing cycli was usually under treatment with classical MAO-inhibitors. hardly or nat possible. Sleeplaten6y increased Duration of treatment is 6 weeks. Daily doses are significantly and the number of shifts decreased. 2 x 50 mg brofaromine resp. 2 x 10 mg tranylcypromine. Sleepefficiency (SE) was higher in the BRO~ treated Responders receive maintenance therapy with unchanged patients compared to ~he TRAN group, however, in both daily dosages, non-responders receive increased doses groups a significant reduction of SE in comparison to (150 mg resp. 30 mg b.i,d.). the SE ~btainedbefore treatment. Parameters for evaluation of efficacy and tolerability Plasma levels: Until now no clear relation was found are H~MD, Bf-S, global judgements, onset of action, RR, between clinical effect, sleep and plasma levels. heart rate and laboratory parameters. Department of Biological Psychiatry, Psychiatric Centre Lelarska Fakult~t d. Univ., Psychiatricka Klinika Bloemendaal, Monsterseweg 93, 2553 RT The ~ague, The CS Hradec Kralove Netherlands. 31.02.54 31.02.55 THE SELECTIVE AND REVERSIBLE MAO-INHIBITOR BROFAROMINE EFFECT ON SH-MONOAMINE L~TAKE IN VITRO OF PLASMA (CGP 11.305 A) IN COMPARISON TO IMIPPJ~MINE OBTAINED FROM HEALTHY MALE VOLUNTEERS TREATED WITH ONE E. K. Fischer, I. B~rner, M. Heim, H.-J. MSl]er t OR MORE DOSES OF THE PUTATIVE ANTIDEPRESSANT R. Obelhack, P. Wun~erlich, U. Binz, G. Wendt SIBUTRAMINE HCL Brofaromine is a new selective and reversible MAO-inhibi- G. P. Luscombe, N. A. Slater, R. D. Wynne, M. B. Lyons tor type A as demonstrated in animal and human pharma- and ~. R. Buckett cological studies. In comparison to tranylcypromine it Sfbutramine HCI (BTS 54 524) is a monoamine uptake inhibitor with a pharmacological profile in rodents showed a much (about 3 times) smaller tyramine-poten- indicative of potential antidepressant activity (W. R. tiating effect and a much shorter pharmacodynamic half- Buckett et el, Br. J. Pharmac. 90, 94P & 26]P, 1987). life [1.5 days vs 2 - 3 weeks). Therefore it was expected We have studied the ability of plasma, obtained from to be better tolerated than the classical MAOIs especial- volunteers at regular intervals after one or more doses ly regarding hypertensive crises. In human pharmacologi- cal studies brofaromine was administered in combination of sibutramine HCl, to inhibit the in vitro uptake of 3H-noradrenalins (NA) by rat cortical synaptosomes, of with tyramine-rich cheese but there was no change in RR 3H-dopamine (DA) by rat striatal synaptosomes, and of and heart rate. The results of a double-blind dose-fin- 3H-5-hydroxytr)~tamine (5HT) by human platelets from ding study with in-patients on strict diet on account of untreated volunteers (R. D. Wynne et el, Acta tranylcypromine in the control group indicated that Pharmacnl. Toxicol. Suppl. 5, 640, ]986). brofaromine displays antidepressant activity with good Sibutramine HCI inhibited the uptake of 3H-monoamines tolerability. In an open study, patients receive food in vitro (NA > 5HT > DA) after administration of one or with relatively high tyramine concentration 2 times a more doses to volunteers. The inhibitory effect was week with repeated measurement of RR and heart rate after dose-dependent (5-20 mg/day) and increased with the the meal. Until now there was no relevant change in duration of treatment (]4 days), reaching a plateau of circulator), parameters. The double-blind study vs. approximately 50% inhibition of ~H-NA uptake and 20-30% imipramine is running in 6 centres without diet. The aim inhibition of 3H-5NT uptake after sibutramine HCI of the trial is to present the data to 100 in-patients (20 mg/day). Higher plateaux of SH-NA (60%) and 3H-SHT with affective disorders. Parameters for evaluation of (40%) uptake inhibition were attained more rapidly by efficacy and tolerability are HAMD, Bf-S, global twice daily sibutramine BCI (15 mg). Plasma obtained judgements, onset of action, RR, heart rate and after either single (50 mg) or repeated (15 mg twice laboratory parameters. Until now we have got the data daily) doses of sibutramine HCl had a weak inhibitory of 66 patients. effect on mH-DA uptake in vitro. The activity of sihutramine HCI as a monoamine uptake Dr. yon Ehrenwall'sche Klinik, 5483 Bad Neuenahr-Ahrweile~ inhibitor in man is similar to its relative activity as a monoamine uptake inhibitor in rodents, and further supports the preclini~al evidence that sibutramine HCI will have an antidepressant effect. Research Department, The Boots Company PLC, Nottingham, NG2 3AA, United Kingdom. 280 31.02.56 31.02.57 S-ADENOSYL METHIONINE IN PLASMA LEVELS OF DESMETHYL METABOLITES IN PATIENTS WITH DEPRESSION: A REVIEW OF THE AFFECTIVE DISORDERS TREATED WITH CHLORIMZPRAMINE AND IT~ DATA POSSIBLE CORRELATIONS WITH CLINICAL PARA~TEES AND WITH 3.M. DAVIS, P.G. 3ANICAK, J.F, ~IPINSKI, etal. THE TYPE OF EFFICACY OF TREATMENT We report a meta-analysls of ii M. NARDINI, G.P. SGARAGLI, R. NINCI, L. DELLA CORTE, N. controlled trials comparing S-adenosyl BELARDINELLI, G. BONELLI, M. VALOTI, S. NICOLAU methionine (SAMe) to either placebo or Plasma levels of desmethyl metabolites has been measured tricyclie antidepressants (TCA) for the in 30 patients with Affective Disorders (DSM III) chroni- treatment of depression. Using the cally medicatedwith chlorimipramine. Mantel-Haenszel, data combined from a number of research centers indicated The aim of our work was to verify and suggest an explana- SAMe's clJncial superiority over placebo: tion of the observation that a proportion of depressed pa when 37 SAble patients were compared tients do not respond to tricielyc drugs. to 25 placebo patients, the Chi Square o~ Plasma levels of metabolites has been measured by a GLC 30.0 was signilicant at the /4 X 10- assay method using a NP detector in order to define the level. A second anMysis showed a slight N-demethylation pathway (N-monodesmethyl and N-didesmethy] superiority for SAMe over TCA's: SAMe (n=i2O) compared to TCA's (n= 112) metabolites of chloroimipramine). yielded a Chi Square of 3.93 (p .05). In Our results show that the plasma levels of desmethyl meta- addition, there were very few side bolites are higher than those of the parent drug and also effects with SAMe as compared to correlated with the therapeutic effects. We also report our preliminary TCA's. The data observed show that in our case study there is a data comparing SAMe to placebo or lmipramine (IMI) under double blind variability in the capacity to N-desmethylate the chloro- conditions for a two week trial 7 imipramine and this fact is suggestive of a polymorphism patients received SAMe, /4 received IMI of this metabolic reaction. A correlation,not significant, and 5 received placebo. Thus far, SAMe is found between N-didesmethyl metabolites' level and the apprears comparable to IMt and responsivity to the treatment. signficantly superior to placebo (t = 3.#I, df = I0, p less than .007) based on Further investigations need to investigate the possibility percent improvement in the HRSD. An that the clinical response to the treatment with tricyclic ANCOVA using baseline scores as drugs depends on the capacity to N-didesmethylate it. covariates yielded a similar result. References Della Corte L. et al.: Br. J. Psychiatry, 134, 390, 1979 Sgaragli G.P. et al.: Psychopharmacol. Bull., 20,165, 1984 Cattedra di Clinics Psichiatrica e Centro [nterdipartimen- tale dei Farmaci Psicotropi - Universit~ di Siena (Italy) 31.02.58 31.02.59 GBR 12909: A SELECTIVE DOPAMINE UPTAKE MODE OF ACTION AND DOSE FINDING OF INHIBITOR AND POTENTIAL ANTIDEPRESSANT. SERTRALINE, A NEW ANTIDEPRESSANT BASED ON *Erik B. Nielsen, *Peter H. Andersen, **M. CEEG-BRAIN MAPPING TECHNOLOGY Geoffroy and **O.J. Rafaelsen § Turan M. Itil*, Sukdeb Mukherjee*, Gulay Dayican**, GBR 12909 is a phenylsubstituted piperazine Gerald Shaw**, and Kurt Z. Itil* derivative which selectively blocks dopamine Sertraline hydrochloride is a structurally novel (DA) uptake (IC50=l nM; corresponding values compound, suspected of having antidepressant potential for NE and 5-HT uptake are 440 and 170 nM, due to its highly selective and potent 5HT uptake respectively). Ex vivo, in rats, GBR 12909 blocking properties. Doses wherein 5HT uptake inhibited DA uptake with an ED50 of 26 mg/kg blocking was demonstrated in-vitro have also been (ip, 2 h). In behavioral experiments, GBR 12909 shown not to elicit psychostimulant and/or ~mfi- caused locomotor activation and, at higher eholiner gic activity in animals. This Quantitative doses, stereotyped behavior. However, the drug Pharmaco-EEG (QPEEG) study, incorporating computer- failed to substitute for the cueing properties analyzed EEQs (CEEG), was conducted with healthy men of d-amphetamine (AMPH) in animals trained to to investigate the Central Nervous System (CNS) effects discriminate AMPH (I mg/kg) from saline. On the of single doses of 50, 100, 150 and 200rag sertraline in converse, AMPH substituted for GBR 12909 in humans. The study was double-blind, single-dose animals trained to discriminate GBR 12909 (i0 crossover in design and included both placebo and an mg/kg) from saline. The GBR 12909 cue was active drug (50rag amitriptyline) as controls. The blocked by raclopride (D-2 antagonist) and by objectives of the QPEEG study were to establish the SCH 23390 (D-I antagonist) indicating DAergic lowest tolerable CNS- effective single dose, determine mediation of this cue. Furthermore, GBR 12909 the mode of action and predict the therapeutic ~ndow was active in a learned helplessness paradigm of sertraline. The results of this study indicated that when given in low doses (2 x 3 mg/kg) for 5 sertra]ine has both time and dose-related CNS effects. days, an effect which may predict antide- Comparison of the CEEG changes IIZI Research Center's pressant action. Thus, the behavioral conse- CEEG Drug Data Base indieated that sertra]ine has a quences of DA uptake inhibition may be re- significant positive correlation with Data Base anti- flected in motor activation without concurrent depressants, with 100rag having the highest correlation stimulant euphoria. Such action may be benefi- coefficients. The optimum CNS-effective single dose of cial in the treatment of depression. sertraline wb/ch can be differentiated from placebo at *NOVO Industri A/S, Departments of CNS and the level of statistical significance was found to be Biochemical Pharmacology, DK-2880 Bagsvaerd, 150mg. It is predicted that this w~ll also be the most Denmark, **Psychochemistry Institute, Rigs- effective therapeutic antidepressant dose. Brain hospitalet, DK-2100 Copenhagen, Denmark. .~lapping of sertraline is similar to other 511T-blocking * Deceased. antidepressants. Multicenter clinical trials seem to confirm the CEEG prediction. *New York Medical College, Div. of Biol. Psychiatry, !50 White Plains Road, Tarrytown, NY 10591 (USA); **Pfizer, Inc., Groton, CT 06340 (USA) 281 31.02.60 31.02.61 CLOMIPRAMINE AS A SEROTONER~IC PROBE RITANSERIN IN DYSTHYMIC DISORDERS (DSM III): A by J.J. L6pez-Ibor Jr., A. Gonz~lez-Pinto DOUBLE BLIND STUDY ~ERSUS AMITRIPTILINE G__t. Meco r S. ~inl, L. Mariani, V. and J. Saiz-Ruiz Pasqualoni. Ritanserin is a new selective seroronin 2 O f the tricyclic antidepressants clomipramine receptors antagonist In previous studies (CMI) shows the highest blocking activity on the Ritanserin showed clinical efficacy in anxiety, tension states and dysthymic reuptake of serotonin, which is purer when it has disorders (DSM III). Ritanserin (iO- 20 mg ) not yet been metabolized into demethyl-clomipramine. and Amitriptiline (25-50) were administered to 30 patients suffering from dysthymic disorders For this reason CMI can be used as a serotonergic in a double blind study for 8 weeks. The probe when administered intravenously, when its effects results obtained showed comparable improvement of anxiety (Hamilton Rating Scale for Anxiety, are measured shortly after its administration STAY Xl) and depression (Hamilton Rating Scale and when the concentrations of CMI and its metabol- for Depression). The antidepressant action of Ritanserin was more rapid than ite are measured. The technique consists of the amitriptiline; in fact at second week administration of 12.5 mg of CMI in a hundred cc Ritanserin was more efficacious in i statistically significant way ( Mann-Whitney U saline solution during 15 minu:es and measuring Test p 31.02.62 31.02.63 SLEEP STUDY OF FLUOXETINE (F) AND AMITRYPTILINE FLUOXETINE (F) AND AMITRYPTILINE (A) : COMPAP,-~, (A) IN THE TREATMENT OF MA3OR DEPRESSIVE TIVE EFF1CACY IN THE TREATMENT OF MA3OR DISORDERS MDD. DEPRESSIVE DISORDER (MDD). M. Kerkhofs, P. Linkowski? C. Rielaert, M. Czarka, C. Rielaert, P. Linkowski, M. Czarka. M. Kerkhofs1 3. Mendlewicz. 3. Mendiewicz. Thirty-lout patients suffering from MDD (RDC) were ~nirty-four patients suffering from MDD (I~DC) were enrolled randomly in this double blind parallel study. The enrolled randomly in this double-blind parallel study. study was divided into two periods : a placebo period Logistic regression analysis was used to examine the of I0 days and an active treatment period of ~2 days. effe~s of treatment) gender and age groups on the Admission procedure included sleep EEG on three conse- following parameters : clinical global severity (CGS), cutive nights (two accomodation nights and a third patients global impression scale and Covi scale. The recording night). The termination of the study included scores at visit 2 (baseline) and last visit (endpoint) were sleep EEG (one recording night). Sleep data was analysed In~uded in the analysis. No significant differences in the using a one way anova with post-hoc Least Significant therapeutic response between F and A were observed, Difference tests. The findings can be summarized as follows gender and age being controlled. Analysis of variance Overall F A (.&nova) was performed on baseline, endpoint and endpoint Sleep efficiency NS ~,IS I~S minus baseline differences for Hamilton Depression (HDFLS~ Number of Stage p-0.01 p-0.01~" NS and Montgomery-Asberg (MARDS) scores. No significant Number of e~fect was shown for these parameters in the two groups awakenings NS p-0.0 I'~ NS Further comparison by paired t-test was computed for Sleep Architecture endpoint to baseline differences only, within each treat- Awake p-0.0t+ NS NS sent group and within each sex group. As expected there Stage 1 NS p-O.O04 "~ NS was a significant decrease in both the HDRS and MADRS Stage 2 p<0.001 p-0.02 ~" p-0.002~ for the whole population (p 282 31.02.64 31.02.65 BRAIN INDICATORS OF THE EFFECTS OF ~AFROTiLINE ~"qIE EFFECTS ON MEMORY OF ANTXDEPR~SSANTS WITH M. Ih~i~ica~0 Horta t J. Barahona da F0nseca~ Silvia DIFFERING ANTICHOLINERGIC AF~ SEDATIVE PROFILES 0uakinin and J. Sim~es da Fonseca H. V. Curran, M. Q. Sakulsripon~ and M. H.Lader Al~hou~h Event Related Potentials of the Brain have The effects on memory and psychomotor functions of been %ridely used as indicators os effects induced by antidepressants with varyin E sedative and anti- psycho pharmaco, those changes they u~dergo have not cholinergic properties were assessed in two studies yet been taken into account as far as their status as with healthy volunteers. In the first independent ep!s~emlc correlates of psychological processes is ~roup study, 90 subjects were given a single dose of concerned. amitriptyline (37.5, 75 mE) , ~razodone (i00, 200 mg), We have chosen as Brain indicators os the effects of viloxazine (i00, 200 mg), pz'otriptyline (I0, 20 m E) Maprotiiine in acute oral administration both in nor- or placebo. Only the more sedative antidepressants mal volunteers and in patients suffering From Disthy- (amitriptyline and trazodone) impaired performance mic Dosorder, the Power Spectrum 0s visual ERPs evoked and these compounds had globi~L1 effects on tests of by distinct but interrelated visual patterns. attention, motor speed and primary memory. Although An interpretation os the effects of M~protiline is pro the amitriptyline and trazodone impaired episodic posed in terms os (a) changes in visual pattern discri memory, the effect of smitrip~line was significantly ruination; (b) form/tion of classes of equivalence; (c~ greater and this may reflect specific anticholinsrgic coherence values; (d) Reaction Times, establishing a action over and above global sedative effects. connection between those changes and the characteris- Tolerance to the effects of amitriptylins and trazodone tics of the Cognitive Set and Mode, is attempted as was assessed in a second study administering these signi.micant differences were found, concernin s those drugs and placebo over a two-'~eek treatment period. tour types 0s indicators. Institute of Psychiatry, De Crespigny Park, Dept. of Medical Psycho~gy, Faculty of Medicine o9 London SE5 8AF, U.K. Lisbon, Hospital Sta. Maria, 1600 Lisboa, Portugal. 31.02.66 31.02.67 FLUVOXAMINE IN DEPRESSED IN - AND OUTPATIENTS: ATTEMPT OF ASSESS THE PREDICTIVE VALIDITY OF DIFFERENTIAL EFFECTS, PLASMA LEVELS, RESPONSE LABORATORY PERFORMANCE TESTS FROM THE PREDICTION RESULTS OF A SUBCHRONIC STUDY OF NEW AND M.#eZwaan, P.Hofmann, G.Sch6nbeck, G.KoiniQ, OLD ANTIDEPRESSANTS (I.E. LEVOPROTILINE AND H.Aschauer, P.Parzer. DOXEPIN, RESPECTIVELY) Fluvoxamine (F) is a new antidepressive drug H. Robbe, E. Schoenmakers and J.F. O'Hanlon with selective activity in inhibiting serotonin In so far as is known this presentation describes the uptake and is therefore possibIy different from first study where the attempt was made to correlate traditional tricyclic antidepressants (TCA) in drug effects on subjects' performance in a battery of clinical application. In our investigation we "typical" laboratory tests with those objectively treated depressives, mostly refractory to TCA, measured in a standardized actual driving test. The with F in two settings: inpatient care (n=10) purpose was not only to more fully assess the and outpatient care (n=23). Study duration was 4 psychomotor effects of an investigational drug weeks respectively 6 weeks. After medical check- (]evoprotiline 25 and 50 mg t.i.d.) versus those of an up, psychiatric diagnostic was performed accor- active drug control (doxepin 25 mE, t.i.d.) and placebo, ding to DSM III. F plasma levels, depression it was also to determine the validity of laboratory ratings (HRS-D, CGI, linetests) and side effect performance measures as predictors of drug effects on ratings were performed at regular intervals. All drixdng. patients were submitted to a TRH-Test at admis- Drugs and placebo were administered to 16 healthy male sion and at the end of the study. A special volunteers according to a subchronic (8 day), 4-way, checklist of behavior or functions putatively double-blind cross-over design. Performance was related to 5 HT brain activity was filled out assessed on days I, 4 and 8 in each subchronic series in (aggression, appetite, sexuality etc.). the laboratory and on the first and last days using the The general antidepressive effect was satisfac- driving test. The battery tests induced critical flicker tory in both treatment groups with prominent fusion frequency, continuous recall, critical instability anxiety reduction. Furthermore the following tracking, divided attention (subcritical tracking and possibly specific effects of 5 HT could be reaction time to peripheral stimuli), memory search and found: general appetite reduction, significant choice reaction time and sustained attention or weight loss, no negative influence on sexuality, %dgilance. The driving test measured road tracking no increase of aggressive traits, no orthostatic precision (standard deviation of the vehicle's lateral dysfunction. Adverse effects were usually mild position) during continuous operation over a I00 km (most commonly gastrointestinal) and of short primary highway circuit. duration. In line with previous findings blunted Preliminary results show differential drug effects on TSH response at admission was related to thera- driving performance and some of the laboratory tests. peutic response. F plasma levels showed great The results will be fully described with respect to the variability in relation to F dosage; no simple antidepressants' effects and also with regard to the relation could be found between F plasma levels correlations among different measures of these effects. and clinical outcome or side effects Institute for Drugs, Safety and Behavior, University of Psychiatrische Universit~tsklinik Wien. Limburg, P.O. Box 616, 6200 MD Maastricht, The WAhringer Gbrtel 18-20,A-IO90 Wien. Netherlands 283 31.02.68 31.02.69 gibcSemical, ~leurophysiological and Behavioral Effects PHARMACOKINETICS AND METABOLISM OF LEVOPROTILINE IN of Wy-45,233 and Other Identified Metabolites of the HEALTHY VOLUNTEERS Antidepressant Venlafexine W. Dieterle, R. Ackermann and G. Kaiser E.' A? Muth, J. A. Moyer, J. T. Haskins, and T. H. Andree The new antidepressant levoprotiline-HCl is the Seven metabolites of venlafexine,, identified in several R-enantiomer of racemic oxaprotiline.HCl. Its phar- species, were examined for CNS pharmacological activity macokinetic and metabolic characteristics were eva- in rodents. The O-des~ethyl compound Wy-45,233, which luated after single or multiple dosing in human sub- is {~e major metabolite in man, had the greatest pre- jects. clinical activity. This metabolite exhibited an anti- After a single 75-mg p.o. dose (N=6), levoprotiline was depressant profile (monoamine uptake blockade, reversal completely absorbed, Cma x in blood being reached at of reserpine hypothermia, induction of pineal ~adre- 4 h (median). The mean elimination half-life was 21 h. nergic subsensitivity) comparable to the parent drug, The drug was mainly excreted in conjugated form by the venlafexine. This compound also inhibited serotonergic kidney. Urinary excretion (0-96 h) of the sum of free and noradrenergic firing rates like the parent compound, plus conjugated levoprotiline amounted to 69% of dose but with less potency. The cyclohexyl ring-hydroxylated on an average. metabolite Wy-47,877 and the N-desmethyl metabolite After repeated daily dosing with 75 mg (N=6) for 15 Wy-45,494 were also active in reserpine hypothermia, but days, the kinetics of levoprotiline did not change. Wy-45,494 was a weaker inhibitor Of serotonin uptake and The accumulation ratio for the blood levels of levo- both metabolites were weaker inhibitors of norepinephrine protiline was 1.9, which corresponds to a 90% increase uptake than Wy-45,233. None of the seven metabolites of AUC during a dosing interval of 24 h at steady- tested exhibited significant binding at dopamine-2, mus- state when compared to the first 24-h interval. The carinic cholinergic, ~-l-adrenergic, histamine-i, or concentration-time profile after the first dose was opiate (u) receptors. These results suggest that described by a sum of 3 exponential functions (=Y). Wy-45,233 the O-desmethyl metabolite of venlafexine, is Using Y, the steady-state concentrations during an active metabolite which retains the benign side-effect multiple dosins were simulated. Experimental trough profile of venlafexine. levels on day 5, 8, 12 and 15 as well as the con- Wyeth-Ayerst Research, CN 8000, Princeton, NJ 08543 USA centrations after the last dose were very well com- parable to the simulated curve. Levoprotiline was extensively metabolized. Both in blood and urine, the direct O-glucuronide was the pre- dominant metabolite. Thus, levoprotiline may possess considerable advantages over the traditional antide- pressants: It can be anticipated that the disposition and kinetics are not significantly influenced by co- administration of enzyme inhibitors or inducers, old age, liver disease and genetic factors. Research and Development, Pharmacokinetics Division, CIBA-GEIGY Ltd., Basle (Switzerland) 31.02.70 31.02.71 ~ (IF FOOD C~ ~}]E RHIATIVE BIOAVAIIABIIATY CF ~IEs A ANTIDEPRESSANTS GI~N REPEATEDLY INCREASES TEE NEW ~ C~mASE-A (MAD-A) n~XBI~rm BEHAVIOURAL EFFECTS OF KETHOXAMINE AN ~-ADRENOCEPTOR M.-P. Schoerlin, M. M~ye_rso~, B. }{~=vp_Isand H. ~q~iers AGONIgT MDCI~ (RD 11-1163) is an effective anti-depressant drug which is a K ~edzonv. Z. Ro~oz. S. Skuza and J.MaJ rapidly acting, reversible inhibitor of the MAO-A isozyme. ~be drug ~ a relatively large systemic cleaz-ance (ca. 40 L/h) and trdergoes suh~tmutial Ye found previously that repeated treatment with first p~ss hepatic metabolism. Since food has been shown to influence the antidepressant drugs (~-D) increases the bebavioural oral bioavailabih'ty of drugs hmdng high i'mtmtic extractian ratios, ,,,e affects mediated by ~-adrenoceptors (e.g. clonidine emmuined the influs~-e of ameal cn m~lohemide absorption. Induced aggressiveness). In the present paper the Twelve healthy male subjects (23-47 yrs) ingested a single oral 100-u~ influence of AD given repeatedly on the behavloural tablet of moclcb~uide on 2 occasicns. On one study day, the drug was effects of methoxamlne, an ~-adrenoceptor a~onist, was ingested after an overnight fast and food wss withheld for 4 h ~ost- studied. Following AD were used: imlpramine dosing. On the other study day, the drug ",.as ingested after an ove_n~gbt (noradrenaline and serotonin uptake inhibitor), (+)- f~-t, b~t 30 rain after eating a standard meal (20% protein, 35% fat, m~d ozaprotiline (noradrenaline uptake inhibitor), 45% ca~te). ~fat meals w~re in~-tsd 4 and i0 h after dosing. ci~alopram (serotonln uptake inhibitor), mlanserin Blood s~ples were obtained for up to 12 h and plasma ccrmawtratic*ts of (without effects on amine uptake). Male u rats moclobemide and metaholites ~re d~.ermined by an HPLC met_hod. ~ue data (150-2508 ) were used. Methoxamine (25 and 50 ~g) a-~lyzed by nan~tal methods and tests of stetistical injected into the lateral brain ventricle increased the sipnif~ ~ ~rf~ using Student's p~ired t-test (a = 0.05 exploratory activity. The exploratory activity was cgnsidelx~ signlficmnt). ~ere %~re no significant differences in the measured in the open field test (total time of walking, mxir~n ~asm ox~atr~tion (C~x) ~d the time of its ~ (Trr~) number of sector crossings, rearing + peeping).AD give~ wh~u cc~ fasting (Coax, 753 rig/el; ~x, 0.71 h) and n~n-fasting repeatedly (10 m~/kg p.o. twice daily for 14 days) but c~diticns (C=sx. 643 rig/el; T~mx, 1.14 h). ~ere ~re no significant not acutely enhanced the effects induced by methoxamine differ~-~es in total areas l~der the c~-~z~tzatian-time curve (fasting, (all parameters mentioned above). Acute or repeated 1676 rig-h/el; ten-fasting, 1752 ng.h/ml) or in appprent oral cl~ treatment with AD did not stimulate the exploratory (fasting, 64.1 L/h; r~n-fasting, 62.9 L/h). q~e r~lative oral hioavail- activity of control rats. ability of moclolmm/de (food/no food) ~s i.i0 (+- 18% CV). [[here was a The present results support our earlier hypothesis carmiste~ ~ in ~ in the ~ of food (L77 h) which, alt:'-n,~ that AD (showing different pharmacological profiles) srsll, ~s signific~Ycly different fram the non-fasting ccrdition (1.60 given repeatedly increase the responses to ~1- h). There was no si~ificant diff~ance in AUCs ~ the v-~lues w~re adrenoceptor agonlst. corrected for t1~, b~t the ratio (food/no food) decreased to 0.98 (-+ 14% CV). institute of Pharmacology, Polish Academy of Sciences, We cc~cl~rle that food (at least the C~mlpositicn of the meal used in this 31-345 Krakow Smetna street 12, Poland study) has no influ~-,ce on the rate or campleteness of the gastrointesti- nal absorption Of noclobemide following a single oral 100-rag dose. Depsrtm~r~ of Clinical l~=~1~cology, F. Hoff.~=~-La Roche & Co. Ltd., Gr~iz~_her~ 124, C~-4002 Basel, Switzerland 284 3102 72 3102 73 ANTIDEPRESSANT DRUGS GIVEN REPEATEDLY INCREASE PARTICIPATION OF~R-ADRENOCEPTORSAND PROTEIN KINASE C IN THEOCI-ADRENOCEPTOR AGONIST AFFINITY THE RELEASE OF NORADRENALINEFROM CAT CEREBRAL ARTERIES M.R. de Sagarra~ G. Balfag6n, S. Arribas, M.T. Barr6s, V. Klimek and J. Ma~ M.i. Capil~a, and J. Marin Our previous findings indicated that antidepres- F~eld electrical stimulation (2 Hz, 0.3 msec) elicited an sant drugs (AD) given repeatedly increase the increase of the tritium efflux over the basal level from behavioural effects of phenylephrine, an~1-ad- cat cerebral arteries preloaded with tritiated noradren- renoceptor agonist. In this paper the competi- aline (NA). This efflux was reduced by clonidine (I HM) or tion of phenylephrine for 3H-prazosin (an O61-ad- B-HT 920 (I pM),~p-adrenoceptor agonists, and unaffected renoceptor antagonist) binding sites in the by yohimbine (i pM), an~p-adrenoceptor antagonist. The brain of rats treated repeatedly with AD was action of clonidine was b?ocked by yohimbine (I #M). studied. Phorbol 12-myristate 13-acetate (PMA) (3 pM), an activator Male Wistar rats {160-200 g) were used. AD show- of protein kinase C (PKC), potentiated tritium release ing different pharmacological profiles in an elicited by electrical stimulation without modification of acute experiment (imipramine, amitriptyline, spontaneous secretion, whereas 4K-phorbol 12,13 didecan- (+)-oxaprotiline, citalopram, mianserin) were oate (3 #M), an inactive compound, had no effect. Tritium given at a dose of 10 mg/kg ~.o., twice daily release evoked by tyramine was not modified by PMA. In the for 14 days. The binding of ~H-prazosin was mea- presence of PMA, the electrically-evoked tritium secretion sured in the cortex, thalamus and hippocampus. was reduced by clonidine (I pM) or by B-HT 920 (0.1 pH). The results indicate that the repeated treatment The presence of clonidine, B-HT 920 or yohimbine reduced with AD used enhances the ability of phenyleph- the action of PMA. The facilitatory effect of PMA was not rine to inhibit the binding of 3H-prazosin to increased by the Ca2+ ionophore A23187 (5 #M). These ~1-adrenoceptors (K~ values were decreased) in results suggest: (I) The existence of presynaptic autoin- the brain regions ss here. hibitory ~2-adrenoceptors in these arteries. (2) The The present data suggest that the increase in participation of PKC of perivascular adrenergic nerve end- the affinity of~1-adrenoceptors for their agon- ings in the exocytotic release of noradrenaline. (3) The ist is responsible for the functional~1-adren- possibility that P~ acts partially by interfering with ergic hypersensitivity found after the repeated prejunctional autoinhibitory~-adrenoceptors. (4) The treatment with different AD. effect of PMA is not related wYth Ca2+ influx produced by A23187. Institute of Pharmacology, Polish Academy of Supported by FISSS, CAYCYT 84/327 and CSIC DI/585 Sciences, Sm~tna Street 12, 31-343 Krak6w, Departamento de Farmacolog{a y Fisiolog~a, and Departamen- Poland to de Bioquimica, Facultad de Medicina, Universidad Aut6- noma, 28029 Madrid, Spain 31.02.74 31.02.75 EFFECTS OF CHRONIC AND ACUTE TREATMENTWITH DESIPRAMINE NEUROPHYSIOLOGIC.J~L EVIDENCE FOR ,~M~TIDEPRES~NT AND COCAINE ON THE MODULATION OF NORADRENALINE RELEASE - INDUCED SUPERSENSITIVITY OF HIPPOGAHPAL OC I- FROM CAT CEREBRALARTERIES BY PRESYNAPTIC~-ADRENOCEPTORS ADRENERGIC RECEPTORS S. Arribas, G. Balfag6n, M.R. de Sagarra, M.T. BarrOs, M. BIZ&AK M.I. Capilla, and J/Marin Cat cerebral[ arteries preincubated with tritiated norad- The effect of prolonged treatment with anti- renaline (NA) increased the tritium efflux over the basal depressant drugs on neuronal responsiveness to level upon field electrical stimulation (2 Hz, 0.3 msec). the ~-adrenergic receptor agonist phenyleph- fine was studied in tne rat hippocampal slice The ~-adrenoceptor agonists, clonidine (I HM), NA (lpM) preparation. and B-HT 920 (1 pM), reduced this efflux, whereas the In slices prepared from control animals (non- ~2-adrenoceptor antagonist yohimbine (I NM) had no effect treated or saline-treated rats) phenylephrine B-HT 920 was more powerful than the other two agonists in (0.2 and 20 pM) evoked a dose-dependent decrea- reducing tritium efflux. Methoxamine (1 ~M), an W1-ago- se in the spontaneous firing rate of CA1 layer nist, did not affect the action of clonidine, but'the neurons. An inhibitory reaction was also indu- effect of the later was blocked by yohimbine. Methoxamine ced by metoxamine (10 ~M)o The effects of phe- (1 pM) did not significantly modify the tritium efflux nylephrine and metoxamine were blocked by pra- elicited by the stimulation. Yohimbine (I ~M) had no zosin CO.Ol pM). effect, but tritium efflux was reduced by the drug at 5 pM. Phentolamine (i pM), and ~-adrenoceptor antagonist, Prolonged administration of imipramine, mianse- rin and (+)-oxaprotiline (10 mg/kg p. Oo, twice as well as prazosin, anKl-antagonist, plus yohimbine, i~ daily for 14 days) resulted in a significant creased the tritium release. The daily treatment with enhancement of the phenylephrine (0.2 pM) - desipramine (I0 mg/kg i.p.) or cocaine (10 mg/kg i.p.) during 12 days (chronic administration) blocked totally induced inhibition of neuronal spontaneous or partially the inhibitory action of clonidine upon the discharges in slices prepared 48 h after the stimulation-evoked tritium release, whereas the acute last dose of the drug. Only a slight potentia- (2 days) treatment did not produce any change. These tion of the phenylephrine-evoked reaction was results suggest: (1) The existence of presynaptic d2-ad- observed in the group treated with (-)-oxapro- renoceptors in these arteries, which modulate the NA tiline. release from adrenergic nerve endings. (2) The chronic The above data support the hypothesis that treatment with neuronal uptake inhibitors, such as prolonged treatment with antidepressants desipramine (a tricyclic antidepressant) or cocaine in- enhances the central o~-adrenoceptor function. duces a loss of sensitivity of 2-receptors, which facil- Polish Academy of Sciences, Inst. Pharmacology, itates the NA release. The time course of this effect, in 12 Smg~na st., Krakaw, Poland the case of the antidepressant, seems to be related with the onset of clinical activity of this drug. Supported by FISSS Departamento de FarmacologTa y Fisiologfa and Departamen- to de BioquTmica, Facultad de Medicina, Universidad Aut6- noma, 28029 Madrid, Spain 285 31.02.76 FLUOXETIRE VERSUS CLOMIPRAMINEIN ENDOGENOUSDEPRESSION AND MELANCHOLIA-MULT!CiNTRIC STUDY P. Moron, G, Besancon, G, Carrier, B. Cordier, A. Desiova~ni, R. Dufour, M. Ferreri, D. Ginestet, L. Leger, J. Pellet, E. Per~vier, L. Singer and G. Ulliac Efficacy and safety of fluoxetinewere studied on a two-month period, Fiuoxetinewas compared to clomipramiuein the treatmeutof patients suffering from severe endogenous depressive states and melancholia. All these patients were hospitalized. During the first month, patients were visited twice the first week, then once the following weeks during the first month and twice during the second month. The do~age wan flexible according to the severity of the depressive symptons: 2~ to 80 mg for fluoxetine, 50 to 200 mg for c]omipramine, Oxazepam was allowed as a~ annolytic. Several scales were used to measure drugs efficac?: -Hamzltun scale for depression (21 items), -~DRS, -Cov~ anxiety scale, -Widlocher-retardationscale, -Self-evaluation scales for severity of deprenniou and fur global evaluation. Results: -62 patients were enrolled, - 8 patients were excluded (no respect of inclusion criteria), -19 patients dropped out (reasons of drop out were similar in the twn groups). Therefore 50 patientswere treated during one month, 35 during two months. After two months of treatment, there is no difference~tween fluoxetineand clomipraminein terms ~f efficacy and tolerance, The global improvementis 68 % in the two groups on Hamilton; on MADRS scale, improve- ~ent is 75 % under fluoxetine and 72 % under clomipramine (this differenceis not significant]. After 4 weeks of treatment, clomipramine improves slightly retardation and anciety but after 8 weeks the hesults are equivalent under the two treatments. Although there is no significantdifference in terms of tolerance and side effects, ~ore patients under c]omipramine are suffering from constipation, dry mouth, dizziness and h?potennion. Under fluoxetine, the number of patients who experienced nausea was more important. No biological (hematologyand enzymology) abnormalitywas reported. In conclusion, fluoxetine is as effective and safe as clomipramine in the treatne~t of severe depressive states and mealancholia. 31.03.01 Prophylactic lithium treatment: response to treatment and patient attitudes toward illness and therapy POSTER St. Schmidt / W. Ludwig / E.SchmSlz / S. PRESENTATION Seibold / W. Greil Psychiatric Hospital of the University of 31.03 Munich (Head: Prof. Dr. H. Hippius) Based an the records of 80 patients with affective and schizoaffective disorders that were treated in the lithium clinic of our hospital, the course of illness before and during maintenance lithium Lithium and Carbamazepine treatment was analyzed. We tried to find out whether or not the patients' beliefs about their illness and its treatment are correlated with parame- ters of treatment response. The patients beliefs were assessed using a compliance self rating scale and an illness concept scale. Our results indicate that there are no correlauions between treatment response and the parameters "reliance on the physician" and "reliance on medication". Patients' beliefs about "susceptibility to illness,, however, were correlated with parameter s indicating low treatment response. Additionally, patients recei- ving concomitant treatment with neurolep- tics emphasized the unpleasant side effects of pharmacotherapy. 31.03.02 31.03.03 CARBAMAZEPINE: POSSIBLE CLINICAL ADVANTAGES OF A SLOW CARBAMAZEPINE VERSUS LITHIUM IN PROPHYLAXIS OF RECURRENT RELEASE FO~4ULATION IN PSYCHIATRY AFFECTIVE DISORDERS B. Tettenborn, G. Kr~mer, R. Besser, K. D. Stoll W. Bellaire, K. Demisch, K. D. Stoll Chronic carbamazepine (CBZ) administration or combined Recently preliminary results of one-year-prophylaxis in treatment with other anti-epileptic drugs leads to 98 patients with recurrent affective disorders, Eandomly auto- and/or heteroinduction of its metabolism with treated with either carbamazepine (CBZ, Tegretal K) or reduced elimination half-life and marked fluctuations lithium (Li) were reported and lead to the conclusion that of serum levels in spite of t.i.d, or even q.e.d. both treatments are globally comparablein effect (1,2): prescription. CBZ group Li-group number of 'patients 46 52' The pharmacokinetics of CBZ slow release (Tegretal 400 mean duration of illness 8,4 yrs 10,5 yrs retard) were investigated in comparison to conventional mean numberof episodes per year 1,5 1,1 CBZ (Tegretal 200) in volunteers and epileptic patients. mean number of episodes in the The slow release formulation revealed a pronounced year before trial 1,76(~I.06) 1,69(~I.02) delay of absorption associated with decreased serum peaks, thus resulting in a markedly lower fluctuation mean number of episodes during index even with a b.i.d, regimen. Clinical effectiveness the year of the study 0,67(~0.54) 0.73(t0.97) was equivalent to conventional CBZ. success rated at least good 41 pts(89 %) 45 pts(86%) tolerability rated at least good 44 pts(96 %) 45 pts(86%) These pharmacokinetic data hint to possible advantages in the clinical use of CBZ in psychiatry with There is data collection for a second year in the majori- - improved compliance due to ty of patients of this multicentric study. Results of - reduced side-effects and prophylactic treatment for two years will be presented - reduced number of daily dosages. with reference to similar controlled studies with CBZ, Li and/or placebo. Neurologische Universit~tsklinik, Langenbeckstr. I, Literature: D-6500 Mainz (I) Demisch K., PSYCHO 14, 88, 1988 (2) Stoll K.-D. et al. ]-6: New Direction in Affective Disorders (Lerer, D. and Gershon, S. eds.), Springer, in press Psychiatrie der Universit~ts-Nervenklinik D- 6650 Homburg (Saar) 31.03.04 31.03.05 CARBAMAZEPINE IN THE PROPHYLAXIS OF COMPARATIVE STUDY BETWEEN TWO GROUPS OF PATIENTS WITH AFFECTIVE PSYCHOSES. MANIC-DEPRESSIVE BIPOLAR DISORDER TREATED BY LITHIUM OR CARBAMAZEPINE. J.~VESTKA, K.NKHUNEK F. Rouillon~ M.B. Durand, T. LEMPERIERE University Psychiatric Department,Brno, ~SSR This study compares the quality of therapeutic results obtained with lithium and earbamazepine in 30 patients Carbamazepine /CBZ/ and Lithium with manic-depresslve bipolar psychosis (Bipolar disorder, manic or Depressed, in remission according to D.S.M. III carbonicum /Li/ were intraindividually criteria). The two groups of patients, sex and age. compared as prophylactic drugs in 24 pts. matched, are comparable as to their soeiodemographie and for a period of 460 days. The average d&ily clinical characteristics and the psychotropes combined dose of CBZ was 706 m E /correspondin G serum with their thymo-regulating treatment. The comparison has been made by one of us among those level 5.2 mikro~/ml/ and Li 835 mg /serum patients being normothymic since at least three months, level 0.52mval/i/. In comparision with Li and with mean lithium or tegretol plasma levels of the occurence of new phases was on CBZ 0,72 Z 0,12 meq/l and 7,5 ~ 2,2 ng/l respectively. signif, lower. There was no difference in The evaluation was based on the Comprehensive Psychiatric Rating Scale (C.P.R.S.), a checklist of side effects the dur@tion of phases and in the number and (C.H.E.S.S.) and a questionnaire on psychological lenghts of the hospital stay /Nilooxon experience of disorders wiewed by patient. test/. The average global score of C.P.R.S. has been improved Disapearanoe of the phases or lowering of in the Carbamazepine group and side effects were less frequent with CBZ than with lithium according to the their frequency was achieved in 62 percent C.H.E.S.S. list. The information from questionnaire also on CBZ and 50 percent on Li. shows trend in favour of Carbamazepine. However none of In an other study prophylactic efficiency these differences has reached a level of statistical of CBZ was compared with a combination significance, except for some items(reduced libido and inability to concentrate, diminution of physical CBZ+Li in 20 patients for 1 year. The capacities and activities, more important in lithidm combination CBZ§ was signif, better in group). shortening the lenghts of the phases and the necessary hospitalization. The number of phases didn't differ. Of the 9 quick cyclers 77 percent was favourably influenced on the combination CBZ§ In the ~hird part, prophylactic Li was compared to the combination L+CBZ. 287 31.03.06 31.03.07 2ROPHYLAXISFOF BIPOLAR DISORDER IN ELEDERLY: A The addition of Carbamazepine to lithium DOUBLE-BLIND STUDY WITH LITHIUM VS CARBAMAZEPINE. induces changes in Red Blood Cell (RBC) A. Lenzi, F. Lazzerini, D. Marazziti, G. Massime~ lithium. C. Udina, E. ~ivarez, R. Martln-Santos, J.M. ti, P. Lucarelli. Queralt6, C. Castillo, J. P4rez-Blanco, M. Several conflicting results have been reporetd on Casas. the use of Lithium for the prophylaxis of Bipolax Carbamazepine (CBZ) plus lithium has been Disorder in the elderly. Fro m a pharmacological suggested as an alternative in the control of point of view, Lithium is potentially toxic in nonresponder bipolar or schizoaffective patients A synergistic action between CBZ and lithium geriatric age. Furthermore, features of Bipolar remains unknown. In order to investigate possi- Disorder in elderly suggest to utilize Carbamaze- ble changes in RBC and lithium levels after addi pine.W~uthus comparedd the effeciacy and tolera- tion of CBZ, 9 patients diagnosed as bipolar max bility of Lithium and Carbamazepine in a group niac and schizoaffective disorders according to of 23 aged bipolar patients, in a double-blind DSM-III-R criteria with a past history of at 3 year trial. least 1 admission to Psychiatry ward and refrac- tory to lithium carbonate for the last 2 years Lithium was effective in 60% of the patients, were studied. There were 6 males and 3 females with no severe side effects. On the contrary, the aged 37+13, with a duration of the disease of group of'patients treated with Carbamazepine 9.8+6 years. RBC lithium levels were performed showed a high number of drop-outs and more severe before and after addition of CBZ. Comparison side effects. The low effectiveness of Carbamaze- was made using Wilcoxon paired t-test. RBC pine may be due to the high initial dosage, in- lithium levels after addition of CBZ dropped from 0.39+0.2 mmol/l to 0.27+0.1 mmol/l (z= dicating the need for a lower dosage of this -2.04, p<~.02). This difference remained signi drug in geriatric patients. ficant during the first 2 months (z= -1.98, Therefore, Lithium salts appear to be an effecti- p<0.02 and z= -1.66, p~0.05 respectively), but ve and safe therapeutic tool for the elderly, not at 5 and 10 months (z= -1:62, p<0.08 and even if they do required regular monitoring of z= -1.38, p<0.09). These results suggest an in serum levels and thyroid, cardiac and renal fun- teraction between CBZ and RBC lithium levels? A possible mechanism of such interaction could ction controls. involve the countertransport of CBZ across the Department of Psychiatry, University of Pisa, RBC membrane. Via Roma, 67, 56100 PISA (Italy). Department of Psychiatry and Biochemistry. Hospital Santa Creu i Sant Pau, Av. S.A.M. Claret, 167. 08025-Barcelona (SPAIN). 31.03.08 31.03.09 A COMPARISON OF CARBAMAZEPINE NORMAL FORMULATIOS PIAg~ ~TION ~ ~]N~(CBZ) AND I]~ -i0,Ii- EPOX]I~ (NF) TO TEGRETOL "DIVITABS" (DT). ME~ IN MANIC PATIO. ~R~_N!~dam, A.J.M. Loonen J.M. A~, G. l~*pesdli,~/h. Bottai and D. ~. Twenty hospitalfzed psychiatric patients, stabi- ~e relationshipsof plasma levels of holh CBZ and its -10,11~de lized on NF, completed an open, randomized, metabolii~ to dose ~ ~d clinical resDonse are still o~ntro- cross-over comparison of the kinetics, tolera- versial in literatlme. C~cemir~ the last point, if there is sane bility and efficacy of NF to the new controlled general 8~reement that plasma values of CSZ beb~een 5 and 12 microgr.lmL release formulation DT. The indications for ear- are widnin d~e dlerapeuticrange, Monaco et al (Neurology~5,9~5,1976) bamazepine (CBZ) were epilepsy, behavioural dis- found no relation~dp between plasma concentrationof the -I0,ii- epox- turbances and/or bipolar disorder. All but one ide metaboliteand clinical 8ntioonvulaivantresponse ~%ile Post et al patients received co-medication. Serum levels of (Ardu.Gen.Psychia~ 40,673,1983) su~ dgat the metabolite con- CBZ and of its metabolite carbamazepine-lO,ll- cen~raticn might be related to hhe degree of clinical efficacy in epoxide (EPO) were assessed during NF therapy affectively ill patients. and 3 weeks after a switch to DT. Serum samples In ord~ to confirm these data, we adTdr/steredCBZ to 18 manic patien~ were drawn just before NF or DT intake and 2, 4, fulfilling the ~ criteria for MAD, manic episode. Pallets had to 6 and 8 hours thereafter. From each day-curve have no charge in ~neir medical h-eah~e~t durin~ the two weeks pre- the following parameters were derived: area un- ceeding the initiationof active drug d~er~py. CBZ was ad~istered for der the curve (AUC), the quotient of maximum and en average of 30 days at an average dosage of 978 rag/day. Clinical res- minimum serum levels (Cmax/Cmin), and the fluc- pcrse was evaluated by mean of ~ Beigel-Murphyscale, the highest tuation index (FI = (Cmax-Cmin) x time/AUC). difference in rat~ between day 21 and day 0 reflectirgthe greatest Results: clirdcal improvemsut. - Cmax/Cmin is lower in 14 patients during DT Plss~ samples were ~ at day 21 (8~4) in order to evaluate pl~ with 9 mean reduction of 4.1% (p=O.131; Wil- ccncentraticllof both (]3Z and its -10,1/- epoxide metabolite which eoxon Matched-Pairs Signed-ranks Test). .e-~ured by ~ li~d ch~t~hy (~C). ~e ~=u~cy of - In all patients (N=9) with a Cmax/Cmin ) 1.30 the ~say ~s of the order of • 2% for both the dr~g ~nd the metabolite. on NF, this quotient is lower on DT. Mean plasma concentrationof CBZ ~s 7,6 +_1,92ndcrogr./mL (mean ~_ ED), - The FI is lower in la patients during DT with while the -10,]i- epoxide metabolite aver~ 1,58 ~l,OZmicrot~,/mL. a mean reduction of 16.3% (p=O.l12). We found a positive correlationbetween the daily dosage of CHZ ~nd the - The mean ratio AUCcbz/AUCepo is almost iden- plasm~ concentrationof beth C~Z (rs=O,518; p=O,05) and its metabolite cal for both formulations (NF: 21.6%; DT: (rs= O,6~38;p=O.01). A Dositive correlation~ also found between the 21.9%). plasma concentration of CBZ and d~at of its metabolite (rs=O,6~5;p=O.O]) - The mean AUCebz is 12.7% lower for DT. }~er, we did not find any correlation bei~eer~clinical response and - During DT therapy no changes in efficacy and plasma concentrationof both CBZ (rE -O,3;NS) and its metmbolite (r~= tolerability are observed. 0,043; NS). Our dal]a rand to indicate that plasma concentration of boltn CBZ and its Psychiatric Hospital Voorburg, P.O. Box 10150, -i0,ii- epoxJde metabolite reflect the da~ly du~a~e of the subs~ NL-5260 GB Vught, The Netherlands. but not the degree of clinical L~rovement. Clinique de Psychiatrie, C4J Tin.he, Rue Saint Pier-r~, F Ifi~ Mar~eille C6clex 5. 288 31.03.10 31.03.11 PHARMACOKINETICS ASPECTS OF LITHIUM TREATMENT EFFECTS OF CHRONIC LITHIUM TREATMENT ON M. Alda, H. Papezova, P. Zvolsky and D. Dufkova SEROTONIN RECEPTORS AND HYPOTHERMIC RESPONSE TO This is a summary of three studies carried out 8-OH-DPAT in order to evaluate possible factors which may Y__~. ODAGAKI, T_~. KOYAMA r R. MATSUBARA and I. influence both interpretation of values of YAMASHITA lithium levels and also power of predictive Serotonin (5-HT) receptors have been divided methods. into two types (5-HT 1 and 5-HT 2 receptors). More I. L. has frequently been connected with the recently, 5-HT I receptors have been subdivided risk of renal damage. Whether reversible or not further into multiple subclasses (5-HTIA, 5- it could lead to a change of i. elimination and HTIB, 5-HT I C , etc "") We investigated the effects to the risk of i. intoxication. The study of long-term lithium administration on the 5-HT included 29 patients starting I. therapy and 12 receptor subtypes and 5-HTIA mediated patients who had been on i. from 2 to 18 years. hypothermia in rats. The rate of elimination of i. was determined Oral administration of lithium carbonate for 3 and mean values in both groups were compared. w~eks did not alter [ H] spiperone or L. half life correlated slightly with age of [JH]ketanserin binding in cerebral ~ortex. On the subjects (r = .3), but there were no t~e other hand, the Bmax values of [ H]5-HT and differences between the short- and long-term [~]8-hydroxy-2-(di-n-propylamino)tetralin treated groups (ms=16.9_+9.1 and mL=20.2+8.0, ([~H]8-OH-DPAT) binding in hippocampus were p> 0.I). reduced significantly by lithium treatment 2. L. levels may fluctuate randomly and the without any change in Kd. Neither binding was extent of these fluctuations limits directly affected in cerebral cortex. Binding the information value of I. concentrations. characteristics of non-5-HTIA sites defined as Therefore, long-term course of steady-state specific [~H]5-HT binding in the presence of 100 levels was studied in 17 patients. An attempt nM 8-OH-DPAT were not altered in either brain was made to draw all samples in particular region. These results indicate that lithium patients under the same conditions (with treatment selectively down-regulate the 5-HTIA respect to the phase of illness, dosage of I. components of 5-HT I receptor s in hippocampus, and the daytime of collection). The value of but not in cerebral cortex. intraclass correlatiOn was r = 0.68, and it Subcutaneous injection of 8-OH-DPAT induced tells what part of variance is attributable to dose-dependent hypothermic response assumably between-subject differences, and also limits mediated by presynaptic 5-HTIA receptors. power of various predictive methods. Lithium administration for 3, 14, or 21 days did 3. As the course of i. levels can be charac- not altered the hypothermic response to 0.25 terized by various parameters, we were mg/kg 8-OH-DPAT. interested which ones are significant for the Department of Psychiatry and Neurology, Hokkaido description of I. kinetics. Computer simulation University School of Medicine, North 15, West 7, employing system of nested models confirmed Sapporo 060 Japan (among other results) that omitting the parameter of absorption usually does not lead to substantial deviations. 31.03.12 31.03.13 THE ACTIONS OF LITHIUM ON AGONIST-STIMULATED INOSITOL NEUROCHEMICAL AND BEHAVIORAL STUDIES OF LITHIUM PHOSPHOLIPID TURNOVER IN RAT CEREBRAL CORTEX ON SEROTONERGIC SYSTEM P.P. Godfrey, J. Swinswood and D.G. Grahams-Smith R. Yoshida and S. Yamawaki Lithium(Li) is widely used for the treatment of affective Since the initial observations that lithium ions inhibit disorders, but the mechanism of action of Li is unclear. In the enzyme Inositol monophosphate phosphatase there has the present study we investigated the effects of Li on seroto- been considerable speculation that the action of lithium nergic(5-HT) system; pre- or post-synaptic function and on Inosi~ol phospholipid metabolism may explain its pharm- behavioral responses. acological and therapeutic effects (Berridge, M.J. etal, Pre-synaptic function of 5-HT neuron: Biochem. J. 20_~6, 587,1982). Although the effects of lith- L i treatment for 3 days signiflcantl~ increased the rate of ium on inositol monophosphate metabolism are well establl- 5-HT turn-over and the release of H-5-HT stimulated by high shed its actions on other aspects of the 'PI' cycle in K + in hippocampus, but not in frontal cortex. In hippocampus, brain are still unclear. Here we investigate the action of the same treatment suppressed the function of 5-HT auto- lithium on both lipid and inositol phosphate intermediates receptors on the 5-HT terminal, which control the 5-HT in rat cortex. release negatively. Cortical slices (SS0xS50 um) prepared from male Sprague- Post-synaptic function of 5-HT neuron: Dawley rats were preincubated for 60min at 37~ in Hrebs- Chronic Li treatment decreased the density of 5-HT1 receptor REPES buffer; 50 ul aliquots of packed slices were then in both frontal cortex and hippocampus. The same treatment labelled in 250 ul of buffer for 60 min with either 3H- decreased the density of 5-HT2 receptors only in hippocampus. inositol (SuCi/ml), 32P-phosphate (20uCi/ml) or 14C-cytid- The activit'y of 5-HT-sensitive adenylate eyclase, which is ine (1 uCi/ml). LiCI (0-30 mM) was then added, followed 10 coupling to 5-HTI, especially 5-HTIA receptors, was increased min later by the a~onist. Incubations ~'ere continued for by chronic Li treatment. On the other hand, the rate of up to 60 min and stopped with 10% perchlorie acid (inosit- phosphoinositide turn-over, which is coupling to 5-HT 2 recep- oi) or chloroform/methanol/HCl (32P and cytidine). tors, wa~ decreased by acute and chronic Li treatment. Inositol phosphates were separated by anion exchange chro- 5-HT related behavioral responses: matography and lipids by TLC. 5-HT syndrome(forepaw treading, flat body posture etc.) LiCI dose-dependently (ED50-0.8 mM, max. effect ~t 3 mM) elicited by 8-OH-DPAT, a 5-HT1A agonist, was enhanced by enhanced carbachol (1 mM)-~timulated IP I and IP 2 formation chronic Li treatment. Wet-dog shakes elicited by 5-HTP, though it did not affect IP levels and actually inhibited which relate to 5-HT2 receptors, were decreased by chronic the formation of IP 4. LiCI 3greatly enhanced CMP-phosphat- Li treatment. idate formation in the presence of carbachol (5-fold) and also had smaller effects on its own (1-2 fold increase); Department of Psychiatry and Neuroseience, Institute of a similar, though smaller, potentiation was seen in the Clinical Research, Kure National Hospital, 3-1 Aoyama-cho, presence of noradrenaline (300uM). Carhachol (imP) plus Kure, Hiroshima 737, JAPAN LiCI (iOmM) reduced the levels of S2P-PIP and 32P-PIP 2 following a 60 min incubation. We conclude that lithium greatly alters cerebral inositol phospholipid turnover. Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK. 289 31.03.14 31.03.15 LITHIUM INACTIVATES RENAL KALLIKREIN KININ SYSTEM LITHIUM:LONG-TERM EFFECT ON SEROTOI~IN METABOLISM C. Reinhard, A. Schlenker, H. Saner, G. B6nner, M. Marin-Grez, IN BP~AIN REGIONS P.Gross D.Ghoshdastidar end M.K.Poddar eTh-e'-{e~al side effects of lithium(Li) therapy are incomple- tely understood.These side effects characteristically in- Long-term exposure(for 7 consecutive days) of volve renal collecting duct functions.Kallikrein is a regu- lithium chloride ( 2.0-4.0 mmol/k~day, p.o. ) to latory enzyme produced and secreted by this same part of adult male albino rets(120-140 g) increased(a) the nephron.We therefore studied in patients(A) and ex- steady state level of tryptophan(29-53%),seroto- perimental animals(B) whether there is an interaction bet- nin(5-HT) (20-35%) and 5-hydroxy indoleacetic ween Li and renal kallikrein.We observed: acid (5-HIAA) (30-65%) (b) pargyline-induced accum- (A) in 14 consecutive patients suffering manic-depressive ulation of 5-HT_(50-120%) and declination of psychoses studied prospectively urinary kallikreinexcre- 5-HIAA(50-85%) (c) probenecid induced accun%alat~n tion(KE) was 267+70 U/day before and 118+40 U/day 14 days of 5-HI~A and(d) mitochondrial .v~a.O activity(26- after the begin~f Li therapy(p<.OS;amid~lytic assay of 36%) in brain hypothalamus(H) end pons-medulla kallikrein).In 14 other,unselected patients which had been (PM) .Extention of the period of treatment to 14 on chronic Li therapy for several years KEwas 94+30 U/day consecutive days with lithium chloride(LiCl) at significantly lower than KE of healthy controls:3T0+80 U/ a dose of 2.0r~mol/k~/day ~ailed to produce any day(p<.0S).Li treated patients had plasma Li concenTra- appreciable change in the above parameters of tions of .51+.08 mM/l.None had subjective or objective 5-HT metabolism in any of the brain regions. evidence of~nown renal side effects of Li treatment.ICE Administration of LiCI at a dose of 4.0 mmol/~/ measurements obtained by amidolytic assay correlated signi- day for 14 consecutive days, on the other hand, ficantly with those obtained by RIA.Li inthe urine did decreased the level of tryptophan(21-34%),5-HT not interfere with the kallikrein assay. (25-35%), 5-HIAA (12-20%, pargyl ine induced accumu- (B) in a polyuric rat model of Li treatment given over 11 lation of 5-HT(24-36%) and declination of 5-HI~A daysCplasma Li concentration .44+.03 mM/l)KEwas 1.26+.08 (20-34%) and orobenecid induced accumulation of ~/day during baseline and .45+.0TU/day on day 11 of L~ 5-HIAA(20-35%) in H, striatum(S)and PM.But the treatment(n=24;p<.05);KE on d~y 11 of sham treated control: MAO activity was increased in these regions un~ 1.46+.12 U/day.This decline of KEafter Li applied eompa- similar conditions. Further prolongation of rabl~to measurements of active and total kallikrein.More- treatment with LiCI (2.0 and 4.0 m~ol/k~/day, p.o) over renal cortical tissue kallikrein was .4+.04 mU/g pro- for 21 consecutive days produced greater effect tein(n=12)in Li treated and 1.24+.18 mU/g in-control rats on the above parameters in H,S and PM of rat on day 11(n=6;p<.05). brain regions. These results suggest that LiCI Conclusion:Low therapeutic lithium concentrations in produces differential action depending on its plasma inactivate the renal kallikrein kinin system by dosage and the duration of treatment in seroto- direct inhibition of connecting tubule cells.This functio- nergic activity in brain. Purther it may also nal alteration occurs prior to any overt side effects of be stated that these long term effects of LiCI lithium but may be related to them. on serotonergic neuronal activity is specific Departments of Medicine and Psychiatry,University of Hei- to brain regions. delberg,Bergheimerstrasse 56 a,D-6900 Heidelberg,FRG Department of Biochemistry,University of Calcutta 35 B.C.Road, Calcutta 700 019, India. 31.04.01 REVERSE SEASONAL AFFECTIVE DISORDER (RSAD) WITH SUMMER DE- PRESSION AND SPRING HYPOMANIA: A PROSPECTIVE STUDY M. von Bose, M. Zaudig, J. Zulley, W. Schreiber, K.M. Pir- ke, H. Emrich, W. Mombour POSTER In recent years, there has been an increasing number of case reports of patients who regularly become depressed in PRESENTATION winter (Seasonal Affective Disorder: SAD), a condition that responds to treatment with light. In 1987, Wehr et 31.04 al. published 12 case reports of patients with a reverse seasonal pattern: these patients become depressed in sum- mer and euthymic, hypomanic or manic in winter. In addi- tion, most patients spontaneously reported a correlation between a rising environmental temperature and the onset of depression. To our knowledge, uptil now no study has systematically correlated environmental temperature (and Treatment Approaches for related variables) with the course of the illness. lhe M~x-Planck-lnstitutefor Psychiatry has since Septenber1987 Mania and Rapid Cyclers followed a 46-year-old female patient with 10 yearly episodes of surmer depression and regular spring hypo~ania. Ibis patient is a non-respon- der to Lithi~n and Tricyclic Antidepressives. Part of the prospective study was a systamatic and periodic asses~nt of envi,~L~tal, chrono- biological and neuro-endocrinological variables believed to attribute to or depend on psyr3zpathological changesthroughout the course of the illness over one year. W~ obtained daily recordings of the follow- ing ~mvir~mmrrtal factors: meantemperature, meanduration of sin-shine, daylength, meanair hunidity, mean barcmetric pressure and mean light intensity. Chronobiologicalasses~rB~ts included periodic polysome- graphic sleep recordings,EEG, EOG, heart rate and mstor activity. Periodic neuro-~ntcrinologicalprofiles (T3, B-FbA, MDPEG; basal Corti- sol, TRH, Dexam~C~asone-Suppm_ssionTests, {~d~ostasis-Tests,Gonado- tropin secretion,~xual hormones,etc.) were aimed at detectingfrac- tional disturbancesof the HPA-, FPT- and ROG-axes - again with respect to changes in psychopathologicalvariables over the course of 1 year. 290 31.04.02 31.04.03 USE OF VERAP~IL IN SE\~RE ~NIC EPISODES. CLONIDINE FOR ACUTE MA,~IIA A. Russova, D. Toschi, A. Lenzi, D. Marazziti. p.G. JANICAK, R.P. SHARMA, 3,M. DAVIS, et aL Several experimental and clinical data indicate Since some have reported that clonidlne may have the effectiveness of calci'~ blockers in mania. antlmanic properties, it would be of great theoretical Our study aim was to inves%igate the tolerability significance to confirm this in light of cIonidine's ability and possible use of Verao~mil in the treatment of to reduce NE synthesis. Further, if clinically effective, patients affected by severe manic episodes. employing clonidine could avoid the use of antipsychotics Fifteen felame patients wi~h a manic episode so which may cause NMS and/or TD. We are conducting a double blind study in which acutely ill manic patients severe that they had to be hospitalized, were receive either clonidine or placebo. After giving included in the trial. The diagnoses were: manic informed consent, 20 patients have completed a washout episode (n. 13) and mixed episode (n. 2). Verapa- phase (mean = 6 days) and then received either placebo or ~il was given at the initial dosage of 240 mg clonidine (up to .g rag/day). Patients were evaluated with thre times a day. Then, the treatment was modi- the BPRS and the Young .'4ania Scale (YMS) at baseline fied according to clinical response and tolerabi- and days 1,2,3,7,10,It+ or when dropped from the study because of significant worsening of symptoms. More lity. Anamnestic data, s vrptoms and side effects patients" in the clonidine group failed to complete the of the drug were evaluated by the con~non psycho- study (primarily due to rash or hypotension) than did those pathological rating scales CAPDI, BPRS, CGI, on placebo. An end point analysis was used to include DOTES, TWIS, PTR). All the patients showed an values in those patients who did not complete the I~ day improvement of manic sy~ptons from the third day trial." The BPRS and YMS change scores were analyzed by of treatment. However the initial dosage was a repeated measures analysis of variance. There was virtually no differences in improvement based on the inable to control all the s~ptomatology and we BPRS or YMS in the clonidine versus the placebo treated bad to increased it and to add neuroleptics in groups. The main effect of clonidine versus placebo all the cases. This associazion showed to be well yielded (F = .03, df = 2/17, p = .97). The BPRS clonidine tolerated. versus placebo difference yielded (t = .23, p = .$2) and the This study confirms the effectiveness of Verapa- YMS change score difference for clonidine versus placebo yielded (t = .03, p = .97). To our knowledge, this is the mil in mania, with earlier effects respect to first report of a double blind, placebo control trial using Lithium and sinergic effect with neuroleptics. In clonidine as an antimanic agent. Based on our findings, addition, it suggests the possible use of Verapa- we would conclude that clonidine produces exactly the mil also in natients with severe manic episodes. same clinical effects on mania as placebo and that the Department o~ Psychiatry, University of Pisa, doses used (0.2 to 0.8 rag/daY) caused significant side Via Roma, 67, 56100 Pisa (Zzaly). effects. 31.04.04 THYROID FUNCTION ASSESSED BY TRH TEST IN RAPID CYCLING BIPOLAR PATIENTS AND THE CHOICE OF TREATMENT. Maria Knsalic Rapid cycling is the most malignant form of bipolar illness. It was already described in the premedication era predominantly among females. Thyroid function is involved in rhythmicity, e.g.: rats rendered experimentally hypothyroid show behaviour similar to that of rapid cyclers, and their behaviour normalizes on treatment with thyroid hormone. Furthermore, 50 to 60 Z of bipolar rapid cyclers are hypothyroid. TS~ is elevated in 92% of rapid cyclers compared to 32% of non-rapid cycling bipolar patients. Hypermetabolic doses of thyroid hormone stabilized rapid cyclers into a euthymic state. It also appears that any psychotropic medication other than mood stabilizers can induce rapid cycling in bipolar patients. Ten patients fulfilling Dunner's criteria for rapid cycling were investigated. Five of these (3 women, 2 men) were hypothyroid. The other five were euthyroid according to the TRH test. In some patients, we measured free T-3 to assess true thyroid state as it has been reported that some depressed patients have low free T-3 akin to that found in the euthyroid sick syndrome. Thyroid therapy normalized 80% of the hypothyroid patients (2 women, 2 men); the third woman continued rapid cycling. One euthyroid patient responded to treatment with carbamazepine. Another, after failing on carbamazepine, responded to elonazepam. A third euthyroid patient withdrew from the study. The fourth has just started treatment with carbamazepine. The tenth patient is in the process of being investigated. St. Mary's Hospital, McGill University, 3830 Lacombe Ave., Montreal, PQ, Canada, H3T IMb. 291 31.05.01 ~'~ITRYPTILINE AIYD SLEEP PATTERN IN HEALTHY N~LES POSTER The following chan~es of sleep parameters have PRESENTATION been described in healthy subjects after amitry- 31.05 ot~line: inerease of deep sleep,reduction of P~EM sleep,decrease of R~ activity. 5 physically and mentally healthy males / 27-42 years / were studied. Sleep and Sleep Disorders The poly Differences between ~hese two patterns of sleep were studied. The results were analysed with Student's t-test and k~[N rule method of classifying objects. The results of the Luvestigation were discussed. Psychiatric Hospital,Kraszewski str. 25, 50 - 226 WrocZaw,Poland. 31.05.02 31.05.03 THE I~LUFNCE OF A~IT>YPTILIh[E ON L~I~ AND OTHER THE EFFECT OF BARBITURATES ON EEG FREQUENCY PJ~ SLEEP E ARA~ETFRS IN ~IPOLA~ DEPRFSSION. SPECTRA IN RATS W . Jernajczyk J. Plevov~, J, Form~nek Parameters of RE~ slee p were measured in lO Multiple time series of the voltages in the endogenous bipolar depressive drug tree patiens delta, theta, alphal, alphay, beta I and and on 7th day of amitryptiline treatment. beta 2 frequency bands were measured in rats Each subject was examined during two consecuti- using the implanted epidural electrodes and ve nights before treatment and two nights dur- a hybrid electronic system. The generally ing amitryptiline treatment.The following com- known changes of the EEG signal after the ponents of R~ sleep were studied: 1.REM time, narcotic doses of barbiturates were repli- 2.REM latency,3.Rl~ activity, ~.REM density, cated and described quantitatively. It was 5.Time of interruptions during P~EM, 6.Latency possible to show using factor analysis /prin- of eye mdvement/LE~/. cipal component model/ that two factors de- The results obtained were largely assessed by termine the majority of the total variance Student "s t-test.Moreover the neerest neighbor of the voltages in the six frequency bands ms decisionrule /NNrule/was s;plied. measured before, during and after the bar- The increase of: REM latency /0.O18 / , biturate narcosis. REM density / O.OO1 / , Chair of Clinical Pharmacology,Postgraduate L~m lO.Ol~ I Medical Institute and Institute of Hygiene were found during amitryptiline treatment and Epidemiology, Vfdensk~ 800, pay. B-3, Prague 4, 140 O0 Czechoslovakia Institute of Psychiatry and Neurology,II Psy- chiatric Clin. al. Sobie~iego 1/9 02-957 qarsaw, Poland. 292 31.05.04 31.05.05 TNE EFFECTS OF TRIM1PRAMINE ON DERRESSIVE SLEEP MELATONIN MODULATES THE ~ITANSERIN-INDUCED SLEEP CHANGES DISORDERS : A MULTICENTER OPEN STUDY. PiEMOINE. J.MOURET. IN THE RAT F. RAFFAITIN C. DuKovlc and A. Wauquier In humans, the selective serotonln-S 2 antagonist rltan- Six hundred and seventy four depressed outpatients (431 serin increases slow w~ve sleep (SWS) (stages 3 and 4). females, 243 males, age : 43 +/- 11.9 years) gave their informed I% has a more pronounced effect when it is given in the consent to participate in a multicentric open study on the effects of morning than in the evening (Idzlkowskl et al., Brain Bes. Trimipramine, a tdcyciic antidepressant, on clinical assessments of 378, 164, 1986). In rats, the deep SWS (SWS2) promoting action of rltanserln has been shown after administration depression and measures of depressive sleep disorders obtained from during the light period (Dugovic and Wauquler, Eur. J. visual analogue scales. Pharmacol. 137, 145, 1987). Admission criteria included MADRS score > 21, clinical In a first experiment, we investigated whether the effects ratings and a check list of depressive symptoms allowing e of ritanserln in rats were modified by the light-dark multiclassification of depressive disorders (LEPINE). Moreover, cycle. Ritanserln (0.63 mg/~g l.p.) injected at the onset patients had to complain of sleep disorders. of the dark period produced no change in the amounts of Clinical assessments were performed at days O, 7, 14 and 28, SWS2 throughout the 24 h recording period. Paradoxical using COV/anxiety scale, MONTGOMERY and ASBERG Depressions sleep (PS) amounts were not modified during the dark per- Rating Scale (MADRS), SPIEGEL sleep scales. In addition, patients iod but were significantly increased in the subsequent had to fill 6ut dayly MOURET analogue visual scale concerning sleep light period. When injected daring the light period quality and morning alertness. ritanserln.induced a signls increase of SWS2 and Each patient was prescribed oral Trimipramine with dayly concomitant decrease of PS daring 8 h. In a second ex- doses ranging from 50 to 150rag (mean : 105 +/- 45 rag) periment, we examined whether melatonln would interact with the ritanserin-induced sleep changes. Indeed, me- The results showed a significant improvement of MADRS (days latonin secretion exhibits a circadian rhythm, night con- 14, 28 ) and COVl (days 14, 28 ). Whereas upon inclusion centrations are several times higher than the daytime insomnia was a prominent symptom : difficulties to initiate (98.9 ones. Melatonin alone injected 15 min before the light %} and maintain ((96.2 %) sleep and morning insomnia (87.2 %), onset (1 mg/kg i.p.) had no effect on the different sleep a clear-cut improvement took place during the study since the stages during the 8 h recording period. When combined percentage of patients who slept "perfectly" or "well" (0.8 % at day with ritanserin injected 15 min later (0.63 mg/kg i.p.), 0) reached 67.7 % at day 28. The subjective quantification on melatonln antagonized both ritanserin-lnduced SWS2 in- intra-sleep wake events dropped by 78.4 % during the study and so crease and PS decrease. was it for the estimated sleep latency. In conclusion, the SWS2-increasing property of rltanserin is only evident during the light period of the rat, when The conciusiorl of this study suggests a beneficial effect of the levels of melatonin are low. The fact that ritanserln Trimipramine on the sleep disorders of depressed patients. fails to induce any sleep changes in melatonln-pretreated rats lends support to the hypothesis that circadian vari- ations in melatonin co-determine the differential effects Unite Clinique de Psychiatrie Biologique, CHRS LE VINATIER, 69677 of ritanserin on sleep. LYON BRON, FRANCE Department of Neuropsychopharmaeology, Janssen Research Foundation, B-23~0 Beerse, Belgium 31.05.06 31.05.07 EFFECTS OF ETHYL LOFLAZEPATE (CM5912) ON SLEEP IN NORMAL SLEEP AND SLEEP APNEA IN THE ELDERLY HUMANS *Shingae T. **~hri Y. **Chiba S. **Matsumoto M. Y. Mizuki, N. Kajimura, M. Yamada, M. Tanaka and **Tanaka Y. **Nunomura A. and *Ohta K. K. Inanaaa Nocturnal sleep of 22 healthy aged subjects (aged The effects of 2 mg and 4 mg of ethyl loflazepate 68-88 yrs.) was examined polygraphically to reveal the (CM6912), a new anxiolytic benzodiazeoine, on sleep were sleep characteristics in the elderly. The sleep studied ~n 12 healthy male subjects. Polygraphic record- architecture and apnea during sleep of the elderly were ings were made for 6 consecutive nights from each subject. compared with those of 5 healthy young adults (aged 20-21 An inert placebo was given on the first 3 nights and on yrs.). the sixth niqht, and 2 mq or 4 mg of CM6912 was adminis- The results were as follows: tered on the fourth and fifth nights to 6 subjects, res- 1)Sleep architecture in the elderly was characterized by pectively. The drug and placebo were administered orally a prolonged TIB, a low SEI, a high ZSW, a high %SI and a 30 min after supper, and the record of polysomnoqrams low %SWS. started at 2230 hr and continued until the natural 2)Number of apnea during sleep in the elderly was awakening of the subjects in the next morning. The poly- significantly large(av. 20.6 per night) compared with somnograms were evaluated by comnuterized automatic ana- that of the young adults(av. 0.4). lysis usina the method of interval histogram. Both doses 3)There were a positive correlation between the number of of CM6912 ~ncreased total sleep time, and reduced sleep apnea and the amount of %SI, and negative correlation latency and total awakening time in a dose-dependent between the number of apnea and the amount of %S2. manner. Both doses slightly decreased stage 1 sleep, 4)There wa~ a difinite sex difference in the sleep significantly increased stage 2 sleeo, but slightly architecture and sleep apnea. The sleep characteristics decreased stages 3, 4 and REM sleep. These changes con- of the elderly was more pronounced, and the number of tinued into the sixth recovery night. No obvious changes apnea was larger in male subjects than in female subjects. were observed in subjective assessments after administ- These'findings indicates that the sleep in the elderly ration of CM6912. These results suggest that CM6912 is an is light and disrupted and that the frequent apnea might efficacious compound and has minimal adverse effects on contribute to these sleep changes, particularly in males. sleep. In addStion, findings of MSLT and daytime Dept. of Neuropsychiatry, Yamaguchi University School of psychological functionings will be presented. Medicine, 1144 Kogushi, Ube 755, JaDan * Sapporo Ohta Hospital,5-1,5-jo,Yamanote,Nishi-ku, Sapporo 063,Japan ** Department of Psychiatry and Neurology, Asahikawa Medical College, 4-5, Nishikagura, Asahikawa 078 Japan 293 31.05.08 31.05.09 ARE TWO GENETIC FACTORS INVOLVED IN NARCOLEPSY? EFFECTS OF MODAFINIL ~ AN ALPHA ! ADRENERGIC TYPE PSYCHOS- T. Pollm~cher, P. Geisler and H. Schulz TIMULANT ON THE SLEEP OF MONKEYS. C. MILHAUD ET D. LAGARDE The Human Leukocyte Antigen (HLA) DR2 or a closely Modafinil is a new psychostimulant molecule already succes adjacent gene is necessary for the development of sfully tested in the treatment of narcolepsy. Its active narcolepsy. We hypothesized, that there might be a mechanisms studies in mice evidenced a specific modulating subclinical form of the disease among DR2 positive (activating) action on central post-synaptic alpha ! adre- relatives of narcoleptic patients. As part of a study nergic receptors. METHOD - conducted at the Max-Planck-lnstitute of Psychiatry, we - Behavioral sleep of rhesus monkeys was observed in a compared DR2 positive and DR2 negative first degree first series of experiments using near infra-red camera relatives, which did not show any clinical symptom of recordings. 16 subjects were injected with 45 mg/kg, 12 narcolepsy, with respect to their sleep pattern during with 22.5 mg/kg and 8 with 12 mg/kg Modafinil. The Student- the Multiple Sleep Latency Test (MSLT). The only Fisher test for matched series was used. statistically significant difference between the two - In a second series of experiments the electrographic groups was a higher number of naps with sleep latencies recordings (ECoG) of 4 subjects were studied during chronic lower than 5 min in the DR2 negative group. administration (4d) of 22.5 mg/kg MODAFINIL and ECoG of 4 On the other hand 6 out of 16 relatives (38 %) showed more subjects were studied during acute per os administra- mean sleep onset latencies (mSOL), which in comparison to tion of 3, 6 and 12 mg/Kg Modafinil. normative values are suspectable or indicate daytime RESULTS - The percentage of total behavioral wake periods drowsinessl Four showed a mSOL between 5 and lO min and significantly increased compared to that observed under two subjects a mSOL shorter than 5 min. Five of these placebo conditions for the three tested doses (p 31.05.10 31.05.11 EFFECT OF DELTA SLEEP-INDUCING PEPTIDE (DSIP) ON A SLEEP LABORATORY COMPARISON OF LOKAZEPAM & FLURAZEPAM GROWTH HORMONE RELEASE (GH) IN VIVO IN RATS AS HYPNOTIC AGENTS IN CHRONIC INSOMNIACS E. Kawata, N. Kato, K. Tsunashima, A. Masui, D.J. McClure, J. Walsh, H. Chan@, A. Olah, R. wilson, S. Takahashi and Y. Aoki J.C. Pecknold DSIP originally isolated from rabbit serum, has Lorazepam 2 mgm and Fl~razepam 30 mgm were found to be been proposed to be a natural sleep-promoting effective and safe for treating chronic insomnia with substance. We have developed an assay for mea- lorazepam having more favourable effects on sleep than suring DSIP and have found the presence of the flur azepam. circadian rhythm of plasma/urine DSIP. Recently Eight chronic insomniacs aged 29-60 years were monitored DSIP is reported to increase GH secretion in in a sleep laboratory twice weekly for a total of 25 rats. It is thus possible that the peptide is nights in a 16 week double-blind cross over clinical involved in mediating sleep-induced GH release trial. The two drugs lorazepam and flurazepam were since the episodic secretion of GH occurs during given for 3. weeks each with 3 weeks of placebo between slow wave sleep after sleep onset at least in the drug periods and also after the second drug period. humans. In the present study the effect of DSIP Baseline values were recorded during a 2 week placebo administered intraventricularly on GH release period before the first drug was given. In addition was investigated in rats and compared with that subjective estimates of sleep, vigilance tests and of intravenous rat GH-releasing factor (rGRF). adverse effects were recorded. Male Wistar rats weighing 300-400g were used. Findings showed lorazepam performed better than Cannulae'were implanted into the third ventricle flurazepam in most sleep parameters. With lorazepam and into the right jugular vein prior to the there was improvement from baseline in percentage of experiment. Blood was dra~ serially before and sleep time (P<. 05) ; in total wake times after sleep after the peptide administration and plasma was onset (F(.01) and in last third of night (P<.05); in subjected to the assay for rGH (NIDDK). percentage of stage 2 (P<.05) (weeks I, 2, 3) and in Under hhe anesthesia with pentobarbital, DSIP percentage of night in stage 4 (weeks 2 and 3). Only failed:to induce an elevation of GH while rGRF total wake time from baseline improved (P<.05) with exhibited a potent effect. However, DSIP was f!urazepam (week 2). found to have a GH-releasing action in unrest- Objective and subjective sleep parameters did not rained, freely-moving rats. In comparison with correlate well for either drug and neither drug impaired rGRF, the action of DSIP appears to be slow, REM sleep or vigilance test performance. Side effects and less marked, but long acting with a peak at were few and none was unexpected. Neither rebound 60-min after the injection. insomnia nor early morning insomnia occurred with either The results suggest that DSIP exerts GH releas- drug. ing action indirectly to the hypophysis, which Some of the findings are in agreement with previous can be abolished under some non-physiological investigations others are not. The reasons for this are conditions. GRF seems to have a primary effect discussed. on the somatotrophs. The effects of P-DSIP and University of British Columbia, Department of anti-DSIP antibody will be discussed. Psychiatry, Vancouver General Hospital, Room 3150, 910 Department of Psychiatry, Shiga Univ. Med. Sci. West IOth Avenue, Vancouver, B.C. , CANADA V5Z 4E3 Seta Tsukinowacho, Otsu 520-21, Japan 294 31.05.12 31.05.13 EFFECIs OF ~ITANSE~IX ON CLINIC~ AX) s SLEEP VARIABLES IN )YSIHYH!C PATIENTS THE EFFECTS 0s CHRONIC RITANSERIN TREATMENT AND kffTHDRAWAL !:hi~: F.~rr_i~g!~6._.Ltug~i~= .E:_L_~rh 8: _L_arg_o_.._d J._Lu~._.t t_..,:_~g ON SLEEP. ~itansm-in ie ~ eelecHve 5-NT2 antag0ni~t ~hich ioocr~e.~ st~ wa~e sleep (.~NB) G. Hammond, C. Idzikowski t S. Burton and R. James in .noraal volunteer~. Several clinical studies show that this coagound is therapeutically ef..'ecti~e in dysthyek patio.ups, iepr0vir, g the depressive Previous studies have shown that 10mgs ritanserln, a 5-~T- sy=pt0ms as ~ell as the subjective sleep disturbances. 2 antagonist, increases greatly the duration of Slow Wave Therea0re, the hypothesis urines that the therapsuticil ~fects of ritanserin Sleep (SWS) (Idzikowski at al, Brain Research, 378, 164, ~re related to its $leep ieprcving qaatitiesl na~el,v to a speci;ic increase of 1986) and that this increase is maintained for at least ~gS. two weeks (Idzikowski et el, Psychopharmacology, 93, 416, ~, order te ts=A this hypoth.~sis, .e studied .~he eL%c~n ~ tiler:eerie i.~ a 1987). A dose-response study has also shown that Img sample of d isthyeic ~.~tiemts "-.n:;l)selected accordi.ngto ~ i11 criteria. ritanserin can increase the duration of SWS (Idzikowski et el, Sleep Research, 16, 83, 1987). This pilot study Fatie.nts ~ere given ,no eedicaii0n, except contraceptices, 2 -~-s prior t.n the extends those findings by examining the effects of 4 weeks baseline reccrdinI. Afterwards s the.* received a double-blind treat~en.t el[her ,ith ritaneerin (!0 ~B/day, p.o.) or =e,tching placebo during 4 ,ks. A sscond treatment with img ritanserin and also looks at the rec.nrdin~~s z:aded~ring the !est 7 days nf trset~e.nt. E~ch recording include,~ effect of withdrawal. Six healthy volunteers participated three nonse..utivenights. P0ligraphic variables sttldiedincluded EEG in four OF in this single-blind study. Subjects began with a one nine ch~nnel~c 2 E~G channsle~ EEG respiration and digital p~ise. ~e clinical ~eek placebo run-in, followed by 4 weeks treatment and then a 1 week wash-0ut, The sleep recordings made on evolution ,as *onitored ~ith p.~.*chiatri~ Fating scales ".'or anxiety and deprssion. Statistical co,~parisons~ers perfor=ed {or both c.q.ni:a! and sleep triplets of nights were scored using Rechtschaffen and ~,arieb'es, be(nre a.nd a~ter treatment, in the two groups of patients Kales. (rilanserin% .n=!i~ placebo~ n:iO),. (Times in minutes) Stage 1 Stage 2 SWS KEM Total Sleep FLitanserin tre.:t~entproduced en increase of -~;~8~-4 NRs ~ut ~he p~.-a~eters Baseline I0 273 62 95 446 related to s)e.~, ncntlnuib,,and RE~ s!eep ,~,erenot changed. Furthermore~ more Early drug 5 250 89 98 450 cycles of SWS ne:e ~hner.~d, F~sitiveand significant correlations ~ere found 1 week " 5 256 81 105 451 be~.~.ee.nthe i~row~ent of soce cli.n~cel variables and the increaae of S@S: both 2 weeks " 5 235 92 III 449 }n !he ritanseri.ngroup and in the total sample. ~itarssrin also changed the 3 weeks " 6 251 92 99 453 amoun~ end di~tributio.n of sees pha:~s events, ~.ith a clear e,;Fect on the 4 weeks " 5 259 85 102 455 occurence u( [-coeplezes. Initial withdrawal 6 259 73 Iii 454 These rl:'.-l!]ie~g~eS ~dth U!e i~y~ol{~esi.:that the there~euiicei properties ~{ One week withdrawal 8 281 53 99 462 =it=,:::;:i: ere :eiaied l:o i;,s e:;scte o.n aleep. r e~.pla~a'.'_i~ can poesi~i!. ~.e Found considering the role of ~e~::tonero_ic9~ti~a.s in the ~en~.ro"cF L~th sleep The duration of SWS increased significantly with rftanserin a~d mood. ]t is also ~_u~g~sted that a detailed a.na~ysie o~ phasic as,eats ~ay (F=4.7, df=23, 114, P 31.05.14 31.05.15 SLOW ~AVE AND REM SLEEP ARE ENHANCED BY RILUZOLE IN FREELY EFFECTS OF MOCLOBEMIDE (Re 11-1163) ON SLEEP IN HOVING RATS AND CATS. HEALTHY SUBJECTS J.M. Stutzmann , J.C. Blanchard and P.M. taduron Th. Reinertshofer R. Lund, E. R~ther, Rjluzole (2-amino 6-trJfluoromethoxyhenzothJazole, PK 26124 or 54274RP) is a drug that possibly interferes at the glutamate G. Laakmann neurotransmission. This drug protects animals against different The antidepressive effect of most antidepres- models of convulsions including those induced by glutamate Icy sant drugs is supposed to be connected with in rats or glutamic acid decarboxylase inhJbitors ip In mice and their REM sleep suppression. Mainly classical rats and those induced by maximal electroshock in mice ; it also ~AO-inhibitors cause a marked REM suppression. affects epileptogenic discharges in the kindling phenomenon in Moclobemide (M),a selective,reversible,and rats. Butin contrast withbarbiturates and benzodia~epines, it is short-acting (half-life about 2 h) inhibitor of ineffective against seizures induced by pentylenetetrazole, the type A MAC showed antidepressant efficacy, bicuculline or pJcrotoxin. Moreover, in biochemical models, it yet no suppression of REM sleep in depressed decreases the spontaneous release of glutamate, the release of dopamine induced by glutamate in the push-pull model in the cat patients,though REM sleep suppression was ob- striatum and the glutamate induced release of aspartate in served in cats in comparable doses.As an expla- rodent cerebellar cells. The present electrocorticographtc (ECoGI nation for this finding,the time of administra- study is dealing with the characterisation of the central effects tion and the half-life of M were discussed. of this compound : 1) on the sleep-wakefulness cycle in the rat In this study the influence of M on sleep para- and in the cat ; 2) on the ECoG spectral analysis in the rat, meters is compared to placebo was investigated using a fast fourier transform analyzer. Riluzo/e was given by in healthy subjects,especially the influence on oral route at 0.5, 1, 2 and 8 mg. kg-I in freely moving rats Ca=6 per dose). Duration of slow wave sleep (SWS) and rapid eye REM sleep after drug intake just before sleeping movement sleep (REM) was found to Increase in a dose-dependent time. manner from 1 mg. kg-1 (+10~, +46~, +52~ respectively for SWS ; Methods: 20 healthy male subjects (aged 22-44) +37~, +84~, +89% respectively for REM) at the expense of were included in the double-blind study (two awakeness (-12%, -27~, -36~ respectively). S~rS latency was drug groups: Group A: PPPV~'PP,group B: PPPPP significantly reduced from 2 mg/kg whereas the frequency of V%').Placebo resp. 150 mg M were administered at appearance of REM phases was statistically Increased. An increase of the power spectrum specially in the tetha (4-7 Ha) 10:30 p.m. Polygraphic sleep recordings were and the delta (~4 Ha) activities In the fronto-parietal cortex performed for 7 consecutive nights (lights off: was shown after 2mg. kg-I of Riluzole. In the cat at the single 10:30 p.m.,lights on 6.30 a.m.). dose of 2 mg. kg-1 p.o. Riluzole was also able to increase SWS and Results: Preliminary data do not show statisti- REM. Awaking effect of caffeine (an antagonist of central cally significant differences between placebo adenosine receptors) but not that of DL-amphetamJne (which and verum nights regarding sleep latency,REM- increases the release of biogenic amines) was blocked by the latency and duration of the first REM episode. hypnogenic effect of riluzole in the rat, thus the adenosine Summary: M in an effective antidepressant dosage hypothesis is plausible to explain its effect on sleep. Since Riluzole increases SWS but also REM, the present study supports does not suppress REM sleep in healthy the hypothesis that RJluzole might he of interest in the subjects.This result indicates that the anti- treatment of primary sleep disturbances related to effective depressant efficacy of a compound and REM sleep disorders and preliminar clinical studies indicate that Rilu~ole suppression are not necessarily connected. can improve negative symptoms in schizophrenic patients. RHONE Psychiatrische Klinik der Universit~t Mdnchen, POULENC SANTE, Centre de Recherches de V/try, 13 quai J. Guesde, NuRbaumstraRe 7, D-8000 M~nchen 2 94400 V]TRY SUR SEINE, FRANCE. 295 32.01:01 EFFECT OF THE ANTI-DEPRESSANTS ON ~-ADRENOCEPTORS AND ISOPROTERENOL INDUCED CYCLIC AMP ACCUMULATION IN C6 GLIONA CELLS POSTER T.Ebisawa.A.Noriya.Y.Watanabe,T,Higuehi and T,Yamauch~ The direct effects of chronic treatment with the anti- PRESENTATION depressants on the number of ~-adrenoceptors and the accumulation of cyclic AMP stimulated with 32.01 isoproterenol were studied on C6 intact cultured cells. The cells were treated chronically for 5 days with I0 -s M decipramine(DNI), imipramine(INI) or mianserine(NIA). Binding studies were performed with the radioligand [ 3 H]CGP-12177. These treatment did not induce the decrease in the number of fl-adreno- Receptor Studies ceptors nor the change of affinitY. On the other hand, chronic exposure(4 days) to DMI or NIA led to a decrease in isoproterenol-induced accumulation of cyclic AMP in a dose dependent manner ( 10-7~10 -s N). When the cells were cultured with ha!eperido!, the decrease in isopr~tereno!-induced accumulation of cyclic AMP was found only in the concentration of 10-bM and 5 Xl0 -a M. These result suggest that antJdepressants(DMI and MIA) directly act on the second messenger system without any change of fl-adrenoceptors when these drugs were administered chronically. In addition, the concentration of 10 -s~10-TM of antidepressants should be used for these kind of experiments because the change of the response of cyclic AMP with I0-s~ 10-aM was found to be not specific for antidepressants Department of psychiatry, SaJtama Medical School, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama 350-04 Japan 32.01.02 32.01.03 PLATELET 3H-CLONIDINE AND aH-IMIPRAMINE BINDING AUTORADIOGRAPHIC LOCALIZATION OF 3 H-IMIPRAMINE BINDING IN DEPRESSION SITES IN RAT BRAIN T.Takeda t T.Harada~ Y.Fujiwara, T.Yamalnoto and T. Tsuiimura , T. Aso, A. Himeno, K. Hayashida, S.Otsuki M. Hayashida, T. Tateishi~ Y. Nakane, M. Niwa*~ We measured both platelet all-clonidine ( a2- M. Ozaki* adrenergie agonist) and aH-imipralnine binding The quantitative autoradiographic localization of ~H- in 17 normal controls and 14 depressed pa- Imipramine (IMP) binding sites in the rat brain was tients (iS unipolars, 1 bipolar) without med- studiedusing a modified version of the technique used ication. An increase in the Bmax for aR-clonidine binding and a decrease in the Bmax fo~ the 3H- by Grabowsky et al.. Likewise localization of ~-5HT imipramine binding from depressed patients were binding sites in the rat brain were studied using a observed as compared to controls. There was modified version of the technique used by Rainbow positive correlation between the Bmax of the et al.. 3H-clonidine and aH-imipramine in normal cont- The areas of highest concentration of 3H-IMP binding rols, but no significant correlation between sites were observed within the dorsal raphe nucleus, these p&rameters in depressed patients.There was and the reuniens thalamic nucleus. These areas were significant positive correlation in all-clonidino also found to have high concentrations of 5-HT cell binding between the Bmax and the total score of body an~ 5-HT neuron respectively. Further, the dis- the Hamilton Depression Rating Scale in depressed tribution of ~H-IMP binding sites showed good cor- patients,'and between the Bmax and the age in relation withthat of 3H-5HT binding sites. normal controls. On the other hand,in SH-imi- i~ administered twice daily for 14 days caused a sig- pramine binding,no significant correlation was nlflcant . decrease in. 3 H-IMP binding sites in both the observed among Bmax, the total score for the dorsal raphe neucleus and the reuniens thalamic Hamilton scale and age. These data suggest that nucleus, but not in other regions. The decrease was platelet SH-clonidine and sH-imipramine binding observed 48 hours after the last injection, hut at 72 may represent different biological and clinical markers and that SH-clonidine binding may be hours the effect had disappeared. more dipendent on the clinical state of depres- sion than 3H-imipramine binding. Department of Neuropsynhiatry, Nagasaki University Department of Neuropsychiatry, Okayama Univer & School of Medicine 7-1 Sakamoto-machi , Nagasaki 852 sity Medical School, 2-5-1 Shikata-cho, Japan Okayama 700, Japan ~Department of Second PharmaCology, Nagasaki Universiy School of Medicine 12-4 Sakamoto-mchi 852 Nagasaki 296 32.01.04 32.01.05 PGE, FORMATION IN BLOOD PLATELETS FROM HEALTHY PLATELET MONOAMINE OXIDASE IN DEMENTIA OF ALZHEI CONTROLS AND SCHIZOPHRENICS MER TYPE H. Kaiya*, M. Uyematsu x, E. Idaka ~, M. Nozaki* U.Bonuccell~,P.Piccini,P.BongioannJ,A.Nuti,G.M. Abdulla & Hamadah(1975) first showed marked reduction in PGE, formation by stimulation of Pacifici,A.Muratorio ADP in blood platelets from schizophrenics, Platelet monoamine oxidase(MAO)abnormal~t~es ha- which was assayed by a silica thin layer ve been proposed as a marker ~n several neurops Z chromatography. This result is one of the bases ch~atric d~sorders. Some authors observed an ~n- of PGE, deficiency hypothesis of schizophrenia. creased platelet MA0 activity Jn patients with To confirm the hypothesis, we re-tested the study, using high performance liquid senile dementia of AlzheJmer type(SDAT), while radi ochromut ography ( radio -HPLC ) . others did not report s~m~lar f~ndJngs. The a~m All subjects including normal control and of present study is to verify these data,using a schizophrenics who were out-patients or in- d~fferent substrate and considering larger con- patients in the open-door station consented to trol and patient groups. We assayed platelet MAO this study. Platelet rich plasma was made from 9 activity by modified Belmaker et al.'s method, ml of blood containing 1 ml of 2.5% sodium citrate. In the first experiment, washed with benzylam~ne as substrate,~n 30(12 males and plate]ets were prepared by a gel filtration 18 females)drug-free SDAT patients. The diagno- method using Sepharose 2B. Uptake of [l-z~C] - sis was made on the bas~s of an extensive ser~es 8,11, ]4-eicosatrienoie acid by the washed of neuropsycholog~cal tests,neurological exams, platelets in the presence of ADP(0-50G-~M)-was and conf~rmed by CT. Twenty healthy subjects( 9 investigated. Metabolic products were determined males and II females)who had no evidence of neu- by a radio-EPLC. In this experiment no PGE, was detectable, but PGF, ~ was identified. The basic ropsychiatric ~llness served as age-matched con- corporated ratio was 0-1.3% for normal control, trols. We reported that the patients had a s~gnl and 0-0.03% for schizophrenics. In the second f~cantly(p 32.01.06 32.01.07 PLATELET SURFACE M~BRANE 5-HT BINDING SITES: MODULATION OCMPARISON OF 5-HT INDUCED SHAPE CHANGE ~,--CI~ 125I-LSD AND INVOLVEMENT OF G-PROTEINS; PRODUCTION OF MONOCLONAL BINDING IN HUMAN ~. ANTIBODIES. C. Brazell r S. J. M~lue and S. M. Stahl. K. S[ha, A. A. Sankar~ J. M. Wilkinson and N. Crawford Evidence suggests that the 5-HT receptor situated on human platelet membranes is analogous to the 5-HT 2 (3H)5-HT binding and displacement studies with highly receptor in the CNS (D. de Chaffoy de Cou~ccelies et purified platelet surface membranes have been carried out al., J. Biol. C~., 260, 7603, 1985). ~nerefore, the to further characterize the human blood platelet 5-HT platelet shape change and subsequent ag.~ticn receptor and transport systems. Additionally, 5-HT induced by 5-HT may provide a functional assay for dependent OTPase activity (i) has been measured, the 5-HT 2 receptors (M. Graf & A. Pletscber, Br. J. involvement of O-proteins studied using bacterial toxins Phazmac. 65, 601, 1979). Unfortunately, the effect of (1,2) and the role of some effeetors of membrane 5-HT on h%~an platelets is weak and reversible, which signalling investigated. As shown for spinal 5-HT binding makes t/he detezmination of sub-maximal s~pe change sites (3), the platelet surface membrane (3H)-SHT binding difficult. The present study describes the advantage states are subject to peptinergic modulation. This of using an analogue to digital converter (ADC) to feature is also reflected in changes in GTPase activity represent the degree of platelet shape c~nge in and in the sensitivity of some of the G-proteins to ADP- ribosylation. n~nerical fozm. ~3ne correlation of 5-H~ induced shape 5-HT bindin~ proteins have been solubilised from human 12~ige with platelet binding of the 5-HT 2 ligand, platelet surface membranes using digitonin (4) and -LSD, was then determined. H~an platelet samples (1-2 x 108 platelets/500 ul) were measured for shape purified further by affinity chromatography on 5-HT- linked to Sepharose 4B (5). Mice were immunized with change by a PA.D-4 platelet aggregometer (BiG-Data these proteins and the resulting ELISA and Wester~ blot Corp. ). 5-HT induced shape change in a dose dependent positive sera used in displacement studies with ( H)5-HT manner, EC50 1.8 ~M. IC50 values w~re obtained by and platelet surface membranes. Six hybridoma cell lines adding test drug 5 rain prior to addition of 5-HT (3 MM). Binding was perfozmed using 125I-LSD (2 rLM), have been cloned and the monoclonal antibodies produced specifically defined %&th ketanserin (i0 ~M). A partially characterised and used for further studies of the interaction of 5HT platelet surface membrane receptor single receptor population was found with a K D of i.i0 and transport complexes. + 0.12 nM and Bmax of 14.5 + 6.0 pm/g protein. i. Housley, D. et al. Biochem. J. (1986), 234, 737-740. ~mparison of IC50 values for inhibition of binding and shape change (potency series spi~ > 2. Aktories, K. et al. Nature (1986), 322, 390-392. ketanserin > RU 24969 > 80H-DPAT > sulpiride) showed a 3. Fuxe, K. et al. Neuropharmacology (1983), 22, 3B, 389- significant correlation (r = 0.75, p = 0.007, n = 2-5) 400. and validates the determination of shape d~nnge via 4. Wesemann, W. & Hoffmann, D. Thromb. Res. (1985), 39, ADC as a functional assay for platelet 5-HT 2 639-700. 5. Sturgeon, R. J. & Sturgeon, C. M. (1982) Carbohydrate receptors. ~e regulation of platelet 5-HT 2 receptors and those in the CNS ~ill be discussed. Research, 103, 213-219. Merck Sharp and Dchme, Terlings Park, ESst%ick Road, Department of Biochemistry, Hunterian Institute, Royal Harlow, Essex, England. College of Surgeons of England, Lincoln's Inn Fields, London, WC2A 3PN, U.K. 297 32.01.08 32.01.09 HIGH NON-SPECIFIC BINDING OF CHLORIMIPRAMINE TO DECREASE OF PLATELET SEROTONIN LEVEL IN RATS ,~ A MONITOR PLATELET AND NEURONAL MEMBRANES OF SEROTONIN UPTAKE II~iBITION IN THE COURSE OF TREATMENT E. T. Mellerup and P. Plenge WITH VARIOUS ANTIDEPR~NTS In patients or volunteers treated with chlor- B. Jernej, L. ~i~in-~ain ~nd S. Iskrid imipramine platelet 3H-imiDramine binding is Platelets are nowadays widely accepted as a peripheral strongly reduced. The reduction lasted for 7 pharmacologic and toxicologic model for presynaptic sero- days after intake of one single dose of 50 mg tonergic nerve terminals, primarily with respect to sero- of chlorimipramine. Also in vitro treatment of tonin (5-hydroxytryptamLne) uptake. Since platelets lack platelet membranes with low concentrations the potential for serotonin biosynthesis their content of (25 nM) of chlorimipramine reduced 3H-imipra- this amine depends on its uptake from the surrounding mine binding. The explanation for the reduction plasma. was simply that a large amount of chlorimipra- The pharmacodynamic effect of various antidepressants is mine remained in the membranes during washing. believed to be associated with the inhibition of sero- In fact more protein than chlorimipramine was tonin reuptake into presynaptic serotonergic nerve removed from the membranes during the initial terminals in the brain. These drugs lead to an analogous washes, so that the chlorimipramine content per inhibition of serotonin uptake into platelets. mg membrane protein increased. Similar results We have recently developed a reliable model for prolonged although to a lesser degree was obtained using individual monitoring of platelet serotonin levels in paroxetine, whereas imiPramine could be washed rats (I). Here we apply the mentioned model in psycho- away. pharmacologic research. In rat as well as in human neuronal membranes In the course of chronic treatment of rats with different chlorimipramine and Daroxetine was even more antidepressants we monitored their platelet serotonin resistant to washinq procedures and practically levels. ~rhis simple method enabled us to get insight into remain4d constant in relation to membrane pro- pbarmacodynamic effects (serotonin uptake inhibition) of tein. The amount of chlorimipramine remaining investigated antidepressants "in vivo" regarding dose- in the membranes expressed as fmol/mg protein -response relationship, time-course of the effect and to was 10-30 times greater than Bmax for 3H-imi- compare their relative potencies (i.e. effects of praminebinding. These findings raises the equimolar doses). question whether chlorimipramine could be given in smaller doses than the usual present prac- (I) B. Jernej, L. ~i~in-~ain and S. Iskri6. Neuroscience, tice. Supplement to vol 22 (1987) $371 Psychochemistry Institute, Rigshospitalet, Institute"Ruder Bo~kovi6", YU - 41001ZAGREB DK-2100 Copenhagen, Denmark. 32.01.10 32.01.11 D-I AND D-2 RECEPTOR ACTIVATION CONTRIBUTE TO 7HE LOCO- DEGLYCOSYLATIO~ OF MUSCARINIC ACETYLCHOLINE RECEPTORS DOPAMINE MOTOR ACT[%qTY EFFECTS OF AGONISTS K. Ohara, T. Haga, A. lchiyama and ..Ken_:_Ohara J. Offermeier and J.M. van Rooyen Dopamine receptors have been classified into t~'o bio- ~uscarinic acetylcholine receptors ~ere purified from chemically distinct classes (D-I and D-2). The func- porcine cerebrum by means of single affinity tional roles of these receptors in the generation of dopamine mediated behaviours remain unclear. In this chromatography as described previously (specific study selective D-I and D-2 agonists and antagonists [3H~ QNB binding activity, 2-4 nmol/mg of protein) were used in an attempt to clarify- the roles of D-I and D-2 receptors in the mediation of locomotor acti- (Haga K. and Haga T. J.Biol.Chem. 260, 792% !985). vity (K&). K& was measured with the aid of a Digiscan After treatment with appropriate concentration of Animal Activity .Monitor System. Seatchard analysis of 3H spiperone binding provided Bmax- and KD-values endoglycosidase F, the molecular weight of muscarinic for striatal D-2 receptors. Dopamine concentrations acetylcholine receptor were deduced from about 70 KDa in the striatum were determined by HPLC. The selective D-I agonist SKF 38393 did not increase to about 50 KDh and the residual glucose was not LA in rats. The LA-increases produced by the selec- tive D-2 agonists apomorphine and bromocryptine were detected by ~heat germ agututinlne pero• attenuated after pretreatment with sulpride (a selec- Displacement curve of agonist for the [3HZ Q~B tive D-2 antagonist) and SCH 23390 ( a selective D-I antagonist). binding with deglycosylated receptor preparations ~ere Pretreatment with metyrosine attenuated apomorphine almost same as that ~ith original receptor. and bromoc~-ptine induced LA and significantly decreased the dopamine concentration in the striatum, but did Scatchard analysis of [3H~ Q~B binding also showed not alter the densities or affinities of ~H spiperone that deglycosylation had no effect for the affinity. binding sites in the striation or nucleus aceumbens. The metyrosine attenuation of the D-2 agonist induced These results suggest that glucose of receptors do not L~ could be reversed by SKI= 38393. It is concluded play an imoprtant role for tigands binding to that D-I receptor activation by endogenous dopamine may modulate the I_~ induced by D-2 selective agonists. receptors. Dept. of Neurology and Psychiatry Hamamatsu Eniv. Dept. of Pharmacology and ~RC Unit for the Design of Catecholaminergic Drugs, Potchefstroom University, School of ~edicine, 3600 Handa-cho, Hamamatsu City, POTCHEFSTROOM, 2520, South Africa. Shizuoka Prefecture, JAPAN 431-31 298 32.01.12 32.01.13 LOCALIZATION OF HUMAN DIAZEPAM BINDING INHIBITOR (DBI) ETHANOL PREVENTS ADAPTIVE CHANGES OF BRAIN RECEPTORS AND GENE BY "IN SITU" A.~fBRIDIZATION. BEHAVIOR TO CHRONIC TREATMENT WITH PSYCHOACTIVE DRUGS M.A. DE BERNARDI and I. MOCCHETTI H. Rommelspacher and J. Wolffgramm, Dept. Neuropsycho- Diazepam Binding inhibitor (DBI) is a putative pharmacology, Free University, D-IO00 Berlin !9, allosteric modu!a 32.01.14 32.01.15 PRESENCE OF A 3H-FLUNITP~.ZEPAM BINDING INHIBITOR PUIIIFICTION OF ENDOGENOUS INltlBITORS OF tN THE SERA OF PSYCHIATRIC PATIENTS [ a H]-FLL~ITRAZEP~ BINDING FROM BOVINE BRAIN A. Lucacchini, G. Giannaccini, C. Martini, C. San- na, S. Michelini, G.B. Cassano, D. Marazziti H.Kawasaki, N.Itoh, A.Nohtomi, M.Fukahori, H.Takeshita The presence of specific receptors for the benzo- diazepines in brain of many species, including Endogenous brain substances having benzodiazepine- man, suggests the possible existence of endogeno- binding inhibitory activity have been extracted us ligands acting on these receptors. with hot acetic acid from bovine brain. After Our study aim was to explore whether compound(s) ultrafi]tration, material with molecular weight less interacting with benzodiazepine receptors might than 10,000 dalton was e~tographed on Sephadex exist in psychiatric patients' sera. 6-10. At least three peaks (peak 1,2,3) were shown to We included in the study 52 patients affected by inhibit the binding of [a H]-Flunitrazepam to different psychiatric disorders, according to synaptosomal membranes. Two of the peaks (Peak 2,poak DSM II[ criteria. The controls were 20 healthy vo 3) had smaller molecular ~eights (below 500 dalton) lunteers. Deproteinized~rum was assayed on the aria were shown to contain inosine (peak 2) and binding of 3H-Flunitrazepam to bovine brain mem- branes. hypoxanthine (peak 3) by using TLE method. Another peak (peak i) lind relatively higher Our results showed that, in the range of concen- tration used, the sera from psychiatric patients ,molecular weights than other two peaks and inhibited inhibited the binding of 3H-Flunitrazepam, altho- f]unitrazepam binding dose-dependently and non-compet- ugh an interindividual variation was present. itively. A rough biochemical analysis of this inhibitor The present results suggest that this substance has shown that it is dialyzable (molecular weight (peakl) may be a possible modulator for central below 1000), is heat- and freezing resistant, and! benzodiazepine receptor. is resistant to proteolytic and acid degradation. The presence of this inhibitor in psychiatric patients' sera open new and interesting perspec- Department of Neuropsychiatry,FacuIgyof Medicine, tives in the knowledge of biochemical basis of Kyushu University,Fukuoka812,JAPAN. anxiety. Department of Psychiatry and "Istituto policatte- dra di Discipline Biologiche, University of Pisa, 1-56100 Pisa, Italy 299 32.02.01 MILD DEFICIT SYNDROME IN LATE MIDDLE AGE : A NEW RATING SCALE POSTER Stdru,L*, Vetel,JM**, Sevestre,M***, Lancrenon,S*, K.iepferld-Saya,L*, StdrthD* PRESENTATION * : LT.E.M., 93 4v. de Fontainebleau, 94270 Kremlb,-Bic~tre, France. ** : Ser~4ce de G6riatrie, Le Mann, France 32.02 *** : Laboratoires Clin Midy, 20 me des Foss~s-St Jacques, F-75240 Palls Cedex 05 The presentation will describe a new rating scale for the assessment of mild cognitive and socio-professional symptoms associated with ageing deficits. A collection of 41 items was validated on a sample of 185 pre-geriatric Basic and Clinical Aspects (age 50-65) patients before any drug treatment and after exclusion of patients either anxious or depressed. The patients were rated by 40 general practioners of Alzheimer's Disease trained together. - New Drugs in Memory A principal component analysis dearly identified a factor representing 19 % of the total variance demonstrating the existence of the syndrome studied. Refered to in French as "Ddllcit Neuro-Biolog~que de la post-Cinquantaine (DNBC)'. From *the 13 items best correlated with the principal factor (R > 0.50) was established a list of 10' items selected according to both statistical and clinical criteria : (1) Difficulty. in gathering his/her ideas ; (2) Difficulty in concentrating, inattentive, loses the thread of ideas ; (3) Slow and impoverished association of ideas (difficulty., poverty and slowness of narration) ; (4) Difficulty in expressing his/her ideas dearly, making him/her understood ; (5) Decreased intellectual capacity (reasoning, calculation) ; (6) Loss or lack of confidence in his intellectual capacities ; (7) Difficulty and hesitance before taking a decision ; (8) Loss of interest for his profession or daily tasks if not at work ; (9) Feeling of inadequate performance, of not being at his/her best ; (10) Decrease in social contacts or friendship. Principal component analysis of these 10 items identified a first factor representing 44 % of the total variance. These 10 items therefore clearty participate in the factor and appear to provide the best representation of the severity, of the syndrome studied. 32.02.02 32.02.03 EFFECTS OF ACETYL-L--CARNITINE ON CEREBRAL BLOOD FLOW IN C[TIDIIE DI~a0$~]0S0LIH (13?-CaOLIIE) II IBX THEL~PYOF CEXE~EIL IISU?HCIHCI PATIENTS WITH ORGANIC BRAIN SYNDROME S. Passero~ N. Ba~tistini R. Eherherdt, K.D. In several experimental reports an excitatory activity on ?his double-blind cross-oyez s~udl of 14 ,eeks ~es perfur:ed ~o assess the in- eholinergic neurons was attributed to acetyl-l-carnitine fluence sod effectivezess uf C~Y-choline in ~eristric pezien:s with cerebral in- (LAC), and in controlled clinical trials the drug has pro- sufficiencI of diffe:eu: ezlologl in comparison with phoebe, liter an initial ~esh-out period of tit weeks :he patients re:aired according to randomized order duced improvement in several cognitive activities. Since either CD~-choline or phoebe for 5 weeks; after a seooud ~ssb-out period of cerebral functional activity is coupmed with cerebral further t~o ~eehs the ;s:!e=s received the sheroati~e drug {C~-choline or blood flow (CBF) the above mentioned results suggest a ;h:eho) for sddidu:al ~ reeks in :he second cross-over ;~ese. 6 pss possible effect of LAC on this parameter. The present stu- ~nd clinical tests (~::e~e:; Geriatric Inventorl, 5:~G} ~ere performed at the end of each medication ;eris~ according to the cross-oyez phases with CDP-choline dy investigated the effects of acute LAC administration or pls:ebo trestmenL on CBF. Ten patients with organic brain syndrome due to cerebrovascular disease and with a degree of intellectual .. e,a,~;~;.~ :f a!l ~es:s revealed: impairment from mild to moderate were studied. CBF was - :Dg-choline, as firsz :rasrment improved the clinical szazus when compared measured by the Xenon 133 inhalation method in 16 regions in~raindividuatll ~u baseline with a statistical signifka=ce of p ( 0,001 in over eacg hemisphere prior and 30 minutes after the i.v. 5 of the 6 tests a:~ uf ; ( 0.01 in one test. infusion of the drug (i g in I0 minutes). Values of gray - Plsceho, us first ~rsszlm=~, cum~ured to hese!ine sho~e~ s statistically signi- matter flow (FI) expressed in ml/lO0 g/min were analyzed. ficant improvement :f ; t LO01 in 4 of the 6 parameters end of p ( 0.01 in one initial values of CBF were on average 69.2 + 11.9 in left ;est and no signific~: ~ifferenoe h the remaining test. and 70.0.• I0.2 in right hemisphere. After drug administra - The further improve~em: during CD?-choline udministraticn ms second treat=ant in tion mean hemispheric CBF values increased to 80.8 + 13.6 :unpurfsan with the ffrnt :reetment (placebo) sas nora distinct and siqnifi- (left) and 80.5 + 12.2 (right) with a percentual increment cantlX better fer e!! ~ ;srnleters, whereas placebo es second treatment did not of 16.7 (P ~ 0.0001) and 13.8 (P < O.O001) respectively. Ana show further statist!rail? significant improvement in an? test. lysis of regional CBF data showed that the increase in - The in~erindividuai ::n;arismm between the tw0 treat=en:s proved e stadstioallx flow was diffuse to all explorated regions but was more significant better effecm for CDP-choline as first tree:meet in 2, and for CDP- evident in precentral and central regions. Our results choline as second :reezae:: in 3 of the 6 peru=enema tested. show that the adminiszration of a single i.v. dose of LAC In general, there ~ss e si;mifican: inprovenent in nhe f!cst cross-over period can induce a significant increase in CBF in patients with fur b0th treatment groups; a further significant i|provewent during the second vascular organic brain syndrome and point to conclusion cress-0ver period o:i? ::z:r:ed after treatment =ith C~P-choline, whereas the that these chan~es in cerebral circulation are related to pheebo treetmeo~ did :=: show further improvement in sol :est. :he neural excitatory activity of the drug. ~A~ALOG Institute f:: =ini:el Research, 31inica della h]alattie Nervose e hlen 300 32.02.04 32.02.05 SCREENING OF THE ANTIDEPRESSANT MINAPRINE ON ENCEPHALOTRO- PHASE i STUDY OF DM-9384 FIC EFFECTS VS PIB.&CETAM AND PLACEBO AFTER ACUTE AND SUB- M. Murasaki, S. Miura, J. Ishi$ooka, H. Wakatabe, CHRONIC~L ADMINISTRATION IN HUMANS - USING HYPOXIA-MODEL K. Schaffler',G. Kauert-- M. Uchiumi, Y. Fukuyama, Y. Mochizuki, and A. Sumiyoshi Minaprlne - an an~no-phenylpyridazinederivative o used as an antidepressant,e~pe- DM-9384 is a new pyrrolidone derivative which has been ciMly in inhibitorystates, is devoid of m~ticholinergiceffects, but facilitatesdopami- developed in Japan. In pharmacological studies, it has nergic, serotonerglc(pre? and postsynaptic)and r transmission. ClinicM shown excellent antiamnesic and antihypoxic effects and studies on depressionin demented patientswere done and showed positiveresults vs pl~cebo.In seniledementia - especiMlyof Alzheimertype (AT) - there existsa lack in also greatly potentiated the action of learning- dop~ninergic~d cholinerglcmechanisms with or withoutconcomlt~nt depressive sta- acquisition. In neurochemical studies, DM-9384 has sNown tes.Due to its pharrn~cologicalprofile {procbolinergie and prodopaminerglc)the drug to activate cholinacetyltransferase. These evidences seems to be ttsefulin AT and NAT seniledementias. A.UlmM ~nd human models of hypo~da have demonstratedto be an adequate'approach suggest the possible involvement of central cholinergic for partialsimulation of dementia states (with the respectiveinfluences on cerebrM mechanism of DM-9384 and the effectiveness for the metabolismand blood supply) and a resultingdown-regulation of CNS-relatedinfor- disturbance of psychomotor function in the aged people. mation pr~:essing (decrease in performance). To approach the respective potency of minaprine as an encephalotropic - a first-step Phase 1 study was performed using male healthy volunteers. experinaentM set-up was designed in healthy subjects, z~s a partial simulation model, i. Clinical pharmacology: Few subjective and objective to avoid drawing of statistically inhomogeneous samples of dementia patients (with findings were observed with single administration up to differentpathophysiologlcM states). It w~s a r~ndornised,placebo-controlled, double-bllnd 3-way crossoverstudy in 9 he- 1200 mg daily. No findings were recognized during one althymale subjectswith acute~nd subchronicaladministration (1 week) of minaprine week-consecutive administration of 600 mg daily. and pix~cet~rnms reference(dosages ac/sc: 200 and 400 mS, 2400 and 2400 nag respec- 2. Influence on the following tests tively). P~ycho- and electrophysiologicMmethods used were: Oculodynamic Test (ODT, 20 rain; Electrooculographyvmd choice reaction; Resting- and Vigilance- (i) blood pressure, pulse rate, body temperature controlledEEG, each under the normobaricadministration of 10.5 ~ oxygen).After (2) urinalysis, hematological parameters, blood- norm0xic ~d hypoxicprevaiues further p.a.-assessments were done at hrs I, 2 and 4 biochemical parameters (~t day 1 and g of e~ch medicationperiod with a one week washout-periodin bet- ween). (3) endocrinological parameters Main vm-iable~of ODT (latency,reaction time~ correct responses), which have a tight (4) ECG and EEG relationto everydaylife conditlons (and its resultingsocio-econornic consequences), (5) equilibrium test were positivelyinfluenced under hypoxiain the directionof a returnto normoxia [im- provement)by the mlnaprinetreatment in the acuteand even more accentuatedin the (6) psychomotor performance tests s~bchroulcMphase. Piracet~mdemonstrated positive influences too, but was lesscon- It should be specially mentioned that DM-9384 showed no sistentin itspattern and even decreasingin its efficacyfrom the acute to the subchro- undesirable influence on the psychomotor performance ulcaldrug ~dn~nistrationregimen. Time-efficacy pattern seems to be ~ttributedmore to the p-OH-metabolite of minaprlne than to the mother drug or the lactmn- test~ because almost all psychotropic drugs show some derivative - as seen in correlationof pharmacodynamics (I) and quMitativekinetics harmful influence on these tests. (2) in thisstudy. 3. Pharmacokinetic study: The plasma levels of DM-9384 Drug effectson EEG were mainly seen in V-EEG. Hypoxia itselfraised total power and absolutepower of the singlefrequency bands. Again minaprlnedemonstrated a were dose-dependently elevated and the significant more stimulatingpattern (a decreasein the lower and an incre~e in the higherfre- correlation was recognized between dose and AUC. Tmax quency bands in relativeEEG-power), more consistentand longer-lastingeffects than was 1.2-1.8 hours and TI/2 was 3.3-5.9 hours. No pir~cetam - thusfitting the same EEG-patternm~ seenin geronto-psychiatricpatients - trea;edwith encephaiotroplcs. accumulation was observed with consecutive administration. I. Institutefor Pharmacodyn~xnicResearch, Charf~rnfmsterstr.4a, D-8000 Munich, Judging from the above-mentioned results, DM-9384 is safe FRG and worthy enough to conduct phase 2 study. 2. Instisu~efor ForensicMedicine, Universityof Munich, Fr~uenlobstr.7a, D~ Munich 2, FRG Department of Psychiatry, Kitasato University School of Medicine, 863-1 Asamizodai, Sagamihara, Kanagawa, Japan, 228 32.02.06 32.02.07 CLINICAL TRIAL FOR SOLCOSERYL~IN DL~MENTIA PATIENTS PRELIMINARY RESULTS OF A SIX-MONTH, DOUBLE- H. Suzuki, S. Harisuchi, T. Nishimura BLIND CROSS-OVER STUDY OF P}EOSPHATIDYLSERINE VS PLACEBO IN PATIENTS WITH EARLY SENILE DEMENTIA Open clinical trial of Solcoseryl~injection was per- OF AI.ZHEIMER'S TYPE formed to dementia patients in presenility and senility W. Satzger, D. Bove, S. Gerke, W. GQnther, and the general improvement index and the usefulness U. MUnch, R.R. ~[l index were evaluated. The goal of the study was to assess the efficacy I) Solcoseryl@ (4 ml) was intravenously injected once a and safety of Phosphatidylserine (BC-PS, Phos- day for 8 weeks to 35 patients, 29 patients with cerebro- phatidylserine preparation from bovine brain) ir~ vascular dementia, 5 patients with dementia of Alzheimer's patients with early dementia of Alzheimer's type. type and i patient with dementia associated with alcohol- In addition the predictability cf therapeutic ism. The general improvement rate and the usefulness outcome and pzactice effects were examined. The index after 8 weeks were 82.9 %. study design consisted of a 4-week wash-out 2) The improvement rate varied according to symptoms, phase, an 8-week first treatment phase (I), with an improvement rate of 77.1% in psychiatric another wash-out phase of 8 weeks, and an 8-week symptoms, 66.3 % in subjective s~ptoms and 50.0 % in second treatment phase (2). BC-PS and placebo neurologic symptoms. were randomly assigned to treatment phases 1 a~d 3) The high improvement rate was ob:ained in psychiatric 2. The'efficacy was assessed through CGI, symptoms such as hallucination (75.0 %), delusion (66.7 %), Gottfries-Brane-Steen Scale, psychological aggressive ~ehaviour (66.7 %) and excitement (66.7 %). It tests, P-S00, and brain mapping. Mini-Mental was effective in controlling emotional disturbance, State, a compliance questionnaire, suggesti- reducing frequency of abnormal behaviours and also bility, depression and short-term increase in improving depressive mood (70.8 %). cognitive functioning by means of multiple exer- 4) The general improvement index revealed a higher in cises were used as possible predictors of eerebrovascular dementia (86.2 %) than in dementia of efficacy. Alzheimer's type (60.0 %). ThUs far 35 patients with e~,rly dementia of 5) Neither subjective nor objective symptoms and signs of Alzheimer's type (Mini-Mental State between 15 adverse side-effects were not observed. and 27) have entered the study, 13 of whom have There were almost no change in labolatory findings. It completed it. PS was well tolerated. During the was confirmed that Solcoseryl~is a drug of high safety FS-phase patients showed a significant increase with excellent applicability to elderly patients with in paired associate learning and tended to im- dementia. prove in DSST, Color-Word-Interference-Test and CGI. Patients with higher Mini-Mental State at the begin of the study improved significantly more ir~ cognitive test scores (Benton, DSST) during the course of the study than those with lower scores. Psychiatrische Klinik der Universit~t M~nehen NuBbaumstr. 7, D-8OO0 MUnchen 2 301 32.02.08 32.02.09 EFFECTS OF PHOSPHATIDYLSERINE THERAPY IN GERIATRIC LONG-TERM ACETYL-L-CARNNITINE MODIFIES EXPERIMENTALLY- PATI~S WqTH DISTHk~IC DISORDERs INDUCED CONFLICT BEHAVIOUR IN THE AGED RAT O. Ghirardi, S. Milano, M.T. Ramacci and *L. Angelucci. Mag~ioni M.*,Picotti G.B.**,Bondiolotti G.p. ~, Panerai A. ~ Acetyl-L-carnitine (ALC) is known to be present in the Brambilla F. w CNS with a role in energy metabolism and in the turnover A double blind study was done in iO hospitalized geriatric of the phospholipid component of the neuronal membrane women with disthymic disorders( DSM III).to evaluate the structure. Previous studies have shown that chronic therapeutical effects of phosphatidu on treatment with ALC in aging rats preserved the morphology mood,behaviour,cognitive functions and memory.Patients of some brain structures and learning capacity at the were treated with placebo for 15 days followed by Bs-Ps same time. The purpose of the present study was to (300 mg/day)for 45 days.Before placebo,at uhe end of it investigate the effect of a chronic treatment with ALC and after Bs-Ps therapy patients were administered the (74 mg kg-I daily per os for 9 months) on the Hamilton,Buschke,Gottfries-Brane-Steen and NOSIE rating experimentally-induced conflict behaviour (aversive sti- scales,to monitor the effects of the drug on psychopatholo- mulation contingent to drinking in thirsty animals) in gical symptomatology.At the same time ,they received a GH- the old rat (age, 25 months when tested). beta-endorphinl~-Ep) clonidine test,and basal plasma levels Latency before the first lick, the time required for 300 of MHPG.h~A',DOPAC and 5HIAA were measured. Our data reve- licks, total number of licks and water consumption were aled a consistent improvement of depressive symptomatology recorded for i0 min during three days of habituation (no of cognitive functions and memory,with no changes in pre- aversive stimulation) and t~Ddays of test sessions. Basal viously normal behaviour.GH and ~-EP responses to clonidi- values showed no significant differences between the ne were blunted before and after therapy.Baseline MHPG, control iC) and ALC-tretated (T) groups in all parameters HVA,DOPAC and 5HIAA levels did not change after Bs-Ps the- consideredL The differences between the values obtained rapy.Bs-Ps-induced positive effects are not mediated by during test and basal sessions expressed in percent were changes of brain monoamines activity. evalu/ted and showed the following: latency before first lick: C = +126%; T = +177%; time required for 300 licks: *Villa Zucehi-Carate;**Istituto Farmaeologia Universit&- C = +137~; T = +27%; number of licks: C = -51%; T = +8% Genova;~ Farmaoologia Universita-Milano; Ospedaie Psiehiatrico Pini-Milano - italy (p~0.02); water consumption: C = -70%; T = -21% (p~ 32.02.10 32.02.11 EFFECT OF LONG-TERM ACETYL-L-CARNITINE ON THE OLD RAT The synergistic effect of cerebroactive drugs on vascular PERFORMANCES IN THE EIGHT-ARM MAZE smooth muscle A. Caprioli, O. Ghirardi, M.T. Rmmacci and *L. Angelucci T. Shibuyal,2, H. Matsuda I , H. H0nda 1,2, Y. Watanabel,2~ Acetyl-L-Cmrnitine (ALC) is a natural substance known to H. Shimural , H. Tsu~il and M. Izumisawal Recently, it was reported that the combined administration play an essential role in the turnover of the phospho- of ifenprodil tartrate and calcium hopantenate produced lipid component of the neuronal membrane structure. A a benefical synergistic effect in the treatment of retardir~ effect on the age-related loss of neurons in cerebrovascular diseases. In order to study the mechanism the hippocampus, the integrity of which is indispensable of this synergistic clinical phenomena, changes in blood for a correct performance in the radial-arm maze, was flow of vertebral and internal carotid arteries were observed after chronic treatment in the rat. This study measured in rats using the transit-time ultrasonic volume flowmeter. Furthermore, the isometric tension of isolated was aimed at investigating the possible effect of a -i canine basilar and internal carotid arteries was tested. long-term treatment with ALC (74 mg kg daily per os for The increase in vertebral and internal carotid arterial 8 months) on the performances of the old rat (Sprague- blood flow induced by ifenprodil tartrate was significant- Dawley, aged 24 months when tested) in the radial maze in ly enhanced by calcium hopantenate. In canine basilar and the absence of visual cues. Previous studies (Ghirardi et internal carotid arteries contracted by K +, the dose- 8/, 15th CINP, 283, 1986) had sho~xl that maze performance relaxation curves of ifenprodil tartrate were shifted to the left by preincubation in calcium hopantenate. The was strongl~ impoverished in old rats compared with young ifenprodil tartrate inhibition of on K + -induced Ca 2+ ones. uptake in canine cerebral and internal carotid arteries In ALe-treated animals, the number of correct choices was was significantly enhanced by calcium hopantenate. found to.increase significantly in the course of the 14 Results suggest that the calcium hopantenate enhancement sessions (one a day), whereas the control group showed no of the ifenprodil tartrate-induced relaxation in basilar s i~n i fica'nt modification. ALC-treat ed animals showed and internal carotid arteries may be due to an influence on Ca 2+ movement in the vascular cell, unimately reflected better/pe~rformances with respect to control animals under in their synergistic effect of on cerebrovascular disease both ~he quantitative and the qualitative aspects: they through increased arterial blood flow. performed a higher number of correct choices using more effective strategies in the choice sequence, so that I. Department of Pharmacology, Tokyo Medical College, their performances approached those of younger animals. Tokyo 160, Japan 2. Department of Biomedical Sciences, University of Thus, ALC can be said to have a retarding effect on Illinois College of Medicine at Rockford, Rockford, age-related memory and learning deficits, presumably Ill. 61107-1897, U.S.A. ibecsuse of its capacity to preserve hippocampal morpho- logy and function in old rats. Biological Research Labs., Sigr~ Tau S.p.A., 00040 Pomezia, Rome, Italy and *Pharmacology II, School of Medicine, "La Saoienza" University, Rome, Italy 302 32.02.12 32.02.13 A new nootropic drug, minaprine, improved "TOTAL" CHOLINERGIC FOREBRAIN NUCLEUS LESIONS: LACK OF BEHAVIORAL the scopolamine-induced spatial cognitive RECOVERY disruption O.G. ~r, Jr., E. Horv~'{h, T. SoF~JUPm~n, H. Do,pert, U. Ber~, and M.Fujiwara and K.Iwasaki J. TPa~Bp Rats ~ere ~rained %o marly errorless perfor~manc~ in an B-arm r~dial Minaprine exerts cholinergic activity and raze, in whic~ a ~-hour delay ~r~s interpolatedbe~eeo {he firs{ six dopamine uptake blockade such as nomifensine. arw~ las{ ~ arm choices. A{ an age of ~ ~{hs, ra{s were given Minaprine also protects the ischemia-induced el{her sham surgery or a bilateral mullisi{e ibo{enic acid lesion neural dysfunction in rats and mongolian aloog the en{ire length of {he for~r~in chollnergic nuclei: medial gerbil. Therefore, minaprine was expected to sep{um, nuclei of lhe vertical and harizcntal lirdos of {he dlagonal be beneficial in the treatment of vascular- b~nd, and st~stantia in~0~ina{a/ntJcl~ basalis magnocellularis, A related dementia. The present study examines ~o{al of 16 ibo{ere{e injection si{es ~ere rt~uired, in which re- the effect of minaprine on disruption of spa- la{ively low concehn{ra{ions and vol~ ~e os~<~: ibo{~na{e II mg/ml) tial cognition following the scopola- br~ prepar-ed in a saline/NaHCO solu{ion IpH ?,@), and volumes of mine(Scop.) in an eight arm radial maze 0.~-0.6 ~I, depending on site, ~ere slowly injected. Rats so treated performance. Male Wistar rats(200-250g) were sho,~ed a large posl-delay deficit in ~ B-am radial maze relative pretrained until correct choice 80% above in {o c'~{rols, ~nd {his defici~ did no{ re~over over Q ~{~ of r~- first 8" choices. Scop.(0.5mg/kg i.p., 30min {raining. Control percent accuracy post-~lay during this period before a session) significantly decreased the aver-~ged approximately 70Z while {ha~ of t~e lesioned rats about ~.. correct choices and increased error choices. 71~reaf{er, a number of fur{hat behavior-a1 {es{s were performed wi~h Minaprine(10~50mg/kg p.o.) was significantly ~he lesioned and control rats, along ~i~ an additional grc.~p of in- impro{red the Scop.-induced disruption of e>qo~ri~d agile%chad subjee{s. The b~havioral defiei% of the spatial cognition in an inverted-U dose lesio~ rats generalized to {he ether b~vior~l procedures, dependent manner. On the other hand, this yielding a pat{era of effects similar ~o ~=a{ seen in normal r=a{s disruption was reversed by cholinergic, cate- ~f{er treatment wi~h scopolamine..S~t hls{ological examir~{io~ cho]aminergic or serotonergic drugs. Scop. ~fi~ the large Pe~Jc%ion in AChE-positive forebrain cells. This decreased brain noradrenaline(NA) levels in finding was also corroborated by lowered c~olir~ acetyltransfer~se frontal cortex and hippocampus. And ~c{ivi~y a~ 1 week ~r~ 1~8 ~ays posi-l~ion in another group of rats. minaprine(50mg/kg,p.o.) increased NA levels The present results support the u~e of animals so leslor~d as in these region to the level of normal r~recoverlng model of hu~n d~mentla. control rats, in accordance with recovering Neurobiology O~pari~t, Tr~rke (B~y~r), Ne~Jra{harRing 1, spatial cognition. D-SOOO KBln 80, FRO Improvement of minaprine for Scop.-spatia] disruption involved the interactions of those multiple neuronal systems. Minaprine can be considered a candidate drug for the treatment of Alzheimer's disease. 32.02.14 32.02.15 B!0C~ffCAL C~ANG~S IN THE BRAIN OF AGING RATS. FACILITATION OF MENTAL RETENTION CAPACITY BY BACOSIDES- TIE ACTIVE CONSTITUENTS OF BACOPA MONNIERA 0.Benew H.Te~kalov~, Z.Kri~toffkovd~ B.BIn- B.N. Dhawan and H.K. Singh-- keyS, N.Dloho~ov~ k~ M.Burq~ovd ~ A.Pavlik~ In our previous studies it has been shown that ethanolic Brains divided in 7 parts ( cortex, hippocampus extract of Bac_~ monniera whole plant produced better hypothalsmus, c.stristum, brain stem, cerebel- acquisition, improved ret@ntion and delayed extinction lum, b.olfactorii) were analyzed in rats, male in several schedules of shock conditioning in rats (H.K. Wistar, at the age of 8, 14, 20 and 24 months. Singh and B.N. Dhawan, J. Ethnopharmacol. 5, 205, 1982). The concentrations of DNA, RNA, protein and its Subsequent studies have shown the activTty to be due soluble and insoluble fractions, neurotransmit- to two saponins named Bacosides A and B. The mixture ters (noradrenaline, dopamine, serotonin and of two saponins was active as individual saponins. their me{abel{tea), density of dopsmine recep- The effect of the mixture was studied in two schedules tcrs, rate of lipid peroxidation and high affi- of shock conditioning. In the shock motivated bright- nity choline uptake were estimated and compared ness discrimination reaction employing a semiautomatic with the values in the brains of 3-month-old Y maze a single oral dose of I0 mg/kg significantly rats. reduced the time per trial and increased the number Alterations in the components of the doosminer- of positive trials as well as the relearning index. gic synapsis Cdopamineland homovanilic acid con- For the active conditioned avoidance response the pro- can{rations, dopsmine receptor density)indicat- cedure of. Cook and Weidley (W.J. Cook and E. Weidley, ing functions1 disturbances in c. striatum were Ann. N.Y. Acad. Sci. 66, 470, 1957) was used. Bacosides detectable already in 8-month-old rats and were were given in a dose ~ I0 mg/kg orally every alternate increasing during the period of investigation. day. A significant reduction was obtained in the react- At the age of 14 months, decreases of noradre- ion tiF~e from the fourth day and also in the number naline concentrations in the hypothalamus~ s~ri- of days for completing the training for 8 days to 6. atum and brain stem were found together wzth a The conditioned taste aversion test was performed by higher rate of lipid peroxidation in the cortex~ the method of Brozek et al. (G. Brozek, O. Buresova In 20-month-old rats, all these changes persis- and J. Bures, Physiol. Bohemslov. 28, 537, 1979). Baco- ted at the same or higher degree with addition sides produced a dose related inc-r-ease in the sucrose of decreased hypothalamic serotonin level and intake and a similar decrease in the lithium chloride the rise of water insoluble protein fraction in in trained rats. They are devoid of any other signi- the cortex. No significant alterations were ficant CNS effect and have a high LD5_. found in other variables under study. Division of Pharmacology, Central Dru~ Research Institute Lucknow 226 001, India Psychiatric Research Institute, 18103 Prague 8, ~stavnf 91, Czechoslovakia. Research Institute of Pharmacy and Biochemis- try, 13000 Prague 3. ~ Institute of Physiology, Czechoslovak Acade- my of Sciences, 14220 Prague 4. 303 32.02.16 32.02.17 EFFECT OF NAF'flDROFUI;IYL OXALATE(LS-121) ON PROTECTIVE EFFECT OF E-2001, A NOVEL Ah~fI-ISCHEMIC EXPERIHENTAL AHNESIA HODEL IN RATS. AGENT ON CEREBRAL ISCHEMIA IN MONGOLIAN GERBILS T. Kameyama, T. Nabeshima, A. Katoh and S. OBawa M. Ueno, M. Mihara, T. Nakazawa, M. Ikeda, Y. Furuya Effects of LS-1218(Nippon Roussel K.K.) on amnesia T. Kaneko and K. Yamatsu models induced by cycloheximide(CXM) , Glutamate is suggested to contribute to the development scopolamine(SCOP) and basal-forebrain(BF) lesion were of ischemic cell damage in brain (S. M. Rothman, Ann. investigated in comparison with Ca-hopantenate(HOPA) Neurol. 19, 105, 1986). E-2001, a newly synthesized and physostigmine(PHY) using step-through passive piperidine derivative, has an inhibitory effect on high avoidance response in rats. In the retention test, K+-induced glutamate release from brain slices (N. Karibe cut-off time of 600 sec was employed for the ,JUC. PHARM. SCI'87, H04-W-II). Thus, in the present measurement of step-through latency(STL). The animal experiment, the protective effects of E-2001 on cerebral showed over 300 sec of STL was regarded as having the ischemia in gerbils were studied. criterion of memory retention. % of retention = l)Effects on the survival rate and the severity of lOOx(the number of animal cleared the criterion)/(the neurological deficits: E-2001 (i0 and 30 mg/kg, p.o.) number of animal tested). Increase in both parameters administered to stroke-positive gerbils I and 4 hrs of STL and % of retention was regarded as the drug is after unilateral carotid arterial ligation reduced the able to improve the amnesia. If only one of two mortality and the stroke index. parameters is increased, we considered that the drug 2)Effects on passive avoidance response (PAR) and has a tendency to improve the amnesia. LS-121(25 conditioned avoidance response (CAR): E-2001 administered sg/kg) and PHY(O.1 mg/kg) improved the CXM- and SCOP- orally 1 h~ before ischemia induced by bilateral carotid induced amnesia, when administered in the pre- arterial ligation (BCAL) of 5min-duration improved the training, post-training and pre-retention tests, while impaired P~2. and CAR in a dose range of 3 to I0 mg/kg. they showed a tendency to improve the BF lesion- 3)Effects on ischemic cell damage and extraeellular induce~l amnesia, when administered in the post- accumulation of glutamate in the hippocampus: BCAL of training test. HOP~ only showed a tendency to improve 5min-duration caused a delayed neuronal cell death in the CXH- and SCOP-induced amnesia. These results the hippocampal CA1 subfield and a marked increase in suggest that the antiamnesic action of LS-121 may be extracellular glutamate. Pretreatment of E-2001 (3, i0 produced via the direct or indirect activation of and 30 mg/kg, i.p.) protected the loss of pyramidal cells acetylcholinergic neuronal system. Since it improved in CA1 in a dose-dependent manner and reduced the extra- the amnesia ~hen administered in the pre-retention cellular accumulation of glutamate determined by micro- test, there is a possibility that LS121 has not only dialysis technique. protective effect, but also therapeutic effect. These data suggest that E-2001 has anti-ischemic effects, Furthermore, it is suggested that treatment with LS- and the effects may, at least, partly be due to the 121 may be useful for the Alzheimer disease, since suppression of extracellular accumulation of glutamate. it showed a tendency to improve the BF lesion-induced Tsukuba Research Laboratories, Eisai Co., Ltd. amnesia. 5-1-3 Tokodai, Tsukuba, Ibaraki 300-26, Japan Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, ~eijo University, Tenpaku-ku, Nagoya 468, Japan 32.02.18 32.02.19 MINAPRINE IMPROVES IMPAIRMENT OF WORKING MEMORY BIOCHEMICAL AND BEHAVIORAL CHOLlqqERGIC PHARMACOLOGY OF INDUCED BY SCOPOLAMINE AND CEREBRAL ISCHEMIA IN RATS TETRAHYDROAMINOACRIDINE T. Yamamoto, S. Yatsugi, M. Ohno and S. Ueki L. A. A. van Pooijen, J. Trat~r, B. Schmidt and The present study was carried out to elucidate the T. S c_huuzman effects of minaprine on amnesia induced by three The acetylcholine esterase (ACHE) inhibitor tetrahydro- different methods. For studying working memory, we aminoacridine (THA) has been used clinically for the used a repeated acquisition procedure (2 min interval) treatment of Alzheimer patients. We here report pharma- in the three-panel runway apparatus (Japan. J. Pharma- cological studies on cholinergic effects of THA. The col. 46, 183, 1988). Male Wistar rats maintained at drug potently inhibited rat brain AChE with a K~ of 80 nM. approximately 80% of the free feeding level in body THA competed with -H-pirenzepine (MiACh-recepto~subtype) weight were trained with 6 consecutive trials (one binding (Ki 1.4 ~M), while the affif~ty for the -H-ACh session) per day. The training was r(zpeated until they ~inding site was 10 fold lower. THA alone did not affect showed total errors (the number of pushing incorrect H-inositol (poly)phosphate (IP) production in rat+cere- gates) and latency (the time required to take food- bral cortex slices, even in ~henpresence of high [K ]. pellets) less than I0 and 50 sec, respectively. Carbamcs,icholine stimulated -H-IP production was antago~ Minaprine at doses of I0 and 32 mg/kg i.p. signifi- ized by THA (ICN~ 10 ~uM, K R 1 ~M)~.* In behavioral studies cantly reduced the increase of errors (24.9 Z 2.1) THA dose-depend~Stly prevented the anlnestic action of induced by 0.56 mg/kg of scopolamine. However, the 0.31 mg/kg b.w. scopolamine in a mouse passive avoidance prolonged latency (100.8 • sec) was not affected test. In.a narrow dose-range THA slightly improved by minaprine at any doses up to 32 mg/kg. Intra- acquisition of 24 months old rats in a water labyrinth hippocampal ethylcholine aziridinium ion (AF64A; bila- test. Taken together, these data indicate that THA does teral 2.5 nmol/~l) also produced increase~ in both the not act solely by inhibiting the ACHE. number ~ of errors and the latency. However, minaprine NetLrobiology Department, Tropor~erke, Neurather Ring 1, up to doses of 32 mg/kg failed to reduce the increase D-5000 ESln 80, F. R. Germany in both items. Depending upon the duration of cerebral ischemia induced by the method of Pulsinelli and Brierley, both the number of errors and the latency were increased. Minaprine (3.2 or i0 mg/kg i.p.) administered imme- diately after blood recirculation and 30 min before the runway test decreased the increased errors (21.6 • and latency (112.7 • 6.2 sec) induced by 5 min ischemia. Thus minaprine has a beneficial effect on impaired working memory induced by scopolamine and by cerebral ischemia in rats. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University 62, Fukuoka 812, Japan 304 32.02.20 32.02.21 EFFECT OF DI BENZOXAZEPI NE ANALOGUE ( BY- 1949} ON THE ROLE OF DOPAMINERGIC RECEPTOR SUBTYPES iN ACQUI SITION PROCESS OF OPERANT BEHAVIOR IN AGED SPATIAL WORKING MEMORY: EFFECTS OF RATS. DOPAMINERGIC ANTAGONISTS UPON Y. 1 keda, S. Tanabe and M. Takat oh. RADIAL-ARM MAZE BEHAVIOR The present experiments were undertaken to iN RATS. investigate the effects of BY-1949 and aniracetam, cognitive enhancer, on acquisition Y. Hira.~a1 and T. Iwasaki 2 process of two types of operant task in aged Fischer344 male rats. In our previous study (Hiraga and Iwasaki, 1984), we found that a (I) Light-dark discriminative learning task of dopaminer~c antagonist, chlorpromazine (CPZ) did not affect spatial food reinforced lever-pressing;- Learning working memory in rats, which was evaluated in radial-arm maze task abilities, such as acquisition curves and final (Olton and Samuelson, 1976). On the other hand, Beatty and Rush percentage of correct response in this task, (1983) reported the disruptive effect of haloperidol (HPD) on spatial ware decl i ned gradual I y with aging ( 2-25 working memory. There is a difference in D2 receptor subtype months). BY-1949{I-I0 mg/kg/day oral ly treated specificity between these antidopaminergic drugs. In the present from 10 days before discriminative learning to study, therefore, we compared the effect of the following the end) improved these reduced learning dopaminergic antagonism differing D2 receptors selectivity on 8-arm abilities in the bell-shaped dose-response radial maz.e behavior; CPZ (2 mg/kg, i.p.), HPD (0.25 and 0.5 manner in aged rats{19-2tl months). Optimum dose mg/kg, i.p.), and sulpiride (SPR; 50, 75, and 100 mg/kg, i.p.). These seems to be 10 mg/kg. Additionally, some of rats drugs were treated 30 rain prior to testing. The animals were tested treated with BY-1949 showed increase of total once under a particular treatment condition at intervals of a few days. lever-pressings. Ani racetam al so improved these The order of treatments was counterbalanced among subjects. HPD abilities. and SPR'significantly decreased the number of correct choices in the (2} Siclrnan type conditioned avoidance task;- In first 8 choices whereas CPZ had no effect. However, SPR was less ensuing sessions, reducing of shocks received in effective than HPD in spite of the highest selectivity to D2 receptors adult(8 months) was more rapid than that in among the drugs investigated. It might be due to the less penetration aged!25 months). Whereas in the aged rats the of SPR into the brain (Mizuchi et al., 1983). Since there was no number of total lever-pressings increased relationship between running time and the number of correct choices, progressively by repeating the session, it was these performance deficits were not caused by drugs-induced motor maintained constant in adult ones. Both disturbance and/or sedation. BY-1949(I-I0 mg/kg) and aniracetam (I0 mg/kg) ware reduced the number of shocks received and These results suggest that dopaminergic D2 receptors are important in increased the number of total lever-pressings. the processing of spatial working memory. These results suggest that repeated administration of BY-1949 exerts an ameliorating I. Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., effect on learning- memory impairment in aged 2512-1 Oshikiri, Konan-machi, Osato-gun, Saltama 360-01, Japan. rats. 2. Institute of Psychology, University of Tsukuba, 1-1-1 Tennodai, Department of Pharmacology, Fuj i gotemba Research Tsukuba-shi, Ibaraki 305, Japan. Labs., Chugai Pharmaceutical Co., Ltd., Komakado, Gotembashi , Shizuoka, 412, Japan. 32.02.22 32.02.23 ANTIAMNESIC EFFECTS OF DM-9384, A PYRROLIDONE EFFECT OF DM-9384, A PYRROLIDONE DERIVATIVE, ON DERIVATIVE, ON DRUG-INDUCED AMNESIA A!(I~AL MODELS BENZODIAZEPINE INDUCED A~NESIA T. Nabeshima~ Y. Noda, l(. Tohyama, S. }farter and T. K. Tohyama, T. habeshima and T. Kameyama ](ameyama Benzodiazepines are widely used as anxiolytics, In relation to the prolongation of life-span, an hypnotics and premedication for surgical purposes. increased number of patients of dementia is making a However, they are known to often produce anterograde new social problem. The development of the effective amnesia in patients. This amnesic action may be nootropic drugs is a social requirement. We attempted desirable in certain situation, e.g., preceding to evaluate an antiamesie effect of N-(2,6-dimetyl- surgery, but is a serious problem for outpatients. It phenyl)-2- (2-oxo- 1-pyrrolidinyl) acetamide (1).~-9384, has been also reported that benzodiazeplne produced Daiichi Seiyaku Co. Ltd., Japan), a cyclic derivative an amnesia in laboratory animals. Benzodiazepines of 6ABA. An effect of DM 9384 on the cyclohe• reportedly produce their effects by facilitating M)-, scopolamine(SCOP)- and hemicholinium-3(HC-3)- central GABAergic transmission via specific induced amnesia was investigated in mice of ddY benzodiazepine receptors. In our previous study, N-(2, strain using passive avoidance(PAR) and rapidly 6-dimethyl-phenyl)-2-(2-oxo-l-pyrrolidinyl)aeetamide learned conditioned suppression(CS) of motility. The (DM-9384, Daiichi Seiyaku Co. Ltd., Japan), a cyclic step-down latency(SDL) of PAI~ was significantly derivative of G~BA, attenuated GABA antagonist-induced prolonged after training. The motility was amnesia. Therefore, we attempted to evaluate the significantly decreased after training. The treatment effect of.DM-9384 on benzodiazepine-induced amnesia by with CXff(s.c.) shortened the SDL of PAR and using a one-trial passive avoidance response(PAR) in attenuated the CS of motility(amnesic effect). The ddY mice. Chlordiazepoxide(CDP) impaired the PAR when treatment with SCOP(s.e.) and HC-3(i.e.v.) showed the administered s.c. 20 min before the training test. DM- same amnesic effect in PM~. DM-9384(3-60 mg/kg) 9384 administered p.o. 15 min before the training test improve~l the CX~(30 and 60 mg/kg)-induced amnesia in improved the CDP-induced amnesia, but aniracetam, the PAR and CS of motility methods when administered other cyclic derivative of GABA, [ailed to improve it. before(p.o.) and immediately(i.p.) after training. The Muscimq], a GABA agonist, improved the CDP-induced effect of DM-9384(5 mg/kg) was attenuated by the amnesia when administered i.p. immediately after the trea'tmeat with hicuculline(0.5 and 1 mg/kg) and training test, but not before the training test. The pierotoxin(1 =g/kg). The SCOP- and flC-3-induced antiamnesic effect of DM-9384 on the CDP-induced amnesia was improved by DM 9384(30 and 60 mg/kg) when amnesia was antagonized by bicuculline, a GAB~ administered before training. He have reported that antagonist. These results suggest that DM-9384 DM-9384 was able to improve the picrotoxln- and improves the benzodiazepine-induced amnesia via GABA bicuculline-induced amnesia models. Taken together, neurons. However, since aniracetam and the these results indicate that D.~-9384 may interact with pretraining administration of muscimol failed to GABfiergic and acetylcholinergic neuronal systems and improve the CDP-induced amnesia, D~-9384 may interact produce its antiamnesic effects. with not only G~BAergic, but also other neuronal Faculty of Pharmaceutical Sciences, ~eijo University, systems. Tenpaku-ku, ~agoya 468, Japan Faculty of Pharmaceutical Sciences, Meijo University, Tenpaku-ku, Nagoya 468, Japan 305 32.02.24 32.02.25 EFFECT OF DM-9384, A NEW PYRROLIDONE DERIVATIVE, ON DISPOSITION AND METABOLISM OF DM-9384, A CYCLIC GABA LEARNING BEHAVIOR AND CEREBRAL CHOLINE ACETYLTRANSFERASE DERIVATIVE, IN THE RAT, DOG AND MONKEY ACTIVITY IN RATS K.Sudo, K.Hashimoto, Y.Fujimaki and H.Tachizawa S. Kawajiri, T. Sakurai, H. Ojima, S. Hatanaka, DM-g384,N-(2,6-dimethylphenyl)-2-(2-oxo-l-pyrrolidinyl) T. Yamasaki, H. Kojima and A. Akashi. acetamide , a new cyclic GABA derivative, has potent N-(2,6-dimethylphenyl)-2-(2-oxo-l-pyrrolidinyl) acetam- effects on improvement of learning and memory in animal ide (DM-9384) has been shown to antagonize the amnestic models(S.Kawajiri et ai.,1988). effect induced by picrotoxin or bicuculline in mice In the present study, the metabolic disposition of DM- (Nabeshima et ai.,1987). In the present work, the effect 9384 was studied in the rat, dog and monkey given I~C- of DM-9384 on learning behavior, ATP content and choline DM-g384 orally at a dose of 30 mg/kg. 14C-DM-9384 was acetyltransferase activity was examined in rats. well absorbed by the three species, and distribute~ Electroconvulsive shock (ECS, 30mA, O.2sec), given rapidly and widely to the rat tissues. The peak blood immediately following acquisition training in one-trial levels of z4C in these species were attained at I-2 hrs step-through avoidance task, reduced passive avoidance after the dosing, and declined with biological half-lives at 24h later. The passive avoidance was also disrupted of 2-3 hrs. Tissue/blood ratios of 14C were approximately by scopolamine injection (Img/kg, i.p.) 15 min prior to 1.0 in most of the rat tissues, indicating DM-9384 and the acquisition training. These deteriorations in its metabolites were capable of crossing the blood-brain passive avoidance were prevented by prior treatment with barrier rapidly. However, from our autoradiographic DM-9384 (l-3mg/kg, p.o., 60 min before training). In studies, na specific localization of 14C was found in the rats that were sacrificed by microwave irradiation rat and monkey brain regions at the dose of 30 mg/kg. immediately after ECS, cortical and hippocampal ATP was Approximately 82-84% of the administered dose were decreased to 85% of control level. DM-9384 (3mg/kg, excreted into the urine of these species.ln the serum and p.o.) prevented this decrease. In the light-dark urine of these species, M-3(hydroxylated DM-9384) was discrimination task, rats were trained with positive found as the major metabolite with several kinds of minor reinforcement for 20 days. Rats that received DM-9384 metabolites. In addition, metabolite patterns in the rat (3mg/kg/day, p.o.) acquired more than 85% correct brain indicated that unchanged DM-9384 accounted for the response on the 14th day, whereas rats receiving vehicle majorypart of total z4C, suggesting that the active alone achieved this level on the 18th day. Choline substance in vivo after the dosing might be DM-9384 it- acetyltransferase activity in the cerebral cortex and self. This study also clarified no species difference hippocampus of rats receiving DM-9384 (l-lOmg/kg/day, in the metabolic dispositions of the drug among the rat, p.o.) for 14 days was significantly increased by 7-9%. dog and monkey. Thus, it is conceivable that metabolic These results indicate that DM-9384 improves the disposition of DM-9384 in humans may be similar to that impaired learning and facilitates the acquisition, in the animal species. effects which may be in part due to protection against Research Institute, Daiichi Seiyaku Co., Ltd., 1-16-13, the decrease in ATP and the augmentation of choline Kitakasai, Edogawa-ku, Tokyo, 134 Japan acetyltransferase activity. Research Institute, Daiichi Seiyaku Co.,Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134, Japan. 32.02.26 32.02.27 DENBUFYLLINE - A NOVEL DRU6 FOR THE TREATMENT OF CEREBRAL VASCULAR DISEASE PRECLINICAL EVIDENCE FOR BENEFICIAL EFFECTS OF THE W.H.Greb, M.O'Connollv. M.-E.R.Mayer; D.Wolf CALCIUM ENTRY BLOCKER NIMODIPINE IN THE TREATMENT OF DENBUFYLLIRE (BRL 30892), ~as tested against placebo in a two-part study using a total of II0 patients with cerebrovascular disease (CVD) 97 pa- GERIATRIC DISORDERS tients with mlti-infarct and mixed type dementia, 13 patients with senile T. Schuurman and J. Traber dementia Alzheimer's type). The clinical diagnosis was confirmed by the clinical picture and the Syndrome Short Test.The diagnoses multi-infarct There is evidence that a dysregulation of the Ca2+-homeo - dementia and senile dementia Alzheimer's type wore characterized by Ha- stasis in neurons plays a role in the aging process of schinski Ischemic Score. THe effect of treatment was examined monthly by the rat brain. Brain aging in the rat and aging in the Flicker Fusion Test, a psychometric test battery (including Benton Test, Digit SyE~bol Substitution Test and Pauli Test), and two external general are characterized by a variety of behavioural and assessment scales (SCA6 and NDSIE). In the first part of the study patients other deficits. Among these are reduced learning and were treated with 50 ~ Denbofylline t.i.d, or placebo respectively. In the memory capacity, disturbed social behaviour, impaired second part an additional group with an administration of 25 mg motor coordination etc. In a series of experiments we DENBUFYLLINE t.i.d, was included in the study. Both parts were carried out Z+ as double blind parallel studies over a period of three m~nths. investigated the effects of the Ca -entry blocker nimo- In this presentation the results of the cofmmon evaluation of the %~ parts dipine on behavioural functions of old rats. Results: of the study are reported concerning the comparison of the 50 mg t.i.d DEN- BUFYLLINE with the placebo group. The evaluation was carried out by ANOVA - 16 months old rats treated for 6 days with i0 mg/kg considering the patients fully corresponding with the conditions of the nimodipine escaped faster from a water-maze and made protocol including the r-cmpliance. fewer errors than vehicle controls From the statistical comgarlson beti~en the two treat~ment groups an exten- sive improvement after Oenbufylline compared to placebo could be found. - 25 months old rats fed for 4 weeks with nimodipine- After one month Ig of 22 criteria showed a statistically significant diffe- containing food (860 ppm) showed more exploratory rence between the trea=nt groups increasing to 21 significant criteria behaviour in an open field test than normally fed rats after two and three months. In most of the criteria a very high significance level was detected. Consi- - the ability to keep balance on a small rod was much dering the calculations after the second and the third month the probabili- better preserved in 24-30 months old rats fed with ty of means being the same was less than I k, mostly less than 0.i k, in nimodipine-food than in age-matched controls all points of the psychometric test battery except the sign "corrections" in the Pauli-Test. Similar results wore seen using the external assessment - chronic nimodipine feeding delayed the onset of ab- scale NDSIE and the flicker fusion test. normal walking patterns (foot print test) and improved Moreover the investigations by means of the external assessment scale SC~G locomotion in old rats. showed statistically significant differences bet~n active and placebo on the 0.I k level in all points already after I month of treatment. These data suggest that nimodipine improves (central) Thus efficacy of DENBUFYLLINE was clearly ;hown compared to placebo. In re- nervous system function in old age. spect to their mental, emotional and social capacities the patients recei- Neurobiology Department, Troponwerke, Neurather Ring I, ving DENBUFYLLINE benefitted already after I month of treatment. Under DENBUFYLLINE treatment ii patients complained about mild to moderate 5000 K61n 80, FRG gastrointestinal disco.nCort, and 2 patients dropped out because of nausea and vomiting. Gastrointestinal side effects are typically known to be asso- ciated with treatment by Xanthine-derivatives. Beecham-WOlfing Clinical Pharmacology Research Institute, Stresemnnallee 6, D-r Neuss I. 306 32.02.28 32.02.29 MICXOH~lu~,N~4CD{.s ~ THE N~OH~: ~IIEO~ODblM~)RyEFFECTS BENZODIAZEPINE USE AND DEPENDENCY RISK IN GERIATRIC ON CEF~L S~APTIC ~I'IVITY ~ED ON ~ICROIOI~tOP~O~TICsTUDIES. PATIENTS. A. Nnillis,. E. Kout~oukos, E. ~gelopoulo~,W. Sm~rnis and C. E.Tempesta,A.Di Giovanni,L.Janiri,P.Mannelli,A.Persico, Stofanis. Hraoetam, Anirncetam, Prnmirncetam and Oxiracetas, the L.Antico. representatives of a non class of droga, the Nootropics, have Benzodiazepine prescriptions to elderly patients should been ahown to improve memory and learning iua variety of animal be cautiously given because drug metabolism is models.Hoxever, lhe exact mechanism of action of the nootropi~n progressively impaired by age and a prolonged use of is still obscure but it ham been shoe= that all the abovm benzodiazepines,even at low doses,is liable to induce substances are able to prevent scopolamine-induced amneaia in dependency. In the present epidemiological study,carried both rats and mce by iof]ue~cingbrnln cholinergio mechanisms (I,2). !o an effort to elucidote further their mode of action we out in a southern Italian region(Molise),446 primary- have ~tudied the effect~ of Pirecstam- the prototype of the care institutionalized geriatric patients were screened ~ootrop,cn - ca s~ngle central neuronal activity of the about psychotropic drug consumption. Out of this sample, ~matosensory cortex and the hippocampos of ~ho rat following 35 subjects who had received benzodiazepine prescriptions sTstemic and microiontophoretic administrations of the substance underwent a protocol consisting of data collected on ~d ~e here reported that Piracetam~es able to modify single ::euron actsvity on a great number of epontaneoualy firing personal,health and drug history and data from an neurons. Cortical ~euro=s respondedmostly w~th depression, whale interview.about their subjective perception of the drug's almost equal percentages of ~he hippocempal z~eoronaresponded effects and their attitudes regarding its use.A number e~ther wtib depression or iae~:Jtat~on. ~oreover ~t was shown ~o of these patients discontinued therapy and were assessed :nteract xl~n :~e ~napcic effects of ~lutamic acid, in the following 4-7 days by means of a withdrawal symp- ~oetyi~hoi{:;e .=~ $~F.J$., either ~ynergtaticniiy ur tom questionnaire . The results were concerned with : =nc~onl~t!ca,:y, -hen liven i~gether w*th each of the above ~ucetances (3,~ ). s .ddition ~o ~ne above observat{ons~e have 1) epidemiological traits of the population investigated; ~Lud,ed the ~:~:~r~c~ioo of Pzracetam ~,th the synap%ic effects of 2) clinical diagnosis; l.opam~ne ann Yorsor~na*ice on the e=mebra;n =,nee end ~e have 3) tteatment's aspects (source of prescription,indication f:~l~d that Pi=~c:~amr sy~ergls%lcc;ly ~!h ~he ~epre~=nt onset,duration,breaks,main and side effects,associated ~ffects ot oatechoiamlneeon th~se :euroaa ~hi~n ~ere ~enaltive therapy,etc.); to ::0 .cnszsten: ~:.on ,,th both =cbstcnces.Hcwever, 4) patients feeling and compliance to the treatment; azetylcholine,c~t~chol~mzn:s or cm;:c~c,dswas ound. -:.e above 5) eventual withdrawal symptoms . ohservationa, ~upport the assumptionthat ~raretam ia cbla to modify ~eurc~a! activity ca ~ell ~n ::euroiro:ism~tiarreceptor Results are discussed with regard to the risk of benzo- interactions at the central ~ynapt,c e:tea. diazepine dependency in elderly subjects . E.N.P.L Dept. of Psychiatry, Zginzmion ~oepztal, Mhene, G~eece. Drug Dependence Unit , Dept. of Psychiatry , Catholic Pepeu G. and SpignoliG.(lg~6):CI.Neuropharm.9:huppi.4:2~-300 University S. Heart , Largo A. Gemelli 8 , 00168 Rome , Giurgea C. and Salama ~.(1577): Prog Neufcp~ychopharmae.l:235-247 Italy Maillls ~. et al.(~9~S):hbstracts p.2a.,:.p.A. Reg. ~ymposium, ~then~ 13-17 0~t. Haillia ~.(1~5?):~bs.,p.llg,Iii Congr.l.P.A.,Cbicago,2:-31 Aug. 32.02.30 32.02.31 LONG TERM OUTCOME OF BENZODIAZEPINE DEPENDENCE ~.aTONIN, N-ACETYLSEROTONIN AND SENOTONIN IN PINEAL ORGANS OF SUICIDE ~ NON-SUICIDE VICTTWS. U.Dickmann, W.Poser and S.Poser G.Kauert, W.Eisenmenger and E.Liebhardt The long term outcome of patients with benzodia- In 200 pineal organs, which have been prepared from zepine dependence or abuse was analyzed. A cohort cases with documented time and cause of death after consisting of 991 benzodiazepine patients was legal autopsies (collection period: March to August observed for an average of 5 years. All full- 1987) the content of Melatonin {MT), N-acetylserotonin filled the DSM-III criteria for a substance use (NAHT) and Serotonin (hHT) was estimated by High Perfor- disorder(nicotine excluded). They took benzodia- mance Liquid Chromatography with Electrochemical Detec- zepines for at least one month. 491 alcoholics tion, After testing the dependencies on demographic (abuse and dependence) served as controls. Only a parameters (age, sex, weight, height and post mortem small proportion of the benzodiazepine patients delay) the contents of pineal HT, NAHT and 5HT were used these drugs exclusively(12%), the majority plotted versus time of death and checked for differences were polydrug abusers, Some preliminary results between suicide and non-suicide victims with regard to of the follow-up were: the circadian rhythm. I. Benzodiazepine abuse was a rare disorder. De- Results: I) There could be found significant differences pendence was much more frequent.The latter was in the day-night content of pineal ~T with large ampli- a rather chronic condition. tudes (Xday=l,84• ; ~night=23,3+43,6; median: 0,0 and 10,8 resp.-ng / pineal organ) with--similar behavior of 2. Isolated benzodiazepine dependence had a bet- NAHT and inversed behavior of 5HT in the non-suicide ter prognosis than a'ny other addictive disorder. cases. 2} In the suicide victims in average there could 3. Isolated benzodiazepine dependence was often be observed a marked lower amplitude of the MT rhythm complicated by severe withdrawal symptoms (fits with significa_nt higher MT values during day time (Xday and psychoses). =12,8 +16,2; Xnight = 43,8+59,4; median: 6,6 and 8,0 resp. ng/ pineal organ) and also similar behavior of 4. The soci~l impact of benzodiazepine dependence NAHT and 5HT. was small in comparison with other substance use Conclusions: The pineal content of ~T in most non-sui- disorders. cide cases reflects the time of death at day or night. 5. The mortality of benzodiazepine dependent Suicide victims exhibit a changed pattern in pineal MT patients was increased (2-3fold) but less than biorhythm compared to cases with death of another cause. that of alcoholics or polydrog abusers. In con- From the literature there is evidence that stress and trast to other substance use disorders most enhanced sympathetic activity do not influence the pine- deaths occured for natural reasons. The only al MT rhythm in humans. The question, whether or not the exception was suicide, altered MT rhythm in suicide is a pathogenetic factor prior to suicide, cannot be clarified from our results Psychiatrische und Neurologische Universit~ts- and must be subject of elucidation by investigations of kliniken, v. Sieboldstr. 5, D-3400 G6ttingen patients with suicidal behavior. Institute of Forensic Nedicine, University of Munich, Frauenlobstra~e 7a , D-8000 MCmchen 2, F.R.G. 307 32.02.32 32.02.33 THERAPEUTICALPROBLEMS WITH LON6-TE~ BENZ~IAZEPINE_ THE DIFFERENT EFFECTS OF HYPNOTICS ON SHORT-YERM MEMORY DEP~iOENCY A~) OD~PARISONOF lie ABUSEPOI~IAL OF TWO J. Ishi$ooka, M. Murasaki, Y. Ishii, T. Kasahara, M. Aida, BEIfZODIAZEPINERECEPTOR AGONISTS N. Watanabe, M. Suzuki, H. Tskeuehi and S. Miura S. Apelt, C. Schmauss and H.M. Emrich The effects of hypnotic drugs on short-term memory were investigated using Sternberg memory scanning task. ~itndrawal phenomena in long-term Benzodiazepine (BDZ) The drugs tested were flurazepam 15mg, triazolam 0.25mg, zopiclone 10mg and placebo. Eight male volunteers aged users were evaluated in a clinical study in 14 inpatients 23 to 26 were given flurazepam or triazolam at 8 in the Specifity and intensity of BDZ withdrawal symptoms' were evening in a double-blind cross-over method, and zopiclone in a single-blind manner. Sternberg memory similar in high- and low-dose dependent patients. scanning task was carried out before and 1 hour after the Another 12 patients with long-term BDZ dependency administration of a test drug and in the next morning. participated in a double-blind study comparing the Overall reaction times were increased 1 h following treatment with all three drugs, especially with signifi- "liking"-potential of alprazolam and diazepam. The cant differences in treatment of flurazepam and zopiclon~ Interactions between drug effect and response pattern at hypothetical equivalent dose as to the hypnosedative- i h were observed in treatment of flurazepam or zopiclone, anxiolytic potency was assumed for alprazolam : diazepam with statfstical difference in the latter. On the other hand, triazolam treatment showed a significant inter- as 1 : 10. In a drug-choice test 11 of 12 patients action between drug effect and set size at i h. These preferred alprazolam to diazepam. The data suggest effects were not observed in the next morning. Th~ results obtained in the present study showed that in patients with long-term BDZ dependency that these three hypnotics could affect short-term alprazolam has a higher abuse-liability than an memory by the possible effect of flurazepam and zopiclone on the response-selective organization, while by that of equivalent dose of diazepam. triaiolam on the serial comparizon stage. Max-Planck-lnstitute for Psychiatry Department of Psychiatry, Kitasato University School of Kraepelinstr. 10, D-8000 Munich 40 Medicine, 863-1 Asamizodai, Sagamihara, Kanagawa 228, Japan. Fed.Rep. of Germany 32.O2.34 TENILSETAM (CAS 997) PREVENTS LEARNING DEFICITS, AND PROTEIN BIOSYNTHESIS IMPAIRMENT INDUCED BY FOREBRAIN ISCHEMIA IN GERBILS U. Schindler, E. Schraven and R. Beyerle Transient forebrain ischemia has been shown to induce profound learning deficits in gerbils trained one day after the ischemic insult. In addition a prolonged reduction in brain protein biosynthesis follows transient cerebral ischemia. The effect of the novel nootropic tenilsetam (CAS 997, (~)-3-(2-thienyl)-2- piperazinon) was evaluated in the gerbil forebrain ischemia model. Bilateral carotid occlusion (3 min) of male mongolian gerbils was conducted under halothane anesthesia. The drug was administered (i.p.) after the end of ischemia. Training and retention testing in a one-trial passive avoidance paradigm was per- formed one and two days after ischemia, respectively. In a seperate set of experiments brains were removed following various periods of recirculation and the incorporation of tritium-labeled leucine was used to measure hippocampal protein biosynthesis. Tenilsetam at doses of 0.3 to i00 mg/kg dose- dependently reversed the ischemia induced learning deficit. Gerbils treated with I00 mg/kg performed as well as sham-operated controls. At this dose tenilsetam significantly attenuated the reduction in hippocampal protein biosynthesis at various periods of recir- culation. These data suggest that the beneficial effect of tenilsetam against the ischemia induced learning deficit could be due to the amelioration of protein biosynthesis. Pharmaforschung Cassella AG, Hanauer Landstr. 526, D-6000 Frankfurt am Main 61 308 32.03.01 ~LONIDINE IN THE OPIATE WITHDRAWAL SYNDROME M. 3a~ovi~Ga~ic t V. ~. Paunovic, S. D._Totic, M. R. Boqdanovic ana G. P. Niko!ic-Balkoski Disturbed noradrenergic transmission is partially zes~on- POSTER sidle for the withdrawal symptoms that arise due ~o tqe abrupt discontinuation of the opiates (M. S. Gold et al., PRESENTATION Lancet: I, 92g-930, i~78; M. S. Gold et al., 3A~A: 2~3, 343-346, 1980). Application of clonidine (presynaptzc aL~- 32.03 na agonist) may reduce the excessive noraorenergic a~ivi- ty and prevent the withdrawal syndrome. This study reports the results of the in-patient %zeot~er;t of the opiate addicts by abrupt Piscontinuation of ire o~- lares and application of a) clonicine and D) neuroleptic drugs ~phenothiazines).Six%een ~ib) male opiate ae~icts submitted to abrupt discontinuation of the opiates ~m;e Benzodiazepine and Alcohol treated with clonidine (8 patients) and promethazine ~ Da tients). Clinical assesment was sone on the 2nd, 4%n amc Dependency 7th day after the discontinuation of the opiates ant cmm- sisted of measuring the blood preassure ~BP)~ freque 32.03.02 32.03.03 COMPARISON OF FLUVOXAMINE VERSUS ARGININE IN 50 PATIENTS PLASMA CYCLIC AMP IN NON-ABSTINENT CHRONIC HOSPITALIZED FOR ALCOHOLIC WITHDRAWAL ALCOHOLICS. RELATION TO CLINICAL PARAMETERS. G.Moussas, L.Lykouras, M.Markianos. ARCHAMBAULT 3.C.* Plasma cyclic AMP (cAMP) levels were determined in a group of 36 male chronic alcoholics during 50 a!coholic-demendant patients {D.S.M. III criteria) a period of their usual alcohol intake and Dave been hespitalized for 28 days withdrawal. They compared to 29 normal controls significantly ~e~._d. in an ,open study, after randomization, either lower values (p<0.005) were found in the patient fiuvoxamine (200 mg/day of FloxyfraIR), or arginine group. The possible influence of age, chronicity tablets/day of Eucol 150). of drinking, family history of alcoholism, 2~ patients, with a mean age of 41,7 ~ 10,4 years, dementia and liver injury on plasma cAMP levels ~eight 68.3 + 11,1 kg, received fluvoxamine. 25 patients was examined by multiple regression analysis. w;th a mean ~ge of 40,1 + 11,5 years, weight 71,2 No influence of those factors could be establish- <2,4 kg, received argini~e. ed except that demented alcoholics showed a trend toward higher levels than non-demented The scores of scales of depression (M.A.D.R.S.) anxiety subgroup. The results suggest a reduced ~-adre- (Tyrer), of alcohol craving, of clinical global nergic receptor activity during chronic alcohol impression and the anto-evaluation of sleep quality, ingestion. s;eep lenght and time before sleeping, decreased in Department of Psychiatry, Athens University the 2 groups. Medical School, 115 28 Athens, Greece. E!uvoxamine was more efficient than arginine on all these ~tems and a significant difference was observed on days 3, 7, 14 and 28. All predelirium symptoms disappeared more quickly in the fluvoxamine group. Both drugs were well tolerated. Normalization of hepatic biological disturbances was observed in the 2 groups. No side effects were observed in the 2 groups. Eluvoxamine improved the quality of withdrawal and was more active than arginine. - Dr ARCHAMBAULT J.P. - Centre R~gional d'Alcoologie ~e Picardie - C.H.S. - 02560 PREMONTRE 309 32.03.04 32.03.05 ABNORMAL P3 IN ALCOHOLICS WITH DISORDERED MOOD AND EFFICACY OF PIRACETAM IN THE TREATMENT OF AGGRESSION. ALCOHOL ORGANIC MENTAL DISORDER M. Branchey, L. Buydens-Branchey and C.S. Lieber. C.Miller, Ch.Barnas, V.GOnther, H.Ehrmann, Abnormalities in the P3 component of event related poten- tials (ERP) have been found in alcoholics taken as a Piracetam (2-oxo-pyrrolidine-l-acetamide) is a group, but these abnormalities have not been specifically derivate of gamma-aminobutyricacid. Despite the studied in subgroups of alcoholics. Our goal was to lack of controlled trials providing positive investigate the P3 component of auditory ERP in alcoholic evidence of any correlation between dose and patients with and without mood and aggression disorders efficacy, there has been a marked tendency in and in a control population (non-alcoholic hospita& pa- recent years to increase the dose of piracetam tients) in order to determine whether alcoholics with in treatment of organic mental disorders of depressive, suicidal or aggressive tendencies differ in varying etiology. The following paper presents their P3 characteristics from patients without these an investigation of the efficacy of piracetam in tendencies. A significantly lower P3 amplitude was ob- alcoholic organic mental disorder. A double- served in alcoholics who had a history of incarceration blind placebo-controlled study design was used for crimes involving violence. The mean • SD P3 ampli- to compare two dosages of the substance in 60 tude for these patients was 3.3• ~V vs. 6.8• pV for patients. Exclusion criteria were forms of alcoholics without such a history (p <.0Ol) and vs. alcoholism secondary to endogenous psychoses, 6.9• ~V for the controls (p <.001). Low P3 amplitudes marked c~inical manifestation of cerebral were also found in patients with depressive and suicidal arteriosclerosis, severe craniocerebral trauma, tendencies when compared to alcoholics without these and major physical illness, especiaZly alcoholic tendencies but differences failed to reach significance. cirrhosis. The study was started after the acute A P3 deficit could thus characterize a subgroup of al- withdrawal symptoms had subsided. This was coholics with disordered regulation of aggression, such between 7 and 10 days after the last alcohol as described in type 2 alcoholics. Alternatively, P3 consumption. The patients were assigned to the deficits could be linked to some psychopathological follqwfng 3 groups in a random double-blind condition other than alcoholism in individuals who also manner: group 1 placebo, group 2 2x3g piracetam, abuse alcohol. group 3 2x12g piracetam. The cognitive functions In conclusion, the decrease in P3 found in alcoholics of the patients, especially short term memory could be associated with disorders in mood and aggression were assessed by the d-2 Test, determination of regulation in this patient population. Critical Flicker Fusion, the Pauli-Test and the "Syndromkurztest" (subtypes A to E) on the days VA Medical Center, Bronx, NY and Mt. Sinai School of 0,7,14,28 and 42. Medicine, New York, NY For evaluation of the data the Wilcoxon-Wilcox signed rank test and the Mann Whitney-U-Test were used. Department of Psychiatry, Innsbruck University Clinics. Anichstr. 35, A-6020 Innsbruck. 32.03.06 32.03.07 EFFECTS OF MATERNAL ALCOHOL EXPOSURE DURING EFFECT OF ETHANOL ON 3H-DOPAMINE RELEASE IN RAT NUCLEUS GESTATION AND/OR LACTATION PERIODS ON RADIAL- ACCUMBENS AND STRIATAL SLICES ARM MAZE LEARNING IN OFFSPRING RATS. V.A. Russell, M.C.L. Lamm, and J.J.F. Taljaard T. IWASAKI Fetal alcohol syndrome (FAS) is one of the Ethanol (lO-2OOmM) transiently increased tritium overflow important current topics in behavioral teratol- from superfused rat nucleus aco~t~s slices previously incu- ogy. Several studies using laboratory rats bated with 3H-dopamine (DA) and C-choline. The effect have shown that prenatal alcohol exposure re- was greater in striatal tissue and did not appear to be a sults in hyperactivity and deficits in avoid- non-specific membrane effect since 14C-acetylcholine(ACH) ance learning in the offspring. Appetitive release was not affected. Lack of antagonism by picro- learning, in addition to aversive one, should toxin suggested that y-aminobutyric acid (GABA) receptors be employed to get a conclusive evidence of the were not involved. Calcium was not a requirement and the learning deficiency. Moreover, effects of DA uptake blocker, nomifensine, was without effect. postnatal as well as prenatal alcohol exposure Ethanol appeared to be causing 3H-DA release into the cy- toplasm. K+-stimulated release of 3H-DA and 14C-ACh should be examined in the rat, which was a from nucleus accumbens and striatal slices was not affec- late-maturing animal. Thus, the present study ted. Clonidine-mediated inhibition of the K+-evoked re- was designed to investigate the effects of lease of 3H-DA remained unaltered. Ethanol attenuated maternal alcohol (15%) consumption during the the isoproterenol-inducad enhancement of 3H-DA release. gestation and/or lactation periods upon learn- Ethanol therefore appeared to interact with components ing of an 8-arm radial maze task by the rat of the DA terminals causing a transient increase in offspring. Acquisition of the maze learning the release of neurotransmitter without impairing was found to be profoundly retarded only in the K+-evoked release but apparently interfering with the offspring of mothers treated with alcohol dur- isoproterenol-induced effect. ing gestation. This result could not be ex- MRC Research Unit for the Neurochemistry of Mental plained by a secondary effect of malnutrition Diseases. Department of Chemical Pathology, University produced by the alcohol treatment, because body of Stellenbosch. Tygerberg Hospital, P.O. Box 113, weight increase in the offspring was suppressed Tyge~berg 7505, Republic of South Africa. by the alcohol treatment during lactation but not during gestation. The possibility of involvement of deficits in brain development (especially of the hippocampus) in the learning impairment was suggested. Institute of Psychology, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305, Japan 310 32.03.08 32.03.09 THE SEROTONIN UI~AKE INHIBITOR, FLUOXETIN~ REDUCES ON THE RELATIONSHIP BETWEEN ALCOHOL AND DRUG ABUS, ALCOHOL CONSI.Jq~SYTIONIN PROBLEM DRINKERS. D~SSZON A~D s~zcz,:~z~. C.A. Naranjo, E.M.Sellers, P.Sanhueza, H. Valencia. D.V.Woodley-Remus, o. ~s.~ovk. G.Kenne~, ICE.Kadlec The rising occurrence rate of depressive states and In our previous studies the serotonln uptake inhibltors zimelidlne, citalopram and suicides among alcoholics and subjects addicted to viqualine decreased alcohol consumption in rats and humans. We assessed the other substances has induced an increased interest in effects of fluoxetine, a relatively selective long-acting serotouln uptake inhibitor, the problem concsr~g the relation between depressi- in 29 male early stage problem drinkers randomly assigned to receive fluoxetine vity and the effect of alcohol and other addictive ma- 40 rag/day (n=8), fluoxetlne 60 rag/day (u= 11), or placebo (n=10) for 4 weeks. terials. The pathoEenesis of these states was obscure, Alcohol intake a~d compliance with drug therapy were assessed by seff-rcports recent biochemical ~nd receptor hypotheses have pro- and objectively and no other treatment or advice was given. Fluoxctine 60 rag/day vided new approaches to possible explanations of the decreased alcohol consumption by 16% compared to pre-treatment. Total drinks depreasogenic effect of alcohol and other addictive per 14 days decreased from CE-+ SEM) 115.8-+ 9.3 to 96.5-+ 9.5; mean daily materials. drinks decreased from 8.3 + 0.7 to 6.9 -+ 0.7; and mean drinks per drinking day Alcoholism and addiction are often taken to be essen- from 8.6 -+ 0.7 to 7.1 -+ 0.6 (all p < 0.01). Decreases in alcohol intake with tial factors furthering suicidal action.The shs_,-e in fluoxetine 60 rag/day were associated with reductions in serum gamma-glntamyl suicidal action of persons addicted to alcohol and transpepfidase (p = 0.10). Neither fluoxetine 40 rag/day nor placebo had effects other agents is growing higher.~ese persons reach on alcohol intake. Fluoxetlne 60 rag/day decreased drinking compared with the firs~ rank in the number of finished suicidal fluoxetine 40 rag/day (ANCOVAs, all p < 0.02), and decreased the variance of cases. These facts can be supported by our ~n expe- the response (change in alcohol intake) compared to placebo (p < 0.01). Effects riences gained from a systematical observatiimn of fi- on drinking appeared and disappeared rapidly. There were large interindividual nished suicides.in our study we submit an analysis variations in pattern of response. Decreases in alcohol consumption were not of the finished suicides of drug-addicts,the observed related to aide effect% an alcohol sensiti25ng reaction, changes in depression or group comprosed 244 cases/230 men and 14 Women /. anxiety, or any other subject trait or drug factor. These results indicate that all O. TESAi~OV~,M.D.,Ass.prof. Postgraduate Medical Insti- serotonin iaptake inh~itors tested thus far decrease alcohol intake in humans. tute,Dept.of Legal Medicine,Sasinkova 4,81108 Brati- Such drugs may be effective pharmacological treatments for reducing alcohol siava,CzechosloTakia. consumption in problem drinkers. Clinical Pharmacology Program, Addiction Research Foundation, Clinical Institute and Departments of Pharmacology, Medicine and Psychiatry, University of Toronto, 33 Russell Street, Toronto, Canada M5S 2S1. 32.03.10 32.03.11 WEIGHT LOSS INDUCED BY SEROTONIN UPTAKE INH]BITORS (SUI) TRANS~E~.IAt'CLONIDINE VERSUS CELORDIAZEPOXZDE TN ALCCEOL IN MALE HEAVY DRINKERS WITHDRAWAL EM.sellers. r ICE.Kadlcr_ DN.Woodlev-Remus G.R. Baumgartner, R.C. Rowen SUI attenuate ethanol intake and may affecI other consummatory behaviours in recent report in the literature suggested that oral humans. Effects of four SUI (zimelidine(Z), dtaloprum(C), viqnaline(V), clonidine may represent a new alternative agent for thq flanxetineCF')) on body weight and appetite were assessed in male non-depressed, management of acute alcohol withdrawal syndrome normal weight, early stage problem drinkers who were not trying to control food (G Baumgartner, R Rowen: Arch Intern Yed 1987;147: or alcohol intake in double-blind, randomized studies. Compliance with SUI 1223-1226). However, no study has yet investigated the treatment was objectively determined and no other treatment or advice was given. transdermal form of clonidine for this indication. In a In a double-blind crossover trial, 2 weeks of treatment with Z200 rag/day (n = 13) double-blind prospective controlled evaluation, 42 decreased body weight by 0.5+ 0.3 leg (~+ SEM) compared to a weight gain of patients were randomly assigned to either transdermal 0.5 + 02 kg during 2 weeks placebo (P) (p < 0.10). In two other double-blind clonidine or chlordiazepoxide. On study entry bot~ crossover trials weight losses were observed with 4 weeks C40 rag/day (0.8+ 0.2 groups were similar regarding demographics, alcohol kg) (n = 19) and 2 weeks V100 rag/day (0.6 + 0.9 kg) (n = 15) and V200 rag/day withdrawal symptoms (AWS), histories of prior alcohol (0.8 _z 0.4 kg) (n= 14) compared to weight gains (i = 0.3 + 0.3 kg) during use, physical findings and abnormal lab results pla~ (all p < 0.05). A similar weight loss (0.6--+ 0.4 kg) during 4 weeks C20 associated with alcohol dependence. Once in significant rag/day (n= 20) was not significantly different from the placebo (gain of 0.1-+ 0.3 withdrawal as measured by the AWS scale, the patients kg). In a double-blind parallel design study, 4 weeks of F40 rag/day (n=8) and started on their respective study medications and then F60 rag/day (a=11) decreased body weight by 1.9+ 0.3 kg and 2.1+ 0.8 kg, had observations made every 12 hours. Study scales respectively, while weight gain (0.1-+ 0.4 kg) was observed with P (n = 10), (F40 vs administered were the AWS, the Cognitive Capacity P: p<0.0R F60 vs P: p<0.05). F, therefore, was the most effective weight loss Screening Exam, the Brief Psychiatric Rating Scale, the treatment. Weight losses were not due to dec.reuses in calories from alcohol since Hamilton Anxiety Rating Scale, the Hamilton Depression V100 and F,40 rag/day had no significant effects oll alcohol intake. Furthermore, Rating Scale and subjective self-rating scales. the changes in weight and drinks were not correlated within any treatment group Clonidi~e was well tolerated with no patient experiencing (e.g., C40 ~ag/day, r = ~ F40 rag/day, r = 0..56; F60 rag/day, r = -0.15, all major adverse drug reactions. No patient in either study n.s.). Subjects reported decreased appetite during C40 rag/day compared to P group progressed to delirium tremens. Analysis of the (p<0.0S) and during F, especially the first 2 weeks, compared to baseline (F40: study data demonstrated more favorable AWS scores, p=0.10, F60:. p<0.05). Decreased caloric intake from food was likewise reported Cognitive Capacity Screening Exam scores, blood pressure, during C.40 rag/day (I)<0.05 compared to P) and during 4 weeks of F40 rag/day pulse, restlessness scores and quality of sleep for (I)<0.05) and F60 rag/day (i)<0.10). Side effects, such as mild, transitory nausea clonidine over chlordiazepoxide. In all the remaining and diarrhea, winch occurred with some SUL were not related to weight loss. comparisons, clonidine was shown to be as efficacious as These results confrere the role of the serotonergie system in the regulation of chlordiazepoxide. These results corroborate the earlier consummatorybehaviours and may have implicatiuns for the development d report on oral clonidine that an alpha9 agonist may pharmacological interventions for weigl~ loss and appetite control represent a new, and possibly even superio~ pharmacologic Clinical Pharmacology Program, Addic~km Re,~uch Foundation, Clinical treatment in the management of acute alcohol withdrawal Institute and Departments of Pharmacology aad Medicine, University of Toronto, syndrome. Transdermal clonidine has important 33 Russell Street, Toronto, Canada MSS 2SI implications in the compliance of outpatient alcohol withdrawal treatment. William S. Hall Psychiatric Institute, P.O. Box 202, Columbia, South Carolina, 29202, U.S.A. 311 32.03.12 32.03.13 GROUP THERAPY AND PROPRANOLOL FOR BENZODIAZEPINE DEPENDENCE LIABILITY OF THE BENZODIAZEPINE HYPNOTICS WITHDRAWAL QUAZEP~M AND TBIAZOLAM IN CATS C. Hallstrom, G. Crouch, M Robson E[_Ongini, M. Marzanatti, C. Barzaghi and A. Monopoli 24 benzodiazeplne dep~e~t p~nts were randomly treated as out-patients with either A clinically important withdrawal syndrome has been re- coginitive group therapy or non-specific group ported to occur after abrupt discontinuation of long-term therapy, for tranquillizer withdrawal. Patients treatment with benzodiazepines (BZs). We designed a study were also given either propranolol, placebo or to assess physical dependence liability of the BZs quaze- no additional pills. They were treated for a 10 pam (0) and triazolam {T). Cats were given Q or T orally week programme and followed-up after one year. once daily for 21 days at m dose 5-fold that used clini- 8 patients stopped their tranquillizers, 10 achieved a substantial reduction and 6 managed cally (Q = 1.25 mg/kg; T = 0.04 mg/kg). Two approaches less than a modest reduction in medication. were used: {I} precipitated withdrawal test upon admini- Cognitive therapy was shown to be significantly stration of the BZ antagonist flumazepil {F), 5 mg/kg ip; be.tter than non-specific group therapy for (2) spontaneous withdrawal after stopping BZ treatment. stopping tranquilizers. Selected behavioral items and sleep-waking patterns were S~ptoms remained relatively constant throughout recorded during dosing period and at withdrawal. tranquilizer withdrawal. Medication reduction in benzodiazepines During treatment period, Q produced mostly sedation. T dependent patients can be achieved without a induced marked ataxia, hyperactivity, and unusual aggres- deterioration of their clinical condition. sive responses. Signs of withdrawal (staring behavior, muscle stiffness, pupil dilation and appetite suppression) were precipitated by F after stopping treatment with both BZs. RE~ sleep decreased and waking increased. In the spontaneous withdrawal test, no behavioral changes were observed after stopping Q treatment. Sleep-waking pat- terns ~radually returned to baseline. Conversely, at dis- continuation of T treatment there were moderate withdrawal signs, mostly limb tremors and altered behavior. The data indicate that the two BZs have different with- drawal-producing properties, being T, but not Q, effective in the spontaneous withdrawal approach. Moreover, with T the most impressive behavioral changes were observed during the dosing period rather than at cessation of treatment. Research Laboratories, Essex Italia, I-2OO60 Comazzo, Milan Italy. 32.04.01 A DOUBLE-BLIND CONTROLLED STUDY OF CM6912 (ETHYL LOFLA- ZEPATE) ON NEUROSIS USING PLACEBO A. Morl, M. Murasakl, K. Ohara, K. Kamijlma, K. Hase~awa~ Y t Hada, S. Mizushlma, G. Yagl, M. Kurihara, S. M/ura POSTER A double-bllnd controlled trial on CM6912, a long-term antlanxiety drug, comparing with placebo in the treatment PRESENTATION of neurotic patients, was conducted. CM6912 was admi- nistered on a fixed schedule of one 2 mg tablet once a 32.04 daily after supper. The observation period was 4 weeks. Both PNRS which was designed in Japan and Hamilton Anxiety Scale were utilized for the evaluation of symp- tomatological parameters. The subjects of the trial consisted of 241:121 cases of CM6912 (CM group) and 120 cases of placebo (P group). I~ overall evaluatlon, CM group was significantly superior Methodology of Drug Studies to P group by U-test concerning to final global improve- ment rating (P<0.001). As to improvement rate, "Markedly and Classification of improved" results were obtained in 18% of the cases for CM group -and 6% for P group, "Moderately improved or Psychiatric Disorders more" results in 46% for CM group and 22% for P group and, "Slightly improved or more" results in 68% for CM group and 52% for P group. The statistical analysis for each of these improvement rates reached at significant levels of P 312 32.04.02 32.04.03 EFFECTS BY REPEATED TESTING ON HALOPERIDOL-INDUCED METHODOLOGICAL CONSIDERATIONS FOR THE ASSESSMENT OF DOSE- EFFECTS ON TREADMILL PERFORMANCE ~ND ON STRIATAL DOPAMINE EQUIV~ OF BENZODIAZEPINE AGONISTS AND ANTAGONISTS IN TURNOVER NORMAL VOLUNI'~S. Hillegaart, S A~lenius, 0 Ma~nusson and CF Fowler In previous experiments we have shown that repeated C. Gorenstein, V. Gentil and S. Tavares treadmill testing of rats, treated with haloperidol, enhance the duration of the effect, in comparison with Dose is a critical determinant of the intensity and the effect seen in animals tested once only, at the duration of the effects of hypnotics. Usually dose- various time intervals. Initial biochemical experiments equivalence is determined in relation to latency, total did not indicate any difference in striatal dopamine (D~) sleep time, nLm~ger of a~ker~, and sleep quality. As turnover between animals of the two test procedures at the time of maximal ~ehavioral difference, 2h after an alternative we suggested the comparison of peak haloperidol, 0.32 mg.kg- i.p. As expected, there was a sedative effects in normal volunteers and the marked increase in striatal D~ turnover by the determination of dose-equivalence by a bioassay haloperidol treatment , and testing of the animals statistical method. This will be exemplified with data immediately before sacrifice produced a further increase frc~ our experiments with triazol~n, flurazepam and in the D~ turnover in the two groups alike. In the zopiclone. Problems with the experimental design present experiments we omitted the last test immediately (parallel ~roups, crossover and incomplete design) will before sacrifice. The animals were tested on the treadmill 30 and 60 min after the haloperidol injection, be discussed. and sacrificed for biochemical evaluation of striatal DA Dose-equivalence studies for benzodiazepine antagonists turnover at 2h. Under these conditions we found a face additional problems such as the need to assure the significant increase in DA turnover in the group tested same level of sedation to be antagonized and the possible repeated times (30 and 60 min), in comparison with intrinsic agonistic or ~rse agonistic effects. Results animals not tested for treadmill performance, 2h after of a study in normal volunteers ~th intravenous haloperi8ol. In conclusion: Our previous findings showed an enhanced duration of haloperidol-induced effects on titrating doses of Ro 15-1788, Ro 15-3505 and placebo, treadmill performance by repeated testing, and increased following a 2rag i.v. dose of flL~nitrazepam will be DA turnover by treadmill exercise in haloperidol-treated presented to illustrate these phenog~na. animals. The present results demonstrate short-term changes in pre- or post-synaptic dopaminergic mechanisms Grupo de ?sicofisiologia Cl~n/ca, Instituto de since, omitting the last treadmill test before sacrifice, it was still possible to see an increase in striatal DA Psi~diatria, Hospital das Clinicas, Caixa Postal 8091, turnover 2h after haloperidol treatment in animals tested Sao P~4/o, Brazil at 30 and 60 min after the drug administration. Research and Development Laboratories. As~ra Alab AB. 3- 151 85 Sodert~iJe, Sweden. 32.04.04 32.04.05 A TOLERANCE AND PSYCHOMETRIC S'TtH)u OF SETASTINE, A NEW EFFICACY (im L~ DOSES OF T~ICYCLIC$ ANTIHISTAMINE. R.F. Coen, M. Kenny~ R. Lambe, F. Goer~eenyi~ L. ~qmaronatti, C" Burrai, L. Tcr~, G.F. Floris, P.P. Pani M.I.K. Fekete~ A. Darragh. Setastine is a new antihistamine which is structurally related to clemastine with a similar activity as H1 ~hile the antidepressant efficacy of Tricyclics is well known there ex&st antagonist. In animal experiments its sedative effects many arguments about the correct therapeutic dosage. In fact ttere is a are considerably weaker than those of clemastine. In diootcmy between doses ~ in literature m~d real doses used clinical trials setastine (i and 2mg t.i.d.) was well in clinical prentice. ~trolled observations of the effectiveness tolerated and was effective in the treatment of allergic of low doses of Tricyclics performed by psychiatrists end practitioners rhinitis and allergic skin diseases. The present study stimulated interest for a more controlled research cn this topic. Fc~ this was undertaken to investigate tolerance (including possible sedative effects) of single rising doses when prc~ an open study v~s carried (m/t on patients wil/n dia~nc~is of administered orally to healthy volunteers. This was a M~jc~ Depressive Disorder, Bipolar Disorder, Depressive or Dysthymic double blind, placebo controlled study in 2 groups of Disorder. Each patient wee treated with 50 rag/die of Amitriptyline, Clo- 8 subjects, with 2 subjects in each group randomly miprmmine and Imiprmmine either orally or e.v. In order to prevent side- assigned to placebo thronghout. The remaining subjects effects such as m~nsea, vomitirg &nd o~tatic ~/potansian e.v. doses received placebo, 2mg and 6mg setastine or placebo 4mg were increased gradually over a few days. Clinical statos was evaluated and 8mg setastine on 3 separate o~casions. Effects of weekly from To "to T2B with H[~S. Pla~natic levels of the ~ ~ mo- setastine on mood and performance variables were investigated using Digit Symbol Substitution, a nitored. Results show that e.v. 1~'ea~m~nthad both more efficacy and Computerised Vigilance / Reaction Time Task, Saccadic improvement latency. !aprowmant ecctrred within ~ ~-~ee Eye Movement, Wright-Codoc Ataxiameters and the Bond weeks and no. important side-effects were detected. After ten days of and Lader Mood Rating Scale. Colour vision was therapy ere patient became manic and required medicaticn with assessed using the Farnsworth Munsell lO0-Hue Test. leptics &nd 'Lithium. 9b_ile the results concerr~ ~ne icwest effective Setastine was well tolerated at all dose levels. There dose for Tricyclics disagree with previous data they nonet#~less confJ_rm were no adverse reactions of any clinical significance, and no clinically significant changes in laboratory or ttmt low doses of trdcyclics are effective in a percentage of c~ses ECG parameters. While evidence of sedation was detected greater tt~n is the placebo. In conclusion low doses of Tricyclics this occurred only at the highest (Smg) dose level and appear to be effective in those patients either never treated before was mild in nature. Colour vision was not affected by or after a lorg time from dneir last antidepressant trea~mmlt. It is su~- setastine and no impairment of performance or mood gestsd that dxing antidepressant t~ a mcdificaticn of the sensiti- occurred at those doses which have demonstrated vity of monc~c receptcrs may occur requirin~ a higher dose of drq6. therapeutic efficacy. Institute of Clinical Pharmacology (Irl.) Ltd., Sir Patrick Dun's Hospital, Lr. Grand Canal Street, Dublin 2, Ireland. ~Egis Pharmaceuticals, Budapest Clinica Psichiatrica Hungary. [biversi~ di Cagliari Via Liguria 13 , 09127 ~_gliari, ITALY 313 32.04.06 32.04.07 JAPANESE PSYCHIATRISTS PRESCRIBE LOWER DOSES OF EMOTIONALITY-ASSESSMENT FOR THE TIME COURSE OF PHARMACO- NEUROLEPTICS AND UTILIZE HEAVY POLYPHARF~CY LOGICAL TREATMENT, EXPERIENCES ON THE FENFLURAMINE TEST M__~. Tateyama, M__~. Kamisada, M_~. Tokuno, G_~_.Yaqi, F.M. Reischies, B. MOller-Oerlinghausen M. Barrels and H. Heimann The emotional response especially in the acute trial of There were arguments whether Asian schizophren- psychotropic medication can be assessed only very poorly. ics require lower doses of neuroleptics than Following the concept of Izard 1977, we therefore deve- Caucasians. The 1984 admission records of i00 loped and tested an emotionality assessment, which can, schizophrenics (ICD-9:295) in both Japan and W. after an instructio% be answered quickly in the time Germany were reviewed for number, type, initial course of a psychopharmscological trial. The intensity of dose, and max. dose of prescribed neuroleptics. 14 emotional qualities are evaluated on visual analogue Patients displaying similar severity of illness scales in 3 categories of assessment: present state, emo- were randomly chosen from university psychiat- tional responsiveness and expression. Normdata were ob- ric hospitals. Doses were converted to chlor- tained from n=97 subj. and a first validation study in- promazine equivalents (Davis 1974) and correct- volved n= 89 successively admitted psychiatric outpa- ed for body weight. Results showed: 76 (76%) tients (ICD-9 giagn.). A disariminant analysis demon- W. German patients were prescribed single strates the diagnostic power for healthy subj. (76 to 87% neuroleptics as opposed to only 30 (30%) Japan- correct classifications), endogenous depression (78 to ese patients [p<0.01]; No W. German patients 100%), anxiety disorder (50 to 71%) and acute schizophre- were prescribed over three kinds of neurolept- nic pat. (50 to 67%) on the basis of the 3 categories of its whereas 30 (30%) Japanese patients were; assessment. We will report on the emotionality assessment Concomitant use of anti-Parkinsonian drugs was in the time course of the acute administration of fenflu- more prominent in Japanese patients (94 versus ramine, a substance which is known for 5-HT depletion; 21, p<0.01); Mean initial daily dose was higher furthermore an antidepressant effect is discussed for the in W. German schizophrenics than in Japanese acute medication of this substance. patients (777 mg versus 449 mg, 11.93 mg/kg Psychiatrische Klinik und Poliklinik der Freien Universi- versus 8.18 mg/kg). tat Berlin, Eschenallee 3, 1 Berlin 19, West Germany Since Sramek et al (1986) found no significant difference in neuroleptic dosage requirements for Asian and Caucasian psychiatric patients we concluded that Japanese schizophrenics don't require lower neuroleptic dosage but Japanese psychiatrists display a clear trend for pre- scribing lower dosage & utilizing polypharmacy. Dept. of Neuropsychiatry, Keio University, 35 Shinanomachi Shinjuku-ku, 160 Tokyo, Japan 32.04.08 32.04.09 SUCCESS AND FAILURE AT INPATIENT HEROIN EFFICACY OF CLONIDINE, METHADONE AND DETOXIFICATION GUANFACINE IN THE RAPID DETOXIFICATION OF L. San. J. Cam[. J. M. Peri, R. Mats. M. Porta PATIENTS DEPENDENT ON HEROIN Predictors of either detoxification success or failure were J. Cam[. L. San. J.M. Peri, R, Mata. M. Porta evaluated during an inpatient randomized controlled clinical The efficacy of methadone (MTD), clonidine (CLD) and trial that compared the efficacy of methadone, clonidine and guanfacine (GFN) in rapid detoxification of heroin inpatiens guanfacine for rapid heroin detoxification. The analysis of was assessed. Signs and symptoms of abstinence and the such predictors was stimulated by the fact that in order to presence of side-effects were analyzed in all 90 heroin achieve 90 patients who completed the study (30 in each addicts (30 in each group) successfully completing a 12 day group), a total of 170 patients had to be included. Of 80 randomized controlled clinical trial. All patients fit DSM-III detoxification failures, 10 occurred in the methadone group, criteria for opioid dependence. 80.1% were males, the age 32 in the guanfacine group, and 30 in the clonidine group. range being 18 to 36 years. Mean length of heroin use was There were not statistically significant differences with regard 5.1 years (SD 2.3). Mean daily street heroin dose was 473.7 to sociodemographic characteristics and drug addiction mg (range 100-1500 rag/day). All three drugs were effective in among patients in the three groups who completed controlling abstinence; however, the course of abstinence detoxification with success or failure. The treatment drug, the was different in the MTD group as compared to the type of schedule and the score obtained from the Symptom adrenergic-agonists: while mean number of withdrawal signs Checklist-90/Revised were the only predictors of either and symptoms was significantly lower during days 2 to 5 in detoxifioation success or failure. The main cause of the methadone group (p< 0.01 in all cases), adrenergic detoxification failure was the subject's decision to discontinue agonist were more effective at the end of the trial. detoxification therapy. Adrenergic agonists show limitations in Incide0ce of side-effects was closely related to the dose the retention of patients when compared to methadone. administered. Hypotensive action of adrenergic agonists was Inpatient opioid detoxification appears to be a useful strategy more marked in orthostatic position. In this respect, for patients with more severe psychological symptoms, guanfacine appeared to have some advantage over because successes were distinguished from failures by clonidine. These findings suggest that new strategies for rapid having higher symptom levels as measured by the SCL-90/R. heroin detoxification, such as starting with methadone during Differences were significant in seven of the nine subscales as the first 2-3 days and then switching to guanfacine, need to be well as in the general symptom index (p<0.05). considered. Hospital del Mar and Institut Municipal d'lnvestigaci6 M~dica. Hospital del Mar. Institut Municipal d'lnvestigaci6 M~dica. P. Maritim 25-29. 08003 Barcelona, Spain. P. Marftim 25-29. 08003 Barcelona, Spain. 314 32.04.10 32.04.11 SERUM GLUT~4ATE AND PSYCHOTIC SYMPTOIIS IN SCHIZOPHRENIC A NEW METHOD OF SINCLE CASE EVALUATIOn! OF DRUG STUDIES: PATIENTS HTAKA-MODELL G. Alfredsson, and F-A. Wiesel E.M.Steinmeyer,H.-J. N~LLER Serum glutamate was measured in acutely ill schizophrenic Mod~n~isTica~o~hes to the analysis of single patients before and during sulpiride treatment. cases are at present still seldem employed in psychiatric The study lasted for 6 weeks and included 24 patients therapy research.Using the evaluation of the effects of who were treated with 400, 800 or 1200 mg sulpiride , antidepressant medication as an example,the results of a according to a randomized schedule. Glutamate and sulpi- new kind of time-series-analysis performed according to ride levels were measured once a week and psychiatric Hierarchical-Trend-Segment-Component-Analysis(HTAKA) are ratings were performed before and after I, 3, 4 and 6 presented. weeks of treatment using the Comprehensive Psychopatholo- The aim of the HTAKA-model is to critically review the gical Rating Scale (CPRS). From the CPRS items three sub- inferentially-based aspects in individual time-series scales were made, one for a wide range of psychotic symp- analyses with respect to their clinical relevance. Regar- toms (ZIO), depressive symptoms (ZDep) and autistic symp- ding their appli'cability for therapy,cumulative processes toms (ZA). and trend alternating parameters will receive special Before treatment there was no significant correlation be- attention,together with the validation procedures to spe- tween glutamate levels and psychiatric rating scores. cify differences in growth curve levels. During treatment, however, there were significant correla- The analysis model suggested above can be utilized for tions betw#en the changes in glutamate levels and the both experimental plannina procedures as well as for non- ratings of morbidity. The changes in serum glutamate were experimental approaches(clinically the far more frequent negatively and significantly correlated to the ZIO, after case).In non-experimental settinos,no influencing phases 3 and 6 weeks (r=-0.43"; r=-0.56") to the ZA after 3 and are calculated in advance.Considering such a situation, 4 weeks (r=-0.43"; r=-0.53") and to changes of the ZDep the task arises how to simultaneously filter possible and after 3 and 6 weeks (r=-0.49 ; r=-0.47 ).Thus, cJlnlcal optimal curve sections from the longitudinal data and then improvement was related to an increase of serum glutamate. to analyse it according to aspects of level or trend alte- It could not be established if the relationship between rations. the i~crease of the glutamate level and improvement was a HTAKA is-a new form of time-series analysis,combining the result of sulpiride treatment, since there was no corre- advantages of trend and ARIMA analysis.With regard to the lation between sulpiride levels and changes of serum practicability of this approach,it is important to emphasi, glutamate nor was there any relationship between the dif- ze that HTAKA,which utilizes non-parametric significance ferent sulpiride doses and glutamate levels. tests,requires considerably fewer continous measurements Department of Psychiatry and Psychology, Karolinska Hospi- over time than is the case for the ARI~'A-models. tal, S-I04 Ol Stockholm, Sweden. Abtl. Psychiatrie der Medizinischen Einrichtungen der Rheinisch-Westf~lischen Technischen Hochschule Aachen, Pauwelsstr.,51 Aachen 32.04.12 32.04.13 CONSTRUCTION AND VALIDATION OF AN ANX_rETY SCALE, METHODOLOGICAL ASPECTS IN CLINICAL EVALUATION OF MIGRAINE T~ F.A.R.D. (Ferreri Anxiety Rating Diaaram) PROPHYLACTIC AGENTS R. yon Frenckell, M. Ferreri, S. Tawil, D. Bonnet, I. Simonidesz-Vermes, Gy. Papp, E. FGrizs, H. Kov~cs, J.P. Girre and J.M. Alby I. Jelencsik, K. Kov~cs and J.I. Sz~kelv (1-me• ~ The authors have first applied to a sample of 81 GYKI-32 594 patients with generalized anxiety disorders (following -thiazolin-2'-vl/-amide bimaleinate) is a new migraine DSM-III) a set of 14 items previously defined by prophylactic agent. During its phase II. clinical evalu- pools of General Practitioners and psychiatrists. ation GYKI-3~ 594 was compared to placebo and pizotilen The list was based on the more frequent items in (Sandomigran -Alkaloida Works, Hungary) in a double- -ollnd cross-over study. In the course of the statistical arxiety, speaially related to the influence of anxiety ~tate on daily living. processing of clinical data the methods used in evalu- ation of antim~graine agents had to be reexamined. The Of the first list of 14 items, 12 were extracted multiplex statistical analysis has led to the following as pertinent by the way of a factor analysis with COnClusions: retained 4 factors (64.5 % of variance explained). - Unless the clinical trials and the subsequent statis- The authors called these factors, which polled 3 tical processing are carefully designed, the genuine items each, somatic, relational, cognitive and vigilance migraine attacks might be easily confounded by various dimensions so it was possible to represent the global forms of interval headache wich are not related to information on a diagram. genuine mtgraine; T~ese results were confirmed on two other samples, - The migraine prophylactic agents decrease the frequen- one rated by General Practitioners (250 cases) and cy and intensity of migraine attacks but they do not the other one rated by Specialists (150 cases). modify their duration; The studies showed that the scale was particularly - The e~ficacy of antimigraine agents can be detected valid, sensitive, reliable and easy to complete abo~e all by examining separately the most severe by G.P. or Specialists. attacks'. T~is new scale is characterized by a predominance Comparing the activities of GYKI-32 594 and pizotifen of ter~ion/irritability items over somatic items in g~neral the former has been found more efficient. as compared to the Hamilton Anxiety Scale. Nevertheless, in a subgroup of patients (unresponsive to Sandomigran) GYKI-32 594 proved to be superior. University of Liege, Neuropsychiatry Unit, Centre Instztute for Drug Research, Szabads~gharcosok dtja Hospi;aiier Universitaire (B 35), B-4000 Liege Sart 4T-49. H-1045 Budapest, Hungary. Tilman, Belgium. 315 32.04.14 32.04.15 THE MUNICH STUDY GROUP: "PSYCHOTROPIC DRUGS IN PRIVATE EXPERIENCE OF A DSMIII-BASED EXPERT SYSTEM (ADINFER). MEDICAL PRACTICE": METHODOLOGICAL ASPECTS. J. Fondarai, G. Vallat, M. Ohayon Blaschke D; Laakmann_G. The authors present the DSMIIl-Based Expert. system Adinfer ( M.Ohayon, Many drug trials have been done in the last years in 1984). The knowledge basis includes the DSM-III critena for all adult mental di- order to determine the efficacy and tolerability of newly sorders on axis I. The computer displays its questions in the very wording of developed psychotropic drugs. In many of these studies DSMHH (French translation, mini DSM4~I), following the decision trees. Moreever,~e clinician has to give the ten main symptoms and his own dignos~, the authors found no difference between the standard and freely expressed, according to his nosographiu referencies and habits. The d;- the new compound. nical and computer diagnoses are strictly independent, Possible reasons for these results can be that either This experI system was used in mufticont~'ic c~inical an'ddepressive drug tdaJs. there is actually no difference between the tested drugs among GP as well as PsychiatrLsts. or that these studies did not consider a number of The authors present the results of the comparison between the spontat)eous methodological aspects which could have proved real and Expert-system diagnoses and discuss the interest of such systems in drug differences or a differential efficacy between the two trials: Adinfer provides a non-biased DSMIII diagnosis and ensureS therefore the drugs. The following will discuss these problems partly homogeneity of diagnostic subclasses, espe~ally in depressive disorders. Mo- based on own studies: reover, the simultaneous free diagnostic and symptom list may confirm this ho- I. Sample size too small: To statistically substantiate mogeneity. Th!s is particulady useful in clinical drug experimentations aiming at the equality of two drugs (exclusion of the ~-error, i.e. the definition of specific target samples. false acceptance of equality) using the standard Laboratoire de Traitement des Connaissances, CHU Sainte-Marguerite, 270, parameters.(i.e. HRDS: sd=10; a=0,05; 5=O,30;mean Boulevard de Ste-Marguerite, 13009-Mareeille (FRANCE) difference=5) one needs at least 50 patients per group. 2. Responder-definition: A score reduction of 50% is normally used to measure response. It can, however, be shown that a change of response-level (i.e. 25% or 75%) leads to a drastic change in the results. For example, with a response-level of less than 30% there is a threefol~ increase in the proportion of placebo- responders. 3. Differential efficacy depending on severity of psychic illness: The assessment of Alprazolam vs. Amitriptyline showed no differences in the total group, whereas significant differences in favor of Amitriptyline where seen in the group of severely ill patients. 4. Differential efficacy depending upon the type of depressive syndrome: The assessment of Fluoxetine vs. Amitriptyline showed no difference in the total group. There were, however, differences in favor of Amitriptyline in the group of patients with a retarded depressive syndrome, and in favor of Fluoxetine in the group of patients with a vitally disturbed depressive syndrome. 32.04.16 32.04.17 THE CLASSIFICATION OF DEPRESSIVE DISORDERS IN DIFFERENT A NEW STRUCTURED INTERVIEW FOR THE DIAGNOSIS OF SENILE DIAGNOSTIC SYSTEMS DEMENTIA ALZHEIMER-TYPE AND MULTIINFARCT DEMENTIA (ACCOR- W. Mombour, W. Hiller DING TO ICD-IO AND DSM-III-R) IN OUTPATIENT CARE Most psychiatrists will be in agreement on the diagnosis M. Zaudig, J. Mitte]hammer and W. Mombour of a depressive syndrome.But they often do not correspond By far the most common causes of cognitive decline in old- on the subdivision of depressive disorders into discrete er persons are dementia of the A1zheimer-type (SDAT) and nosolog~caI groups. Depending on the nosological system to some extent multiinfarct dementia (MID). Detecting the used the number of these groups and the criteria for in- presence of the disorders (diagnosis) and their stages clusion or exclusion vary to a considerable extent. The (severity) is central to any clinical study of SDAT and world-wide use of ICD-8 in the years 1970-1980 concealed MID. Up to date, SDAT is a disorder of unknown etiology these discrepancies which again appeared after the intro- and no specific treatment. However, with the marked inter- duction of recently developed systems like DSM-III, DSM- est recently manifested in this disorder,our knowledge and III-R and ICD-IO. The use of different diagnostic systems understanding are rapidly increasing. Consequently, meth- at the same time makes comparing diagnoses between coun- ods shou]d be developed for earlier detection and diagno- tries and institutions difficult and requires a poIy- sis of the illness and should result in rationa] treatment diagnostic approach. Accordingly a considerable "migra- approaches. Many rating scales assessing behaviour and zion" of patients between nosological groups can be stages of the disorder have been developed using lengthy shown if one diagnostic system is replaced by another psychometric tests. But almost no diagnostic instruments (e.g. ICD-9 by DSM-III-R). Empirical data on outpatient have been developed supporting physicians in rapidly de- depressives, diagnosed according to ICD-8/9 and DSM-III- tecting SDAT and MID. In addition there is need for a com- R/ICD-IO are presented. The category of "major depres- prehensive but short diagnostic assessment in view of the sion" in DSM-III-R subsumes a great number of depres- difficulty testing demented people with lengthy psycho- sives formerly given multiple other diagnoses according metric ba~cteries. The authors describe a structured inter- zo ICD-8/9. Many of the neurotic depressives and the ad- view (SIHP) for a standardized assessment of SDAT and MID justment reactions with depressive symptomatology accord- according to the diagnostic criteria of DSM-III-R and ing to ICD-8/9 were diagnosed as a "major depression" in ICD-IO. The instrument can easily be utilized by physi- DSM-III-R or did not receive any specific diagnoses; only cians~nd clinidans. The average time for the interview a few of them retained the corresponding diagnosis of is about 20-40 minutes. Scores for the Mini Mental State dysthymia or adjustment disorder. Manipulation of (Folstein et aI. 1975) and the modified Hachinski-Score psychiatric diagnosis in therapy and research through (Rosen eta]. 1980) are included. Preliminary results in- the choice of a "suitable" diagnostic system could be dicate a good reliability, results of the test-retest- one consequence of the actual situation, study and other statistical data are discussed. The SIHP was found to distinguish diagnostic categories among older subjects with a wide range of cognitive defects. These advances have immediate relevance with respect to the choice of therapy and pharmacological treatment trials. 316 32.04.18 A DIAGNOSTIC CHECKLIST FOR CLINICAL USE BASED ON THE CRITERIA FROM THE CLASSIFICATION SYSTEMS DSM-III-R and ICD-IO W. Hiller, M. Zaudig, W. Mombour, J. Mittelhammer R. Rummler, M. von Bose Structured diagnostic instruments (serving as guidelines for the evaluation of psychiatric signs and symptoms) are needed when clinicians refer to criteria and to opera- tional]y defined diagnostic categories as provided by the new classification systems DSM-III-R and ICD-IO. Covering both systems the Munich Diagnostic Checklist (MDCL) have been developed as a polydiagnostic instrument for routine use in outpatient evaluations, specifically designed for both diagnostic and scientific purposes. A total of 15 sections covers 33 of the most prevalent and common psy- chiatric disorders. Psychopathological findings based upon the clinician's judgement (following a clinical inter- view) can-be structured and standardized to a high degree. The instrument constists of approximate]y 1000 items re- presenting symptoms as wel] as criteria defining present status, course and outcome of specific disorders. Of spe- cial re{evance are present status and longitudinal (life- time) findings. Diagnoses are given with the aid of a compute~program. Using MDCL in diagnostic exploration, the clinician checks in a systematical and comprehensive mann@r for a number of most relevant possible diagnoses, asks explicitely for the characteristics of the patient's present status and collects all information pertaining to a psychiatric diagnosis. Usual modalitJes of investi- gation may be maintained so that time requirements can be kept within traditional limits. In contrast to the appli- cation of clinical interviews the clinician can immedi- ately focus on the most predominant symptoms and is flexible to use the checklist under conditions when pa- tients show acute symptomato]ogy (e.g. states o{ disori- entation, delirium, agitation, intoxication, mutism). First data about the evaluation of the MDCL are presen- ted. 32.05.01 INFLUENCE OF CYTOSTATIC TREAT~NT ON EEG ACTI- VITY-HYPOTk~T!CAL EFFECT OF NOOTROPIC PREPARA- TIONS ON TBU~ TOXICITY OF CYTOSTATICS POSTER HoTONDLOV~, JoBASTECKY, K.HYNEK~ O.ANDRYSEK Psychiatric Unit,Railway Hospital and Outpa- PRESENTATION tient Clinic ~ Deptoof Psychiatry,Postgraduate ~edical and Pharmaceutical Inst. ; Dept. of Psy- 32.05 chiatry,Charles University; Clinical Ontology Center, UnivoHospital, PraEae It follows from our ebservations that some cytostatics evoke symptoms of organic brain damage on EEG.These changes probably play their part in the etiopathogenesis of the organic psychosyndrome and of the impairment of cogni- Miscellaneous tive functions in cancer patients. The aim of ~he present study, concerned with lO cancer patients /without brain metastases/ treated with ;~ifferent cytostatic drugs~ was to demonstrate the side effects of these drugs on the EEGo 9_fTer 6 weeks of cy~ostatic treatment, a significant decrease of alpha,beta and gama activity was found in the parietooccipital re- gion; on the other hand,an increased beta acti- vity was ascertained in the frontocentral re- gion~ changes are indicative of an inhibi- tion:of brain electrogenesis resembling EEG changes in acute drug intoxications. The paper goes on To discuss the effect of cinnarizin /STUGERUA/on These changes in some patients. A randomize~-~rial project aimed at searching for the ~roi~hylactic action of some nootropic drugs /meclophenoxate, piracetam/ on EEG side effects of cytostatic treatment has been elabo- ra~edoln this cop_nec~ion,an ex~eaaive screening examination of patients suffering Erom moHodkLu ~nd CA mamma is under -;;ay,-~'ith a view to arrive aV a more accurate E} 317 32.05.02 32.05.03 EFFECT OF SUBCHRONIC ADMINISTRATION OF PCPA AND/ L~LORPRONAZIt~E I~IBITS PHOSPHATIDYLINOSITOL TU2JIOVER IN OR IMIPRAMINE ON 5HT-STIMULATED INOSITOL-I-PHOS- THRO~IN-SYIMULATED HUMAN PLATELETS PHATE ACCUMULATION IN RAT EIPPOCAMPUS. H. Wakatabe, T. Tsukahara, J. Ishigooka and S. Miurs M. MIKUNI, I. KUSUMI and K. TAKAHASHI Chlorpromazine (CPZ) inhibits secretion and aggregation Recently, it has been shown that the biochemical responses in human platelets stimulated by thrombin. effector system of 5HT-2 receptor involved This indicates that CPZ might inhibit the liberation of increased phesphoinositide(PI) hydrolysis in rat araehidonie acid from membrane phospholipids which is cerebral cortex, but not in hippocampus. It has induced by activation of phospholipase A2. On the other been also demonstrated that chronic treatment of hand, platelet activation has been known to involve mianserin caused a significant reduction, but phosphatidylinosltol (PI) turnover which is initiated chronic PCPA treatment had no significant effect by activation of Pl~specific phospholipase C, resulting upon the maximal PI response to 5HT. in the transient formation of 1,2-diacylglycerol(DG) and In the present study, ritanserin, a selective 5H the formation of phosphatidic acid (PA). This response T-2 antagonist, inhibited 5HT(!0uM)-stimulated might be followed by the specific activation of the inositol-l-phosphate(IP-l) accumulation in rat protein kinase C that phosphorylates a 40,000-dalton hippocampus with a Ki value of 25nM,indicating protein. In the present study, the effects of CPZ on the activation of 5HT-2 receptor produced PI PI turnover and successive phosphorylation of endogenous hydrolysis in the hippocampus. 10-Day treatment proteins by protein kinase C were investigated using of PCPA(300mg/kg) resulted in a marked increase human platelets. in the response of IP-i accumulation in the hipp- The results were as follows: (i) When [3HI arachidonate- ocampus, whereas this treatment had no signifi- labeled platelets were incubated with thrombin (0.3U/ml) cant effect upon the density of 511T-2 binding at 37~ the radioactivity of DG was increased within 15 sites in cerebral cortex. PCPA caused 98% reduc~ sec, and was then progressively decreased with further tion in-5KT content and 40% reduction in NE incubation. A marked enhancement of radioactivity in PA, levels. These observation suggested that lower- converted from DG by DG kinase, followed a concurrent ing of 5HT and NE synthesis induced increase in decrease in radioactivity in DG. This transient formation 5lIT mediated PI hydrolysis with no significant and successive degradation of DG were partially inhibited effect upon the number of 5HT-2 receptor. 10-Day by CPZ (IO0~M), while the formazion of PA was blocked. (2) treatment of imipramine had no significant ef- The degradation of phosphatidylcholine and the liberation fect on 5}IT stimulated IP-I accumulation in the of arachidonic acid possibly by phospholipase A2 were hippocampus from the rats with or without co-ad- blocked by CPZ. (3) In [32p] phosphate-labeled platelets ministration of PCPA. These results indicated the phosphorylation of a 40,O00-dalton protein reached that functional biochemical changes did not ~o the maximum within 60 sec, and was inhibited by CPZ. related to the changes in the density of 5HT-2 These findings indicate that initial changes in PI receptors. turnover may be inhibited by CPZ. Div. of Ment. Dis. Res., Natl. Institute of Neuro- science, NCNP. 4-1-1,Ogawahigashi, Kodaira, Department of Psychiatry, Kitasato University School of Tokyo, 187, Japan Medicine, 863-1 Asamizodai, Sagamihara, Kanagawa 228, Japan. 32.05.04 32.05.05 DRUG TARGETS ADENYLATE CYCL~Ss Ah~ PROTEIN KINASE C: MOR- AIIACHMENI ~ F::~Z~XI~AL SLEZP: EFFECT OF ANTI-DEPRESSANT D~L3S PHOLOGICAL BASIS FOR "CROSS-TALK" IN HIPPOCA~US M. Dhayon I B. Cy-ui~ik and J.C. Fady Jurgen Deckers* and Martin B. Jorgensen# Two of the major second messenger systems in the mammalian The basic hyo~-esis states that the suppression of paradoxical sleep CNS are the cAMP system and the diacylglycerol/IP3 system. leads to major c;9=i:i.e troubtes, in particular as regards Using radioligand probes for components of these two acquisition pre~s=e-a. In the animal, the cognitive processes are of second messenger systems we studied adenvlate cvclase major importance !~~ a certain period called the sensitive ~ericd. [3H]Forskolin binding sites) and protein kinase C ([3HI During this period, attachment processes are established and develop. Phorbol-12,13-dibutyrate ester binding sites) four days We therefore wa~ed :o verify whether paradoxical slee'p, in an after selective depletion o{ CAt pyramidal cells in rat essential or =ajc~ ,ay, doesn't sustain the attachment processes that hippocampus by transient cerebral ischemia in a quantita- intervene during :me sensitive period in the young animal. This is tive autoradiographic study. Results in fmel/mg dry tis- catted the i~pri~t ,nose constitution is probably related to an ~ypee- sue weight: memory phenomenon. ~3H~Forskolin control ichemia Their demonstration ,as greatly facilitated.by the existence of very CAI region 54+3 13+3" specific behav~ora: ano neurobioiogical references. CA3 region 156512 137~15 Given : [3H]Phorbol-12,13-dibutyrate ester i) the existence of specific behavioral and neurobiological control isehemia references enaoli~g the study of the process CAI region 1671+35 1091+85" 2) the effects of trioyclic antidepressants, true "chemicat scalpels" CA3 region i171556 i087~63 suppressing paradoxical sleep, (mean + SEM: n = 5/group; * = p <0.05). we felt that it was possible to test : The reduction of both [3H]Fnrskolin and ~3H~Phorbol-12,13- i) whet~er there is a correlation between sensitivity to events and dibutyrate ester binding in the CAI region strongly sug- the amount of ~aradoxical sleep, gests that adenylate cyclase as well as protein kinase C 2) the hypothesis e-f a !ink between paradoxical sleep and attachment and thus both second messenger systems are localized in processes. CA1 p~ramidal cells of hippocampns. Drugs acting at a ~he experiment ~as carried out on f~ur groups of kittens : compoAent of one of the two second messenger systems are clomipramine, viloxezine, =aprotiline and untreated controls. The therefore likely to affect the other system via "cross- protocol includes social tests, "familiar objects" tests, tests of talk" in CAt pyramidal celIs. new socially explo*ed situations, tests of new situations explored i: PEAS USA 83, 4053-4057, 1986; 2: Acta Neural Scand alone and an analysis of the vocalizations emitted during the test 66, 536-546, 1982. situations. Universitats-Nervenklinik, Fuchsleinstr. 15, D-8700 Wurz- The tests presented in this poster were carried out between week two burg and #Institute of Neuropathology, Frederik V's vej and wee~ eight, lhe results are provided For each compound used and Ii, DK-2100 Copenhagen enable verification c~ t~e initial hypotheses. taboratoire de Traltewent de Connalssances (Director : M. Ohayon), CHU Sainte Marguerlte. 270, boulevard de Ste-Marguerite, L3OOg MARSEILLE ~FRANCE) 318 32.05.06 32.05.07 BEHAVIOL~AL "DESPAIR" IN MICE: INFLUENCE OF 5-HT FUNCTION ACTIVE AND PASSIVE AVOIDANCE LEARNING IN NEONATALLY M.Maling#, M. Bourin, M.C. Colombel. 6-0HDA-TREATED RATS. Mice and rats respond differently to antidepressants M. TAKASUNA and T. IWASAKI (ADS) when tested in the swimming model; 5-HT function To examine the effects of neonatal dopamine (DA) deple- does not seem to play a critical role in ADS effects tion on aversive learning performance, we used two in rats (R.D. Porsolt, Eur. J. Pharmacol. 57, 201, 1979). kinds of active (shuttle and rearing) avoidance and Ue examined its influence in the mouse procedure. one passive avoidance tasks. Groups of 6-12 male Swiss mice were subjected to a forced- On days 2 and 4 after birth, each rat of F344 strain swim (R.D. Porsolt, Arch. Intern. Pharmaeodyn. 229, received bilateral intraventricular injections of 327, 1977) 30 min after I.P. injection of the following 70Ng 6-hydroxydopamine (6-OHDA) or vehicle solution drugs (mg/kg): methysergide and ketanserin (.5-8), 5- after desmethylimipramine (20mg/kg, IP) pretreatment. i~eODMT and 8-OH-DPAT (.5-4), citalopram (2-16), indalpine From 90 days of age, each rat was trained in one of and fluvoxamine (4-32). Immobility duration was timed the three avoidance tasks. 6-OHDA-treated rats during the last 4 min of a 6-min swim (statistics: showed significantly less avoidance responses in the Kruskall-Wallis test, * p(O.05, ** p(O.Ol). Methysergide, shuttle avoidance, but performed as well as control ketanserin and 5-MeODMT were inactive; the putative rats in the step-through passive avoidance task. 5-HTI agonist 8-OH-DPAT was active between 1 and 4 mg/kg Their impairment on shuttle avoidance performance (~*~) as were 5-HT uptake inhibitors, the first active was not due to motor deficit, since they were hyper- doses of which were: citalopram 8 (**), indalpine 8 active iN the open-field test. Rather the impairment (*), fluvoxamine 16 (*). However, methysergide (2) and seemed to be derived from the predominance of inappro- the 5-HT2 blocker ketanserin (8) given 45 min before priate escape responses such as rearing and jumping. testing increased the effect of the ~-agonist clonidine The evidence that in another kind of task, the rearing (i mg/kg at 30 min pretesting) from 44 and 52 % to 1 avoidance, their performance was not significantly and 13 % of controls respectively (**). Conversely, a different from that of control rats may support our subthr2sfiold dose of clonidine (.06 mg/kg at 45 min) notion. Analysis of brain catecholamine contents made 'effective 8-OH-DPAT .5, citalopram 2, indalpine using HPLC proved selective DA depletion in striatum, and fluvoxamine 4 (** in all cases) but not 5-MeODMT. hippocampus and cortex. These results were discussed 5-HT mechanisms may thus account in part for ADS-induced in terms of motor response hierarchy, CS-US association, reversal of immobility in mice and stimulation of ~- and memory. This kind of comparative analysis of receptors due to NA uptake inhibition is presumably aversive learning performance serves a useful tool for increased by blockade of 5-HT2 receptors. Moreover, drug studies. additive or synergistic interaction would occur between Institute of Psychology, University of Tsukuba, direct or indirect ~-stimulants and agonists of the [-l-I Tennodai, Tsukuba-city, Ibaraki 305, Japan 5-HTI receptor subtype. Lab. Pharmacologie, U.E.R. M~decine 44035 Nantes C~dex France. 32.05.08 32.05.09 CHOLLNERGIC DYSFUNCTION AFTER HALOPERIDOL ~AL BY RO 15-1788 OF THE SEDATIVE, AT/E~TIONAL AkD TREATMENT: PROTECTION BY GANGLIOSIDE GM1. AMNESTIC ~bCTS OF LORAZEPAM IN MAN. S.P. Mahadik, A. Korenovsky, H. Laev and S.E. Karpiak. G.C. Preston, M. Traub r C. Ward, P. Broks & S.M. Stahl. We have shown that the haloperidol treatment of rat alters It has been suggested that the memory deficits produced the CNS cholinergic system. After short-term (7-21 days) by henzodiazepines ane resistant to the effects of the treatment both cholinergie marker enzymes (choline acet'),l- benzodiazepine antagonist Ro 15-1788 (Hammer, Breier, transferase, CHAT; acetylchollnesterase, ACHE) were m- Paul, Davis & Weingartner, ACNP proceedings, 1986), creased in hippocampus and in str/atum. After chronic whereas the anxiolytic, sedative and attentional (40-60 days) treatment the levels of both cholinergic en- actions of the drugs are antagonized by Ro 15-1788. zymes were decreased. There were also morphological chang- Such a dissociation would imply that the amnestic es determined by immunohistochemical analysis of ChAT in propert/es of benzodiazepines are independent of their both brain areas. Cortical changes were marginal Also, no other actions, particularly their production of chemical or morphological changes were detected fullowing sedation. treatment with either clozapine, a drug with low incidence In this study ~ investigated the effects of lorazepam of motor dysfunction or with imipramine, an antidepres- (2.0 mg p.o.) on various aspects of m~ory, attention, sant. The changes in cholinergic enzymes indicated that and sedation in normal healthy volunteers. We found the short-term haloperidol treatment caused a hyperarousal that, relative to placebo, lorezepam produced deficits of the cholinergic system (considered essential for anti- in verbal secondary memory, which accompanied changes psychotic action of haloperidol) and long-term treatment in choice reaction time perform~nnce, critical flicker caused a hypocholinergic state in striatum (probably con- fusion, sustained attention and self-rated alertness. tributlng to motor dysfunction) and in hippocampus (prob- It also produced changes in the accuracy, but not the ably contribute to negative symptoms associated with chron- speed, of ballistic ~ts. In addition, on three ic treatment). ~_perate occasions the subjects were given the same Since ganglioside GM1 treatment of rat has been shown to dose of. lorazepam (2.0 mg p.o.) followed by one of protect the haloperidol treatment associated dopamine re- three doses of Ro 15-1788 (0.3, 1.0 and 3.0 mg i.v.). ceptot~ supersensitivity in striatum and also striatal do- ql%e RO 15-1788 showed dose-related antagoni~ of the pzmlrfergic structure/function following CNS injury we have amnestic effects of lorazepam, blocking deficits in the examined its protective effects on the levels of choliner- total ntmS~r of items recalled, the cc~sistency of gac enzymes in striatum, hippocampns and cerebral cortex. recall and the ntm83er of intrusien errors. It also Rats were divided in four groups: control; haloperidol showed a monotonic dose-dependent reversal of the (2rag/ks/day, ira.); ganglioside GM1 (10mg/kg/day, ira.) and changes in sustained attention, choice reaction time halopendol/GM1 for 8 and 40 days. After 8 days of treat- and self-rated sedation. Only the effects on critical ment the increases in both the enzymes were not changed flicker fusion and on perfon~anee on the ballistic significantly by treatment with GM1. However, after 40 ~t task were spared by the antagonist. Frc~ these days of treatment the decrease in the ChAT activity was data it is not possible to dissociate amnesia from protected in all brain areas tested. The data su,,~,est that sedation, and it remalns feasible that the amnesia GM1 treatment may protect cholinergic vutneral3~'~ty from produced by benzediazepines are a consequence of their toxicity associated with potent neuroleptic treatment. sedative action rather than a primary effect of the NY State Psych. Inst. & Col. Univ. New York, NY. 10032. drugs. Merck Sharp & Dohme, Terlings Park, Harlow, Essex, U.K~ 319 32.05.10 32.05.11 THE EFFECTS OF ~-BLOCKERS ON THE PSYCHOMOTOR FUNCTION, THE CHANGES OF BEHAVIOR AND BRAIN AMINE LEVELS - WITH SPECIAL REFERENCE TO MULTIPLE SLEEP LATENCY TEST - AFTER REPEATED ADMINISTRATION OF 6-PHENYL- M. Uchiumi, M. Murasaki, J. Matsumoto, Y. Fukuyama ET~YLAMINE AND METHAMPHETAMINE and S. Miura M.YAMADA, M.HASHIMOTO, Y.KIUCHI, K.OGUCHI The effects of atenelol and pindolol-R on and Y.YASUHARA the psychomotor function were studied in a double-blind In this study, we compared the response to placebo-controlled trial. The drugs studied were atenolol acoustic stimulation (AS) and the changes of 50 mg, pindolol-R 20 mg and placebo. All experiments were brain amine levels after repeated administration performed using 6 male healthy volunteers. The subjects of ~-phenylethylamine (PEA) and methamphetamine were tested three times(stepl-step3), each step period (MAP) in rats. lasting 3 days. In the step i study, all subjects were For inducing reverse tolerance, rats wereadmln- given placebo once-daily for 3 days. On the third day of istered PEA (50mg/kg) i.p. once daily for 10 the experiment, MSLT(Multiple Sleep Latency Test), days or MAP (2.5, 5, 7.5 and 10 mg/kg) i.p. SSS(Stanford Sleepiness Scale), SAM were repeated three times daily on day I, 3, 5 and 7, respec- every 2 hours after drug-administration. In addition to tively. The response to AS by buzzer was ob- these tests, three psychomotor functional tests(kraepelin served on day 2 and I, 2 and 4 weeks after the test, reaction time test and flicker fusion test) and drug administration using open field apparatus. equilibrium test were performed between MSLTs. The contents of amines and their metabolites in In the stay 2 and the step 3, the subjects were randomly the brain regions were measured 4 weeks after assigned to be ziven either atenolol or pindolol-R the last dose using HPLC-ECD~system. in a cross-over manner, and all tests were carried out Both drugs induced and maintained reverse toler- in the same schedule as in the step !. ance of stereotypy for 4 weeks after withdrawal SSS and SAM shewed that general fatigue was increased by of dru~s. In PEA and control groups, the pindoloi-R. MSLT reveald that atenolol significantly increase in ambulatory activity by AS and its increased sleep tendency, while pindolol-R decreased, suppression after AS were remarkable. In MAP The effects of atenolol on psychomotor function were more group, however, this response to AS was not favorable than those of pindolol-R. These two ~-blockers ebvieus up to 4 weeks after administration. did not significantly affected the equilibrium tests. The increase in total norepinephrine (NE+MHPG) It has been reported in oth~ clinical studies that in cerebral cortex (CX) and 5-HT turnover in sleep disturbance and other advers effects of CNS were hypothalamus in PEA group and the decrease in higher with lipophilic 8-blockers than with hydrophilic total 5-HT (5-HT+5-HIAA) in CX and midbrain in ones and were thought to be related to intrinsic MAP group were observed. s~pathomimetie activity. The result in the present study These data suggest that the different response using MSLT and other psychomotor functional tests to AS observed between PEA and MAP group may be supported the above findings. associated with that of the changes of amines Department of >sychiatry, Kitasato University in the brain. School of Medicine, Dept. of Pharmacology, School of Med., Showa 863-1 Asamizedai, Sagamihara, Kanagawa, 228, Japan University, Tokyo 142 Japan. 32.05.12 32.05.13 "The ~echas ~f the T=anb-S':~z~tz: E:~r ell DEPRESSIVE STATES IN PATIENTS WITH ACUTE SPINAL !n]ury I~ 7ransient Ischemla an/ tn~ Preach,'!:(- t~y of ~ts Preventives" CORD INJURIES AND THEIR TREATMENT IN COURSE OF REHABILITATION. H. Piatkowska Fyuya Kogure, ~.D.,C.v.5:: Tsutomu ~cakl, M.S. Z~DIO Oga~awar~, M,S. Department of Neurology ANALYSIS OF DEPRESSIVE STATES AFTER ACUTE SPINAL Tohoku Univecszty Schobl of b~edic!ne CORD INJURIES AND THEIR PHARMACOLOGICAL TREAT- I-I Seiryo-n~cEl, Sen~l ~0 MENT IS PRESENTED Japan THE VERY IMPORTANT INFLUENCE OF LUDIOMIL IS DISCUSSED. The.mechanisms of acute neuronal ~eath, maturatlonal deatz, delayed death, and survival of the Dcst-ischemic selectively Department of Psychiatry, Warsaw, Poland vulnerable brain cells were found to be similar. The dying process starts with the perturbatlonal ion gate opening at the qlutam~te receptor sites and the size of the pores settles the fate of the neurons. However, the ischemia-indueed ion channels can bemodified by pharmacological means. Chemicals reported to block the clutamate effect and the cal~--ium effect-, and to facilitate re-synthesis of the membrane lipids, arid chemicals reported to enhance the effect of irinibitory neurotransmitters, effectively prevented the iszhemia- induced neuronal death. A few other chemicals such as ergotamlne, vincaloids and its relative co~pounds, also exhlblted certaln protective effects, although the mode of action of those drugs !s not yet fully understood. We also found many other compounds which may act merely as a plug or a coat for the perturbed ion chanmels can prevent those selectively vulnerable neurons to die in ischemia injury. A common denominator obtained from a computor-assisted analysis of those molecules suggested that an inert structure featured with a large and a small hydrophobzac moieties connected by a hydrophilic, flexible short chaln can be an ideal compound as a preventive of the ischemia-induced Draln cell necrosis. 320 32.05.14 32.05.15 SHORT-LATENCY EEG EFFECTS and PLASMA A CLINICAL PHARMACOKINETIC DATABASE FOR ALPRAZOLAM CONCENTRATION of :HENOBARBITAL 50- or 100 mg USING LIMITED SAMPLING SINGLE ORAL DOSES in HEALTHY VOLUNTEERS C.L. DeVANE, T.H. GRASELA, Or., and E.J. ANTAL Interindividual differences in drug response are crucial WG Sannita L Maggi G Rosadini E Sottofattori considerations in designing dosage regimens. Pharmaco- kinetic variability, a major determinant of drug Single 50- and 100 mg doses of phenobarbital response, is frequently evaluated in pre-marketing or matching placebo were given orally to 8 studies designed to collect the maximum amount of drug healthy subjects. Multi-lead EEG samples were disposition information on individual subjects. We recorded prior t:, and at regular intervals tested an alternative to this traditional approach of within the 2 hrs following administration; kinetic data evaluation. A database consisting of the signal was p~otessed by power spectral demographic, psychiatric, and drug disposition data was analysis, and bidimensional color maps were collected for 100 inpatients (mean age 46 +/- 15 years) produced. The drug plasma concentration was who were receiving alprazolam for a variety of cIinica] assessed concomitantly; plasma peaks were indications. Each patient had a blood sample collected 3.38+/-I .29 and 4.09+/-1 .24 ug/ml at the 50- at a random time during 2 different dosage intervals. and 100-mg doses respectively. Despite the Plasma was assayed for alprazolam concentration by a low drug plasma concentration, a systematic newly developed HPLC method. The NONMEN computer and significant power increment occurred in program wa~ used to calculate pharmacokinetic parameters the EEG fast freoJency ( 12.5-32.0 Hz ) band for comparison with data collected in pre-marketing after administration of the 100-mg dose; it clinical trials. The mean (SEM) alprazolam clearance was evident from the 30 min postdrug control, (CL), volume of distribution and absorption rate and was topographically restricted to the constant'was 0.07 (0.006) I/hr/kg, 0.7 (0.1) I/kg, and anterior scalp areas. The drug plasma 1.2 (0.4) hr-1, respectively. CL was 30% slower in males concentration was significantly correlated ( (p 0.01); however, neither an effect due to age nor Kendal's coefficient ) with the increment in smoking status was detected. These pharmacokinetic fast frequency po~er only on the ( anterior ) parameters, estimated from a diverse population of electrode derivat';ons where it was systematic patients, are similar to those determined from rigorous across subjects and attributable to drug preclinical studies. These results suggest that action, while no correlation was observed aIprazolam's primary pharmacokinetic parameters have a with the EEG variations on posterior scalp relatively small variabiiity across a heterogeneous areas. patient population. They also confirm the utility of using a population kinetic database for seeking Center for Neuropsychoactive Drugs, Institute variables in individual patients which may affect drug of Neurophysiopathology, and Institute of d~sposition and, therefore, clinical response. Pharmaceutical Sciences, University; Center University of Florida, Box 0-486, GainesviIle, Florida, for Cerebral Neurophysiology, C.N.R.,I-16132 32610 U.S.A. Genova, Italy 32.05.16 32.05.17 MEASUREMENT OF PLASMA ANTI-DOPAMINE, CONJUGATED AND UNCONJUGATED LEVELS OF CLOMIPRAMINE AND ITS ANTI-NORADRENERGIC AND ANTI-SEROTONIN HYDROXYLATED AND DEMETHYLATED METABOLITES IN PLASMA AND ACTIVITIES OF SHIZOPHRENICS RECEIVING URINE OF DEPRESSED PATIENTS, NEUROLEPTICS MEDICATION M.Pays,O.Varoquaux,O.Morin,J.Plas,S.Brion,C.Advenier T.YamamototT.HaradatT.Takeda,M.Sato* and Clomipramine (CMI) and its 8-hydroxy (8-OHCMl),2-hydroxy S.Otuki (2-OHCMl),den~thyl (DMC),8-hydroxydemethyl (8-OHDMC) and Most of neuroleptics have not only anti- didemethyl (DDMC) metabolites were determined by HPLC with dopaminea(Da) activities, but also anti- noradrenergic(NA) and anti-serotonin(5HT) coulometric detection. Both unconjugated and codJ~ugat4d activities. We measured plasma activities compounds (after S-glucuronidase hydrolysis) were determi- {anti-Da, anti-NA and anti-5HT activities) of ned in the same sample of plasma or urine: I ml,buffered schizophrenics receivig neuroleptic medication at pH 9.8 is extracted with 20% ethylacetate in n-heptane. using radio rece~ter assay(RRA).We used in the After back extraction into an acid phosphate buffer(pHa.4) RRA the folloing jH-ligand,displacer and 20 ~I were injected into a 5 vm C-18 IP-RP column and elu- brain region: ted with a mobile phase containing a phosphate buffer with D2 recepter: InM 3H-(-)-sulpiride, tetramethylammonium chloride and acetonitrile 59-41 v/v. 100nM haloperidol and rat striatum. This method was used to determine the steady-state conju- NA recepter: 0.anM 3H-prazosine, gated and unconjugated plasma levels of CMI and its meta- 200nM prazosin a~d rat frontal cortex. bolites reached in patients given CMI daily, either 75 to 5HT recepter: InM ~H-ketanserine, 150 mg orally or 50-75 mg by infusion. Following oral ad- 500nM" pipamperone and rat frontal cortex. ministraCion, DCMI is the predominant form as shown by the Schizophrenics were divided into the following high steady-state concentrations. In contrast, following two groups: repeated IV administration, plasma DCMI concentrations are group 1:maintenance treatment group only slightly higher than those of CMI. 8-OHCMI and 8-OH- containig 42 remitted outpatients. DCMI plasma levels are similar to those of CMI. At any par group 2:aute treatment group ticular dose,inter-individual variations of up to five- containing 18 hospitalized patients at the first onset or with acute fold were observed even in this small sample. 2-OHCMI was exacerbation. not detectable in plasma. The conjugated 8-OHDMCI and 8-OH Their clinical symptoms were rated by physicians CMI were respectively 2.5 and 3.4 fold higher than the using BPRS. Most of all were treated with respective unconjugated compounds. Steady-state 24 h uri- monopharmacy, respectively in group I n=34(81%), nary levels of CMI and metabolites of 6 iV treated pa- group 2 all(100%).Furthermore, we investivated tients showed a high proportion of conjugated compounds relationship among the mentioned three plasma being 300 (for 2-OHCMI), 20.8 (8-OHCMI), 7.9 (8-OHDMC) and activities, plasma drug concentration, clinical 1.8 (CMI) fold higher than the respective unconjugated effect and patients' profiles. compound in the same urinary sample.Conjugated and uncon- Department of Neuropsychiatry, Okayama University jugated CMI metabolites amounts are very high. These un- Medical School, 2-5-I Shikata-cho, Okayama conjugated metabolites may be taken into account in meta- 700, Japan bolic and pharmacological studies. *Department of Psychiary,Tohoku University, Departement de Biochimie et Pharmacologie, Centre Hospita- School of Medicine,l-1 Seiryo-cho, Sendal lier de Versailles, H6pital A Mignot F-78 157 Le Chesnay. 980, Japan 321 32.05.18 32.05.19 THE MORE STABLE DRUG LEVEL THE BEq~FER HALOPERIDOL KINETICS IN CHRONIC SCHIZOPHRENIC CLLNICAL OUTCO~ DL~ING TREAqS~[ENT ~T}I PATIENTS WITH ACTIVE PSYCHOTIC SYMPTOMS. DEPOT h~UROLEPTICS ? T.Itaya a K.0guri, K.Shiozaki__L K.Kobazashi, B. Lipska~ L. Welbel M.Nakashima K.Ohara The aim of our study was to check if sertun We studied pharmac'okinetics of haloperidol in levels provide information in practical chronic schizophrenic patients with active management of schizophrenia. 121 chronic psychotic symptoms despite usual neuroleptic schizophrenics were observed. ~"ne doses in treatment after oral administration. These single injection given every 23 days for 6-~2 patients under continuous oral treatment with months were: flupenthixol decanoate 20-60 mg, haloperidol(daily dose 9-24 mg) participated in clepenthixol decanoate 200 mg, pipothiazine the study on a informed consent. Serum level of ha loperidol were determined by palmitate 25-150 mg, perphenazine enanthate radioimmunoassay. Previous studies have shown 100 mg, fluphenazine enanthate 12,5-50 mg. Mental state was assessed by BPRS~ extrapyz-a- that the mean lag time after oral midal symptoms by Simps@n-A-ngus scale. Respon- administration of psychotic patients was 1.3 • 1.1(SD)hr and the terminal half life(tl/2) was ders had reduction of BPRS score ~50% at the end of treatment. The RRA was used to measu~'e 1 8.1 +_ 4.5 hr (Y.F.Cheng et al., Psychopharmacology, 91,410-414,1987). Tmax was serum neuroleptic activity on the day 7 after the injection /max/ and prior to the next one reported to be 3-I 0 hr (G.Yagi et al., Seishin /mill/. Max./min ratios 8/id coefficients of va- igaku,2~,1149-1157,1980 in Japanese). In our riation /c.v.~/ were analyzed. Linear correla- study, however, the mean lag time after oral administration was 0.36 + 0.38 hr and ti/2 was tion ~as found between c.v.~ values and clini- 5.0 _+ 2.6 hr. The peaks of the serum level were cal response /~S/ for pipothiazine /r=-O. 90, two points which were 0.9 + 0.6hr and 2.8 _t 1.6 p 0. O01/, clopenthixol /r= -O. 61, p 32.05.20 32.05.21 PLASMA HALOPERIDOL AND LORAZEPAM LEVELS IN ACUTELY LEOIC-Lz2~S' CLASSIFICATION OF CHRONIC SCHIZOPHRENIA AND SCHIZOPHRENIC PATIENTS AND THEIR RELATION TO PSYCHCTROPIC DRUG TREATMENT RESULTS THERAPEUTIC SUCCESS AND INTENSITY OF SIDE EFFECTS G.A.A.M. Wetzer, A.J.M. Loonen, C.H. Doorschot G.Pfab-~-dlk!ein, A.Nshal, R.Wiegsnd and H.J. Gaertner A cohort of 157 schizophrenic patients (DSM-III), The psychopathologic status of newly admitted acutely selected from a chronic psychiatric in-patient popula- schizophrenic patients on haloperidol (20-40 mg/day) and tion (N=602), were classified according to the princi- lorazepam (0-5.5 mg/day) was recorded weekly using BPRS ples of K. Leonhard and their reactions to former rating and GAS; intensity of the extrapyramidel-motoric psycho~ropic drug treatment were assessed. In order to side effects was assessed with the Webster and Simson distinguish three main categories, each with two sub- scales. At this time, plasma haloperidol and lorazepam types, of Leonhards' classification, a set of criteria levels were determined by gas chromatography (Forsman et was developed and a group of 8 psychiatrists and 3 al. 1974, Greenblatt etal. 1978). psychologists were trained in its usage. Former drug At assessmen~ the intensity rating of the scales was con- therapy benifit was classified as having been conside- sidered and the patients correspondingly elassifled ac- rable, moderate, slight or absent on the achieved level cording to whether haloperJdol treatment could be con- of social functioning. Vulnerability to negative drug tinued or whether, because of side effects or inefficacy, effects was classified into three categories upon the they should be changed over to another drug. level of interference of adverse reactions with daily The quest}on is whether adjunct administration of loraze- functioning. pam influences the intensity of the side effects of halo- Results: - peridol and whether the course of the psychopathologic - 59 (~8~) patients were classified hebephrenic, 32 disturbance can be related to plasma levels. (23-~) catatonic and 66 (42%) paraphrenic. Within each category about 1/5 of the patients were consi- Forsman, A., E. Martensson, G. Nlberg, R. 0hman: Naunyn dere~ to belong to the non-systematic sub-classes. Schmiedebergs Arch Pbarmacol (1974) 286, 113-124 - 132 (84,1%) patients, equally distributed over each Greenblatt, D.J., K. Franke, R.J Shader: J Chromatogr. (sub-)class, were currently under drug treatment. (1978) 146:311-320 - Non-~'stematic subclassified patients had generally sh~wr, more drug-induced improvement than systematic Department of Psychiatry (Director: Prof Dr H Hetmann)~ type. Within the latter sub-groups, somewhat less University of T~bingen, Osianderstr. 22, 74 TQblngen (40~ vs 52% and 58%) paraphrenic type schizophrenics had shown at least moderate improvement. - Systematic-type patients were considerably less vulnerable to (extrapyramidal?) side-effects with very few differences between hebephrenic, catatonic and V~aphrenic type schizophrenics. Psych. Hosp. Voorburg, P.O. Box 10150, NL-5260 GB Vught The Ketherlands 322 32.05.22 32.05.23 DIFFERENT THERAPEUTIC WINDOWS OF HALOPERIDOL IN SERUM NEUROLEPTIC LEVILS MIASUKED BY RADIO- SCHIZOPHRENIC PATIENTS AS A FUNCTION OF THE TIME- PdSCZPTOR ASSAY ( D D.,, m-Ach ) AND CLASSIFICA- SPAN OF THE ILLNESS. TION OF SCHIZOPHRE~IA ~ S. Nakajima, S. Kamba, T. inomata, H. Koshikawa, J. L. Santos. J. A Ramos. C. V~zauez. I. Almoeuera. G. 7agi and R. Kato F. Fuentenebro. and J/k Cabranes In recent years, many s~udies concerning about Levels of hatoperidol were determined by radio-immuno- serum neuroleptic levels measured by radiorecep- tot assay have been report@d. But in these re- assay (RIA) in 30 schizophrenic patients (DSM-Ill), who ports, examination of clinical significance is were treated with fixed-dose of this neuroleptic for a mainly about D~ levels and regardless of classi- period of 21 days. An inverted "U-shaped" relationship fication of scEizophrenia. And the meaning of was found between the percentage of improvement D~ / m-Ach ratio in relation to the effects of observed in the BPRS global score and the steady-state n~uroleptics has been discussed in many reports, but it remains little-investigated subjects. In of halopertdol. An interval of effective concentrations of this study, we divided the patients into sub- haloperidol was set between 12.0 and 35.5. ng/rnl. groups of schizophrenia in several ways, meas- However, the limits of that type of interval found in the ured not only D~ levels but also D I and m-Ach subchronic schizophrenic subgroup (SS) ranged from 7.4 levels and examined the clinical s~gnificance of DI, D~, .m-Ach levels an~ D o / m-Aeh ratio etc. to 24.9 ng/ml whereas in the chronic schizophrenic SubjeCts are 52 schizoph~enTcs receiving long- subgroup (CS) ranged from 14.8 to 38.5 ng/ml. term neuroleptic treatment. As one way of clas- These findings suggest that the interval of effective sification, patients were divided into two concentrations may vary as a function of the number of groups, patients who cannot respond favorably to any kind of neuroleptics and in any dosis ( years of evolution of the subjects illness. This may be group i ), and patients whose psychiatric condi- compatible with [~ development of tolerance in the tions could be suitably adjusted ( grouplI ). mesolimbic and/or mesocortical dopaminergic systems D o ~evels were in very wide range ( 2 - 340 as a response to prolonged neuroleptic treatments. n~ / ml HPD-~ ). Althou~h D~ levels of group i were generally high, there w~s the tendency that D> levels of group !Z wer~ concentrated in the Hospital Universitario San Carlos. 28040-Madrid. r~latively narrow range of 2 - 20 ng/ ml HPI- !. Together with the results of D.and m-Ach, Classification of schlzophrenza . ( includlngJ . sub- typing of longitudinal process ) and neuroleptic maintenance therapy will be discussed. Tokyo Musashino Hospital. 4-11-11Komone, ftabashi-ku, Tokyo, 173 JAPAK. 32.05.24 32.05.25 A.hITR_rPTYLINE MONITORING AND CLINICAL OUTCOME IN DEPRESSIC~ HABITS OF CONSUMPTION OF TRANQUILLIZERS ~ HYP-NOTICS IN G.L. Corona, M.L. Cucchi, P. Frattini, G. Santagostino, S. HEALTHY SWISS MEN OVER 13 YEARS Schinelli, F. Zerbi~aod _E,~Savoldi R. Battegay, H.R. Wacker, C. Schl6sser ~he interactive relationship anong the antidepressant main tenance dose, steady-state plam~a l~els and clinical out- In 1972/73 4082 randomly selected 20 years old Swiss come is highly variable and impredictable (P. Baumann, Int. military recruits were interviewed with a standardized ~_in.Psychopharm. 1,89,1986)'; hence it has been suggested questionnaire about their consumption of tobacco, alco- tZ-mt the antidepressant plasma levels monitoring may impro_ hol, tranquillizers, hypnotics and illegal dregs. In ve t_ha safety and efficacy of the therapy. We searched for addition standardized questions about sociod-~mographic characteristics, physical well-being, physical complaints a relation between amitriptyline (AMT) and nortriptyline and health behavior were asked. In 1979 and in 1985 1658 (}~) plasma concentrations and clinical response in 59 fe- respectively 1554 men out of the original sample were male depressed inpatients [D~M III: (I) major depression: asked similar and identic questions in postal interviews. .%~ 296.20 n=14 and B: 296.30 n=31; (~J dysthymic disorders 843 men took part in all three surveys.The results con- 300.40 n=14] treated with ~4T (100 mg/day i.m.) for 4 we4~s cern this sample In 1985 41 (4,9%) reported to take _No correlations between steady-state AMT or NT plasma le- tranquillizers seldomly or repeatedly. In 1972 there were 69 (8,2%) consumers of tranquillizers (p 323 32.05.26 32.05.27 LONG TERM PHENOBARBITAL TREATMENT INDUCES PSYCIIOTROPIC DRUGS UTILIZATION IN CZ~CIIOSLOVA- ENDOCRINE CHANGES REVERSIBLE UPON DRUG DISCONTI- KIA NUATION IN EPILEPTIC PATIENTS. J,.~lis! O.Vina9 r L.~tika~ KoElisov& R.Manni,G.Murialdo~ Palma~ In the fourth phase of the elinloal evaluation U.Filippi ~ and A.Tartara of a newly introduced drug, the benefit of the Alterations of adenopituitary function and sex new drug is evaluated in the routine medical practice. One simple measure of this benefit steroid peripheral pattern have been reported in is the amount of the drug prescribed in com- epileptic patients. However, the connections parison to the other drugs with similar phar- between hormones,epilepsy and antiepileptic drugs macological properties which already have been (AED) are far from complete elucidation. on the market. We have previously demonstrated that ii epileptic In Czechoslovakia such studies hove one of the male patients in remission, undergoing long term longest traditiom and psyohotropie drugs have phenobarbital (PB) treatment, showed baseline and been among the first one involved. Systemic study of their utilization began already in Gonadotropin Releasing Hormone stimulated levels 1965 incl. studies on the prescribing behavior of serum Luteinizing Hormone (LH) significantly and on the possibilities to influence it. The lower than normal male controls. Since these method of defined daily doses (DDD) enabled patients were seizure free and with normal EEG comparison of the psyohotropie drug utiliza- recordings, their endocrine changes have been tion in Czechoslovakia and Seandinevian countries o ascribed to PB treatment. Longitudinal trends of psychotropic drugs In order to confirm this hypothesis, 7 subjects utilization in Czechoslovakia and results of this group have been retested 1 year after of such comparison will be presented. complete PB withdrawal; particularly,LH pulsatile State Institute of Drug Control~ ~rob&rove 48, secretion throughout a six hour period (15 min 110 00- Prague 10, Czechoslovakia sampling intervals) has been studied. In fact higher mean LH levels,enhanced secretory areas under the curve and increased frequency and amplitude of the LH peaks have been observed after drug discontinuation in unrelapsed patients These findings confirm a role of PB in inducing the endocrine changes observed in our epileptic patients. o Institute of Internal Medicine, University of Genova and Epilepsy Center, Neurological Institu- te, University of Pavia, 27100 Pavia, Italy 32.05.28 32.05.29 LACK OF Ah~ICHOLINERGIC ACTION OF MIDALCIPRAN COMPARED EFFEC!5 OF HEMICHDLINIiJM-% ON IDENTIFIED TO AM!TRIP~fLINE IN NORMAL SUBJECTS. SEPTO-HIPPOCAHPAL NEURONS IN TH[ qmT. C, Serre*, M. Elohick*, D. Orahame-Smith§ C. Moret~and M. Briley*. One of the most common undesirable effects M.H. BASSANT~ ~. JOBERf and Y. LAMOUR of tricyclic antidepressants is their an~icholiner~ic action. Midalcipran, a new non-tricyclic ~ntidepressant The medisl septal area contains neurons ~nich project to has been shown and in vitro in animals to be devoid of the hippocampal formation. A sizeable proportion of any antioholinergic activity (Moret et al., these septo-hippocampal neurons (SHNs) are ~ho]~oergic. Neuropharmaool. 24, 1211, 1985 ; Stenger et el., About 40% of them also d~splay a characteristic Psychopharzacol. 91, 147, 1987). This study compares, discharge pattern in rhythmic bursts. We hypothesized in healthy volunteers, the anticholinergic effects of that 5HNs with s rhythmically bursting activity (RBA) midalcipran with those of amitriptyline and placebo. are the cholinergic ones. To test this hypothesis, we Eight healthy male volunteers were administered a studied the effects of acetylcholine synthesis blockade single clinically equivalent oral dose (half the by hemicholinium-5 (HC-3) on the properties of the SHNs. average daily-dose) of midalcipran (50mg), HC-3 (16, 32 or 6& pg) or saline were injected in the amitriptyline (75mg) and placebo in a double-blind lateral ventricles if adult male Sprague Dawley rats three sequence cross-over paradigm. anesthetised with urethane (n = 24 animals). Salivation 2 h after drug administration was measured Extracellular recordinos from SHNs in the medial septal by absorption onto preweighed dental cotton wool rolls. area were-obtained within hours after HC-5 injections. Blood samples were taken at 2 h for analysis of drug Theta activity in the hippocampal formation was plasma level and the inhibition of muscarinic receptor abolished even after the smallest dose tested (16 ~g). binding (3H-QNB) to rat cerebral membranes. The Choline chloride (lO0 mg/kg i.v.) did not reverse the volunteers were asked to mark a visual analogue scale effect of HC-3. No significant change in SHNs conduction of "dryness of mouth" and to report any adverse effects velocity or spontaneous activity was observed at any during the study and in the following 24 h. dose of HC-]. The percentage of SHNs with RBA was In midalcipran-treated subjects saliva secretion was unchanged either. In contrast the mean frequency of the increased by 4%, while under treatment with RBA #as decreased by HC-5 in a dose-dependent fashion. amftriptyline it was significantly decreased (- 30%, The mean frequency was lowest within the first 3 hours p<0.05) as compared to placebo. Neither inhibition of after injection. These results suggest that 3H-QNB binding by plasma samples nor visual analogue acetylcholine synthesis blockade by HC-3 leads not only scale were significantly different between treated and to the disappearance of the 4Hz theta hippocampal control groups. activity in urethane-anesthetized animals, but also to a Thus that amitriptyline showed a significant decrease in the frequency of the rhythmically bursting anticholinergic effect as measured by the inhibition of activity of the SHNs. Since the 4Hz hippocampal theta is salivation whereas midalcipran showed no atropine sensitive, the results provide indirect anticholinergie effect and even had a non-significant evidence that the septo-hippocamDal neurons with tendency to increase salivation. rhythmically bursting activity are the cholinergic SHNs. *Centre de Recherche Pierre Fabre, 81100 Castres, France. +Radcliffe Infirmary, Oxford. England. INSERM U 161. 2, Rue d'Al@sia 75014 PARIS France. 324 32.05.30 32.05.31 DISCRIMINATIVE STIMULUS PROPERTIES OF THE MUSCARINIC MAGNETIC ~7~IO MODULATION OF NqCOTLNqC AGONIST RS-86 IN THE RAT ACETYLCHOLLA~E RECEPTOR Ft]NC]qON J. De VrT, D.G. Spencer Jr. and J. Traber C. Chiles, E. Hawrot, J. Gore, and R. Beck Male Wistar rats were trained to discriminate a com- Although it is ~dely held that the magnetic fields encountered during bination of RS-86 (2-ethyl-8-methyl-2,8-diazaspiro- Magnetic Resonance Imaging (MRI) and other procedures have no (4,5)-deean-l,3-dion hydrobromide; 0.45 mg/kg) and discernible effect on biologic systems, we found that the rate of N-methylscopolamine (NMS; 1.25 mg/kg, i.p., t - 15 binding of the neurotoxin alpha-bungarotoxin to nicotinic acetylcboline min) from saline in a standard two-lever food-rein- receptor was significantly reduced in a constant 2.0 Tesla magnetic forced procedure. The dose-response curve obtained field. Alpha-bungarotoxin (BTX) obtained from elapid snake venom is with RS-86 was not affected by co-administration of a high affinity, competitive antagonist of the well-characterized NMS, although NMS, when given alone, induced partial nicotinic acetylcholine receptor (AchR), derived from Torpedo generalization (36%). Among the musearinic agonists californica electric organ (M.P. McCarthy, et al., A. Rev. Neurosci., tested, pilocarpine completely generalized, whereas 9: 383; 1986). The kinetics of AchR-BTX interaction are distinguished oxotremorine and areeoline partially generalized (67 by a relatively slow association rate (J. Schmidt and M.A. Raftery, J. and 50%, respectively). The nicotinic agonist com- Neurochem., 23: 617; 1974). AchR contains transmembranous, pounds nicotine, anabasine and cytisine induced sa- alpha-helical segments which are a common conformation of line-appropriate responding. Tetrahydroaminoacridine membrane proteins and are known to produce an electrostatic dipole (THA) and physostigmine induced intermediate (50%) and (W.G.J. Hol, Prog. Biophys. Molec. Biol., 45: 149; 1985). It is saline-appropriate responding, respectively. Co-ad- conceivable that AchR contains one or more magnetic dipoles within ministration of lecithin failed to increase the extent the receptor which may make the conformation of the receptor of generalization to THA. The discriminative effects vulnerable to a strong magnetic field and that this effect is revealed in of RS-86 were virtually antagonized by scopolamine an alteration of functional activity such as ligand binding. (0.32 mg/kg), but were unaffected by mecamylamine. It Formation of the receptor-ligand complex was initiated by the addition is concluded that the discriminative effects of RS-86 of 125I-BTX (final concentration 0.4nM) to affmity purified AchR are mediated by a muscarinic cholinergic mechanism, (0.37 gg/rnl) at 25~ Half the samples were held in control conditions although further work is needed to elucidate its cen- and half were placed in a 2.0 Tesla, 31 cm horizontal bore, tral and/or peripheral nature. The data additionally superconducting magnet (Oxford Instruments Ltd). The amount of suggest that the discriminative properties of muscari- 125I-BTX bound to AchR was measured by a DEAE filter-disc assay nic agonists are heterogeneous in nature. (J. Schmidt and M.A. Raftery, Analyt. Biochern., 52: 349; 1973). Neurobiology DepartmentdTroponwerke , Neurather Ring i, After 45 min of exposure to the magnetic field, the initial rate of 5000 Cologne 80, FRG association was reproducibly reduced relative to unexposed control and the effect persisted at 90 min of exposure. The mean + gEM of radiolabelled toxin (tzbI-BTX) specifically bound to nicotinic AchR in the exposed samples relative to controls was 0.85 + 0.02 at 45 min and 0.82 + 0.03 at 90 min (n=I3). The rate of association for samples exposed to the magnet differed significantly from the rate of association of those samples kept under control conditions (p < 0.0005). Yale University School of Medicine, Sterling Hall of Medicine, 333 Cedar Street, New Haven, CT 06510, USA 32.05.32 32.05.33 COMPAP~SON OF THE BEHAVIORAL AND BIOCHEMICALS EFFECTS OF SIMULTANEOUS DETERMINATION OF URINARY METHAMPHETAMINE THE N)~DA RECEPTOR ANTAGONISTS, ~-801 AND PRENCYCLIDINE AND PHENYLETHYLAMINE IN PATIENTS SUFFERED FROM METHAM- M. Hiramatsu and A. K. Cho PHETAMINE PSYCHOSIS ~-801, (+)-5-methyl-10,11-dlhydro-5-H-dibcnzo[a,d] cyelohcpten-5,10-imine maleate, was described previously S.Yamada~ Y.Mine~ M.Ishibashi~ T.Yokoyama~ T.Koga~ as a potent antlconvnlsa~t drug. More recent studies H.Kojima~ K.Miki} T.Inokuchi~ S.Nishiland K.Inanaga 2 have shown that it binds with high affinity to sites proposed for other non-competitive N~A antagonists such A sensitive gas chromatographic chemical ionization mass as phencyclidinc (PCP) and related drugs. PCP produces a spectromatric assay has been developed to measure the complex behavioral syndrome in the rat that is mediated urinary contents of methamphetaine(MAP) and phenylethyl- via various neuronal systems but little information is amine(PEA) of patients suffered from MAP psychosis. available on mechanisms of ~K-801 behavioral activity. These amines were isolated by Extrelut (R) column. Our This study compares the behavioral profile of ~-801 and method was capable of measuring 200 pg/ml of urinary PEA its effects on monoamine metabolism with those for PCP. and MAP, simultaneously. When administered to rats, ~-801 and PCP produced Urinary concentration of PEA in normal volunteers was hyperactivity, ataxia and stereotyped behav ior that 35.4 • 12.5 ~g/g creatinine (mean • S.D., n=12) and that included sniffing, head-weaving, turning and in patients was 11.4 • 10.4 ~g/g creatinine (mean • S.D., backpedalling. Forward locomotion, sniffing and head- n=11) which was significantly lower than that of normal weaving induced by }~-801 increased in a dose-dependent volunteers (t=3.88, P 325 32.05.34 32.05.35 NEUROPHARMACOLOGY OF CADMIUM 1231-SPIPERONE AS A LIGAND FOR DOPAMINE RECEPTORS: IN V.N.Puri...... and G.Shanker VITRO AND IN VIVO EXPERIMENTS Cadmium is an environmental toxicant.Psychophar J.A. Van der Kro~t r O.J.S. Buruma~ P.A.P.M. Van macological effects of this metal has not been Doremalen~ E.K.J. Pauwels~ C.F.M. Van Valkenbur~ and evaluated,therefore an attempt was made to G. Wijnhoven study the effects of cadmium acetate on male C. Nowadays there is great interest in the development of D.R.I. bred albino mice on various psychopharm positron or single photon emitting radioligands for acological screens.Male mice (25-30 gm) were imaging neuroreceptors in the living human brain. In the provided pellet diet and water ad libitum 0nd present study we evaluated the dopamine receptor binding housed in temprature controlled room 23+2 C. properties of the potential SPECT ligand 123I-spiperone (SPI). 123I-labelled SPI was prepared by radioiodination Cadnium was injected intraperitcmeally(~.p) in doses of 0.1.0.3,1.0 mg/Kg and behavieral data at the N-phenylring and purified by BPLC. Specific was recorded as described by Canpbell and Rich activity was in the order of i000 Ci/Imnole. Binding ter(!967).Cadmium (0.I mg/Kg i.p) did not prod properties of 123I-SPI were compared with those of 3H-SPI in parallel in vitro and in vivo experiments. In uce significant changes,compared to saline tre vitro binding to rat striatal membrane preparations was ated controls.However middle(0.3 mg/Kgi.p) and studied in two types of experiments: saturation higher(l.0 mg/Kgi.p) doses produced'central ner vous syslem depression as compared to controls. experiments (applying 0.i - 5 nM labelled SPI) and Cadmium produced decreased in locomotor activi competitio~ experiments with (+)- and (-)-butaclamol ty and decreased reactivity to touch and sound. (I0-i0 - 10-4M). No specific binding of 123I-SPI was observed in these experiments. For in vivo binding Cacmium did not produceiataxia,puosis or catal studies 0.1-0.2 nmole labelled SPI was administered to epsy in mice. Important finding observed was th rats via'a jugular vein cannula. After 2 h the animals at cadmium produced dose and time dependent hy were killed and radioactive contents of dissected brain oothermic response in mice. ED.~ of 1.0+0.38, regions were measured. Binding to cerebellum was used to 0.70~0.20,0.75t0.29,0.68~0.23 ~/Kg i.p-follow reflec~t non-specific binding. For 123I-SPI a striatal/ ing~l,2,3,5 hours respectively were obtained on cereb~llar ratio of 1.8 was found. By pretreatment of inzraperitoneal cadmium administration in consc the rats with i mg/kg haloperidol i.v. this ratio was ious mice.These results indicate that cadmium reduced to i.I. For 3H-SPI the ratio was 3.5. In con- may be having some atypical neuroleptic profile clusion, although we did not found evidence of specific Based on the information provided,role of cad binding of 123I-SPI to rat striatal membranes in vitro, nium in psychiatric illnesses and therapy shou in rive clearly specific accumulation in rat striatum !d be evaluated. was seen. Probably, homogenization of brain tissue Division of Pharmacology. Central Drug Reseach unmasks a large amount of non-specific 123I-SPI binding institute.Lucknow 266001.1ndia. sites. The extent of in vivo striatal accumulation, however, is too small for SPECT studies. Department of Pharmacology of the University of Leiden, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands. 32.05.36 32.05.37 PROLONGED ELECTROSHOCK CH.&NG=~.q Tk~ COUPLING BETW'EEN APOMORPHINE INDUCES INTENSE GROOMING ~- AND 2- ADILENOCEPTORS IN RATS BEHAVIOUR IN MICE TREATED WITH DISCRIMINANT A,y~ic. I. Naleoa. J.Vetulani. BENZAMIDE DERIVATIVES. Stimulation of ~-adrenoceptors is regarded as a main cause of increase in cyclic AMP formation in brain slices M. VASSE and P. PROTAIS exposed to noradrenaline. However, in the rat, a specific ~-adrenoceptor agonist, iseprmterenol is less efficacious Grooming behavlour evaluated by a scoring method in mice was dose- than neradrenaline, a mixed o-and s agenist. dependently increased by the selective D-1 agonist SK&F 38393 (1.87-30 mg(kg, This action of isoproterenol is potentiated by co- s.c.) whereas it was dose-dependently decreased by the selective D-2 agomsts administration of an ~-adreneceotor agonist- 6-fluoronor- RU 24926 (2.5-10 mg/kg, i.p.) or LY 171555 (0.4-1.6 mg/kg, i.p.) alone or adrenaline (6-FNE), suggesting t~--~=t a coupling between ~- associated with SK&F 38393 (s.c.) as well as by apomorphine (0.39-6 mg/kg, and 2- adrenoceptors favors the formation of the second s.c.). The inhibitory effect of 0.75 mg/kg apomorphlne (s.c.) on grooming messen- ger. Treatment of rats with electroconvulsive behaviour was not modified by SCH 9.23390, chlorpromazine, clozapine and thiorldazine. In contrast, it was antagonized by 8 other tested dopamine shock once daily for 7 days wms without influence on the antagonists. Nevertheless, whereas with flupentixol, haloperidol, isoproterenol-iaduced cyclic ~ accumulation, however metoclopramide, thioproperazine and tlapride, a restoration of a grooming the accumulation of the second messenger induced by score lower or roughly similar to that determined in control mice was only either noradrenaline alone, or in combination with 6-FNE observed, a score higher than that determined in control mice was observed in was markedly (by about 50%) reduced. That result resembles mice treated with (_) sulphide, amisulpride or RIV 2093. Furthermore, of the our earlier data on different antidepressant drugs six dopaming antagonists tested against SK&F 38393 (1.87 reg.&g, s.c.), only chlorpromazlne and clozapine antagonized SK&F 38393-induced grooming treatment (Pilc and Enna, Life Sci, 1985,37, 1183) behaviour, whereas the effects of thioridazine, metoclopramide, haloperldol therefore We suggests that the possible target of and amisulpride in SK&F 38393-treated mice paralleled their effects in control antidepressant treatment might be. the coupling of ~- and mice. Fin~llly, RU 24926 (5 mg/kg, Lp.) did not induce grooming behaviour in 2-adreno~eptors rather than the ~-adrenoceptors alone. mice treated with haloperidol, metoclopramide, (_) sulphide or amisulprlde, Since the function of ~,-adrenoceptors, as measured by whereas SCH 23390 (20 ug/kg, s.c.) antagonized apomorphine-induced the nor~dreDm!ine - induced inositol tris- phosphate grooming in mice treated with amisulpride, (_) sulphide or tiapride. These accumulation was not changed by prolonged electroshock it data ~i) conforte the potential role of D-1 dopamine receptors in the expression of grooming behaviour, (ii) indicate from the intense grooming may b~ inverted that antidepressant treatment changes the behaviour induced by apomorphine in mice treated with the discriminant coupling between 2- and ~ subtype benzamide derivatives [(• sulpiride, amisulpride and RIV 2093] that the Institute of Pharmacology. Polish Academy of Sciences, dopamine receptors involved in the i-hlbition of grooming could be of the D-4 12 Smyrna Street, 31-843 Krakow, Poland. subtype , (iii) reveal the D-1 antagonist properties of chlorpromazine and clozapine, and (iv) suggest that the modulation of apomorphine-induced grooming behaviour by dopamine antagonists in mice could be a test for their classification according to their activity at the different dopamine receptor subtypes. Laboratoire de Physiologie (U.A. CNRS 2170), U.E.R. de M#decine-Pharmacie de ROUEN, B.p. 97, 76800 Saint Etienne du Rouvray, France. 326 32.05.38 32.05.39 SIMULTANEOUS EVALUATION OF 5 BEHAVlOURS IN QUANTITATIVE AUTORADIOGRAPHY AS A TOOL TO MICE AS A TEST FOR A RAPID FIRST CLASSIFICA- STUDY DISTRIBUTION AND REGULATION OF CENTRAL NEUROTRANSMITTER RECEPTORS; FURTHER EVIDENCE TION OF DOPAMINE ANTAGONISTS. FOR DOPAMINERGIC RECEPTOR HETER0-REGULATION. P. PROTAIS, M. VASSE and A. CHAGRAOUI F. Trovero, D. Herv4, G. Blanc, J. Glowinski We have tested in mice introduced in cylindrical cages with vertical metal bars and J.F. Tassin. (climbing cages) the effects of increasing doses of 12 dopamine (DA) INSERM U. 114, Coll~ge de France, Ii Place antagonists on the behavinurs spontaneously displayed by naive mice (climbing, Marcelin Berthelot, 75231 Paris cedex 05, sniffing, gnawing and grooming) and on the behaviours induced by 0.75 mgfkg France apomorphine (APO)(climbing, sniffing, licking, gnawing and grooming). The IDs0 determined on spontaneous behaviours allow to classify DA antagonists in The distribution of the dopaminergic (DA) at least two groups: those which decrease the scores of all spontaneous receptors positively coupled to the adenylate behavioars at similar doses (SCH 23390, ehlorpromazine, clozaplne, cyclase (DI receptors), closely resembles that thioridazlne) and those which decrease grooming behaviour at higher doses of the DA innervation in the prefrontal than other behaviours (others). The ID50 determined on APO-induced cortex. behaviours allow to classify DA antagonists in at least 3 groups: those which Different mechanisms of regulation of these receptors can be shown in the rat central antagonize climbing and sniffing with similar IDs0 and which do not promote nervous system following either destruction of grooming behaviour (SCH 23390, ehlorpromazine, elozapine, thlondazlne), afferent fibers or blockade of heterologous those which antagonize climbing and sniffing with similar IDso and which receptors: promote relatively low scores of grooming (flupentixoi, haloperidol, thioproperazine, metoclopramide and fiapride) and those which antagonize I) A cortical serotonergic (5-HT) denervation sniffing with an [Ds0 higher than that determined on climbing, which potentiate obtained.by an injection of 5,7 DHT into the licking and gnawing behaviouss and which promote high scores of grooming median and dorsal raphe nuclei, induces, five (sulpiride, amisulpride and RIV 2093). These data suggest that the weeks later, a small but significant decrease simultaneous evaluation of five behaviours in control mice and in APO-treated of the DA-sensitive adenylate cyclase activity mice could be used as a test for a rapid first classification of dopamine measured in homogenates of microdiscs punched antagonists according to their activity at the different DA receptor subtypes: (i) out frem the medial prefrontal cortex (-25%). DA antagonists acting preferentially at D-1 receptors which decrease all spontaneous bchaviours with similar IDS0 and which do not promote grooming 2) The,blockade of several aminergic receptors behaviour in APO-treated mice (SCH 23390, chlorpromazine, dozapine), (i.i) by an irreversible ligand, EEDQ (i), may allow DA antagonists acting preferentially at D-2 receptors which decrease to study some of the mechanisms responsible spontaneous grooming bchaviours at higher doses than other behaviours, which for ~ the regulation of the D1 receptors. antagonize with similar IDs0 APO-induced climbing and sniff'rag behavlours Indeed, the dose-dependent decrease of 3H-SCH and which promote low scores of grooming in APO-treated mice (flupentixol, 23390 binding observed by quantitative haloperidol, thioproperazine, metoclopramide and tiapride) and 0il) DA autoradiographic analysis in the striatum and antagonists discriminating D-2 and D-4 receptors which decrease spontaneous the prefrontal cortex was different from the grooming bchaviour at higher doses than other behaviours, which antagonize dose-dependent decrease of DA-sensitive APO-indueed climbing with an IDs0 lower than that determined on APO- adenylate cyclase activity in the same induced snlffmg, which potontiate APO-induced licking and gnawing structures. We propose that these differences behaviours and which promote intense grooming behaviour in APO-..a~ated are related to the simultaneous destruction of mice (sulpiride, amisulpride and RIV 2093). other non DA receptors, a phenomenon which Laboratoire de Physiologic (U.A. CNRS 1170), U.E.R. de M4decine-Pharrnacie de might interfere with the coupling of DI ROUEN, B.P. 97, 76800 Saint Etienne du Rouvray, France. receptors to the adenylate cyelase. (i) Hess et col., Molecular Pharmacology, 1987, 31, 50-57. 32.05.40 32.05.41 POSSITIVE INTERACTION BETWEEN ALPHA-ADRENERGIC AND D2 EFFECTS OF SELECTIVE D-I AND D-2 DOPAMINE DOPAMINE (DA) RECEPTORS IN LOCOMOTOR ACTIVITY OF NORMO ANTAGONISTS ON METHAMPHETAMINE-INDUCED AND SUPERSENSITIVE MICE BEHAVIORAL SENSITIZATION M. Rubinstein, A. Schinder, O. Gershanik and F. Stefano ~UiiketT.Onoue,K.Akiyama and S.Otsuki Stimulation of both nl and D2 DA receptors is necessary In this study we aimed at clarifying effects o induce locomotor responses in normosensitive animals of selective D-I and D-2 dopamine antagonists whereas under supersenslt~ve conditions the separate ad- on the development of behavioral sensitization ministration of either D1 or D2 agonists is enough to produced by repeated methamphetamine (MAP) produce an adequate locomotor behavior. However, in these administration. Male S.D. rats were divided conditions,pretreatment with alpha-methyl-ptyrosine(AMPT) into four groups. Each group received daily inhibits D2 hut not D1 agonist-induced responses. In order injection of saline (control group), MAP to study The apparently crucial role of the D1 receptor in 4mg/kg (MAP group), YM 09151-2 0.5mg/kg + MAP supersensitive mice (reserpine I mg/kg/day,s.c., for 5 4mg/kg (YM+MAP group) or SCH 23390 0.5mg/kg + days), we analyzed the effect of the DI antagonist SCH MAP 4mg/kg (SCH+MAP group) for 14 days. After 23390 (0.05 mg/kg,s.e.) on responses elicited by the com- abstinence period of 7 days, all groups bined use of a D1 agonist SKF38393 plus a D2 agonist LY received a challenge dose of MAP (2mg/kg). 171555 (4 mg/kg,s.c., each) or by the mixed DI/D2 agonist Repeated MAP administration produced a pergolide (2 mg/kg,s.c.). A bimodal pattern of responses progressive augmentation in locomotor and was found: a subpopulation of mice did not show reversion stereotyped behavior, whereas concomitant of reserplne-induced akinesia while the other showed nor- administration of YM 09151-2 and SCH 23390 mal locomotor scores. In both cases AMPT (200 + I00 mg/kg, completely abolished progressive behavioral i.p., 3 and 1 h before) abolished DA agonist-induced loco- augmentation by repeated MAP administration. motor responses suggesting a possible noradrenergic parti~ Challenge of MAP (2mg/kg) resulted in ipation.;Clonidine (CLO, 2 mg/kg,i.p.) also showed a hi- reproduced hyperlocomotion and intense modal pa;tern of responses in the reversal of aklnesia in stereotyped behavior only in MAP group. chronic reserpinized mice but it did not induce locomotion However both YM+MAP group and SCH+MAP group in acut~ reserpinized mice (5 mg/kg,s.c., 2 h before). In . sh6wed only hyperlocomotion and no stereotypy these~last conditions, CL0 + SKF (2 mg/kg,l.p. + 8 mg/kg, which were similar to those observed in s.c.) did no~-reverse akinesia but CL0 + LY (2 mg/kg,i.p. control group. + 8 mg/kg,s.c.) did. The responses induced by CLO + LY These results indicate selective D-I were not prevented either by SCH23390 or by AMPT but were antagonist as well as selective D-2 antagonist abolished by the separate use of prazosin (0.5 mg/kg,i.p.) not only reversed MAP-induced motor effects or yohimbine (2.5 mg/kg,i.p.). These results suggest that but also prevented the development of clonldine could mimic, interacting simultaneously with behavioral sensitization induced by repeated alpha-1 and alpha-2 adrenergic receptors, the effects of MAP administration. D1 stimulation necessary to generate DA-mediated locomotor Department of Neuropsychiatry, Okayama responses. University Medical School, Shikata-cho, Instituto de Investigaciones Farmacol6gicas (CONICET). Okayama 700, Japan Jun~n 956 - 5~ 1113 Buenos Aires. Argentina. 327 32.05.42 32.05.43 CHRONIC EFFECT OF A SELECTIVE D-2 ANTAGONIST, YM-09151, CENTRAL PHARMACOLOGICAL EFFECTS OF 5-HT, B RECEPTOR AGONISTS. ON DOP~41NE AGONIST-INDUCED STEREOTYPY IN RATS ~CHO/NACKA-u A.K~ODZINSKA. J.~ S. Usuda,M. Terai,T. Yamaquchi,F. Wanibuchi and K. Hidaka m-Triflusromethylphenylpiperazine (TFMPP) Chronic administration of neuroleptic drugs altering D-2 add m-chlorep~enylpiperazine 32.05.44 32.05.45 THE INHIBITION OF NEUROTRANSMITTER RECEPTOR 5-HT BINDING SITES IN POST-MORTEM HUMAN BRAIN BINDING TO HUMAN BRAIN PREPARATION BY S.C. Cheetham, Y. Yamaquchi and R.W.Hcrton PSYCHOTROPIC DRUGS Receptors for serotonin (5-HT) have been M. Toru, H, Shimizu, N. Hata and H. Ogata classified into 5HTI, 5HT2 and 5HT3. 5HTI The inhibition of dopamine D2, adrenaline aI,~2, sites have been shown to be heterogeneous and muscarinic cholinergic and serotonin 5HT2 re- have been further sub-divided into 1A, B, C, ceptor binding to human brain by various psycho- and D. We have used 3H-5HT (3 nM, non-specific tropic drugs was studied. Human putamen was binding defined with 5xl0-4M unlabelled 5HT) used for I>2 and cerebral cortex was used for to label 5HT binding sites in post-mortem other receptor binding assay. 3H-spiperone was human brain and have studied the displacement used for labeling D2 and 5h~2 receptors, with sub-type selective drugs. In frontal 3H-WB4101 for al, 3H-idazoxan for a2, 3H-quinuc- cortex, 5HTIA selective drugs (8-OH DPAT lidinyl benzilate for musucarinic cholinergic buspirone, ipsapirone, spiperone and 5C~ receptor binding. Antipsychotic drugs assessed displaced from a similar proportion of sites were: chlorpromazine, levomepromazine, cloza- (35-53%) with high affinity (KD 7-200 nM) and pine, thioridazine, propericiazine, perphena- the remaining sites with low affinity (4-69 zinc, zotepine, haloperido!, timiperone, brom- ~M). TFMPP (5HTIB selective) was only a weak peridol, carpipramine, clocapramine, oxypertine, displacer (32% inhibition at 10-5 M) . sulpirid~, YM-09151, etc. Antidepressants were: Ketanserin (5HT2 selective) displaced from 70% imipramine, clomipramine, desipramine, trimipra- of the sites with low affinity (KD 1.6 ~M). nine, lofepramine, amitriptyline, nortriptyline. GR 38032F and MDL 72222 (SHT3 selective) only amoxapine, maprotiline, mianserin, dosulepine, displaced from 31% and 15% of sites etc. Antiparkinsonian drugs were: promethazine, respectively at 10-4M. 8-OH DPAT displaced trihexyphenidyl, biperiden, piroheptine, profe- with high affinity from a similar proportion namine, etc. There were some antidepressants of sites in the amygdala (43%) as in the which inhibited D2receptor binding as strong as frontal cortex (42%) but a higher proportion antlpsychotic drugs, al-receptor inhibition of (63%) in the hippocampus. RU 24969 (equivalent phenothiazines was generally stronger than affinity for IA and IB sites) displaced from a butyrophenones. Of all antidepressants, mian- higher proportion of sites than 8-OH DPAT in serin most strongly inhibited both a2 and 5HT2 the hippocampus (90% v 63%), amygdala (70% v receptors. 43%) and frontal cortex (61% v 42%). The results demonstrate the selective labelling of Department of Psychiatry, Shinshu University 5HTl-like sites by 3H-5HT in the human brain School of Medicine, 3-i-1 Asahi, Matsumoto, with little or no labelling of 5HT2 or 5HT3 Japan 390 sites, and indicate a higher proportion of 5HTIA sites in the hippocampus compared to the frontal cortex and amygdala. Department of Pharmacology, St. George's Hospital Medical School, London SWI7 ORE. 328 32.05.46 32.05.47 CHARACTERIZATION AND LOCALIZATION OF DOPAMINE TEE DIEYDROPYRIDINE C~LCIUK CHANNEL ANYAGORIST NI~ODIPINE AND SEROTONIN UPTAKE SITES IN HUMAN BRAIN ~S &N &~TIDEPEESSANT DRUG J.M. Maloteaux, J.N. Octave, M.A. Vanisberg, A. Czvrak. E. Mo~inlcka. I. Mal E.C. Laterre and P.M. Laduron* ~imDdipine (NI~), a calcium antaEonist is a vasodilator ~H-GBR 12935 binds with a high affinity (Kd: 3.2 with a preferential action on central vessels. Apart from nM) to dopamine uptake sites in human striatum cerebral vascular effects, NIM has also been show1~ to (Kd: I.I nM in rat). ~H-GBR 12935 specific possess some central pharmacoloEical effects. Recently, we bindin~ was inhibited by several dopamine uptake de~nstrated that ~IM reduces the mouse immobility in the blockers in the striatum and there was only a behavloural despair test (MoEilnlcka et el,, 1987). At very low bindin~ in non-dopaminerEic areas. The present we found that various antidepressants (imlpra~Ine, subcellular profile of the specific binding amltriptyline, mianserin, cltalopram), used at doses which revealed a principal synaptosomal localization are not effective themselves, facilitate the immobility- which is quite different from that of dopamine- reducln S effect of ~I~ in the despair test when they are D~ receptors. The ~H-GBR 12935 specific bindin E administered jointly with this drug. is a ~ood marker of dopaminer~ic nerve endings Purther behavioural experiments demonstrated the effect of in human striatum and has been used for the NIX (2.5, 5, i0, 20 m~/kg p.o.) in other tests for antide- study of the dopamine uptake sites in pressant activity. NIM antagonized the hypothermla induced extrapyramidal disorders. by a hish dose of apomorphlne (16 mg/kg) in mice. It po- ~H-parox~tine specifically recognizes the tentiated ~he action of L-DOPA in mice (Everett's test) serotonin uptake sites which are concentrated in aud reduced the clonidine-induced sedation in rats. The subcortical structures of human brain whereas reserpine- and clonidineninduced hypothermias in mice wer~ both serotonin S, and S~ receptors were not chan~ed by NI~. concent!ated in the cerebral cortex. The Kd In blochemical experiments the effect of NIM on the uptake value of ~H-paroxetine was of 0.15 nM in human of 5-hydroxytryptamine (5-HT) and noradreualine (NA) ia putamen (Kd: 0.22 in rat). The subcellular vivu (protection aEainst the H~-~/~ [4,alpha-dlmethyl- distribution profile of ~H-paroxetine specific meta-tyramine]-Induced displacement of 5-HT and NA) was bind%ng revealed the association of serotonin inves~isated. NI~ sisnificantly reduced (by about 30%) the uptake sites with the mitochondrial fractions H~,~m-induced displacement of 5-HT, but not of ~A, in the and the synaptosomes. Both ~H-paroxetine and rat brain cortex. ~H-GBR 12935 were found associated, to a lower These results indicate that in some tests NIM in its pro- extent, to microsomal structures s~gesting the file resembles antidepressant dru~s; moreover they support presence of amine binding sites which are the idea that concominant administration of antidepres- specific but not functional in the microsomes. sants and dlhydropyridlne calcium channel antagonists may Laboratoire de Neurochimie, Universit~ de result in a steerer therapeutic efficacy. Louvain, B-1200 Brussels, Bel~ium and *Rhene- Mo~ilnicka E., Czyrak A. and MaJ I. Poulenc Sant@, Centre de Recherche de Vitry, Eur. 1. Pharm~col. 1987, 138, 413-416. F-94407 Vitry sur Seine, France. Institute of Pharmscolosy, Polish Academy of Sciences, 12 Sm~tna St., 31-343 Krakow, Poland 32.05.48 32.05.49 RIT~IN ]3e ~D~S811/E P~I~ RELATIONSHIP OF HUMAN PLATELET AND BRAIN MAO: (A double-blind placebo controlled study in general practice) L. CROC0 t, P. BUGARD*, Ph. BOUHOURS** STUDIES BY ISOELECTRIC FOCUSING (IEF) Ritanserin is a selective, potent and centrally acting serotonin-S 2 P. Koronakis, J. Fritze, P. Riederer antagonist. Ritanserin was studied in dysth~ic disorders (DSM XII) MAO has been characterized according to substrate in a double-blind placebo controlled ~ultJcentric general practice trlal. and inhibitor specificities. Although MAO-B has The dosages of ritansezin were 5 mg b.~.d, and 10 mg b.i.d. The been identified in human brain by such bio- treatment duration was 4 Weeks. The evaluation was made by using the #~s~e~mia ~le of C~ and chemical and also immunological means, only few BUCkleD. This scale is divided in 15 clinical items: Presentation and is known of whether the enzyme is identical in cantact, language and oral expression, general condition, appetite disturbances, sleep disturbances, sexual ~isorders, muscular fatigue, brain and platelet. IEF has proved to be a very intellectual fatigue, sensitivity to the external world, cephalic and sensitive method to detect protein heterogeneities. sensorial s~,mptoms, somatic distress, psychic anxiety, depression, disturbance of character, hypochondria. Therefore, MAO was labeled by 3H-pargyline This scale is evaluated by a Global Severity score and a symptom-sum (0,i VM) in both tissues, solubilized by Triton of the 15 clinical items. x-t00 (0,5 %; v/v) and submitted to IEP. In 134 patients entered the study and 121 patients were finally analyzed, 13 patients were excluded fzo~ the efficacy analysis for platelets, labeled material focused at pH 6.4 insufficient data. 39 received I0 m~ ritanserin, 42 received 20 mg without interindividuel differences. In the 9 ritanserin aod 40 received a placebo. Results : l~g ritanserin at Week 2 was more effective than plBcebo brain regions studied, the material focused on the global severity evaluation (MWU-test); at Week 4 the global between pH 5.7 and pH 6.4 without revealing severlty is also significantly improved (M~-test) a~d the item intellectual fatigue improved at a significant level (p<0,01). distinct bands within this range. 3H-pargyline The global severity evaluation of 20 mq ritanserin was better than affinity.labeling in the presence of various placebo at Week 2 but not at Week 4 (~U-~est). At Week 2 and Week 4 reversible and irreversible inhibitors shewed analysis the results showed no statistically significant difference between 10 mg and 20 mg ritanserin. the material to represent MAO-B. MAO-A from If the intezgzoup comparison was m~de separately for male and female human placenta was not labeled under the con- patients, global clinical improvement on :itanserin was found better in male patients. ditions used. Thus, the heterogeneity of brain PatieRt's Visual A~alog Scales (present state, sleep, fatigue): there MAO-B in IEF is probably due to lipids still was a~significant difference between I0 ~ ritanserin and placebo for the present state ltem, There was no difference between i0 mg and attached to MAO. Modifications of the solubili- 20 mg ritanserin. ration procedure should further clarify this At Week 4 (final evaluation), 81% of patients were considered cured or improved with I0 mg ritanserin; 80 % with 20 mg ritanserin and topi~. 54 % with placebo. Klinische Neurochemie, Universit~ts-Nerven- Side effects were minimal and tolerance was generally excellent in the three groups. klinik WOrzburg, FOchsleinstr. 15, 8700 WOrz- Based on these results a new trial using lo~er doses of ritanserin burg, FRG will be implemented in dysthymic disorders. * G~oupe d'E~udes de la Fatique (G.E.F,), 2 square du Cro[slc, 75015 PARIS =* Leboratoires JANSSEN, 5 r@e de Luback, 75116 PARIS 329 33.01.01 THEP~fIC PRINCIPI~ AI~ PRACTICE IN 8055 PATI~ OF A I~/N-ICIPAL PSYCHIATRIC DEPARE~='~T Gy..~k~in~ and I. Gy. Magyar yor 7 years, the data of every acut and chronic relapsed POSTER cases we_re processed and analyzed by C-128 cc~uter prog- ram /ICD-9, AFDP system, specialized drug subroutine codes PRESENTATION 1-9/. In this evaluation, 4 patients' group were assessed /DgM-III, ICD-9; 295, 296, 300, 301/ to make graphs for 33.01 yearly cmmparison /1981-87/ with their "first adjustment" of drug regime. In schizophrenics -acut and cbm-onic relapsed- the first choice of pharmacotherapy was tr• /6 years/. Its use was revalry with butl~rophenons which turned to be favoured only last year in reduced doses or instead of that more frequently given milder antipsychotics /thiori- Schizophrenia dazid, perfenazin, chlorprotixenl. In affective psychoses, the "hospitalization index" reve- - Basic and Clinical Aspects aled an increased rate. Because of severe psychotic episo- des, the neuroleptics, tricyclics, Li and "antiepileptic - antima_nic" drugs /CARB/ were added more frequently. qhe admission of neurotics, -rsDst of thegn with grave anxi- ety and depression, increas<~d in the last 3 years. The gravity of the slm~ was "c/r=Tracterized" by raising first choice of tricyclics, neuroleptics with milder tranquillation, added to anxiolytics in spite of intensi- fied psychotherapy. At last, personality disorders observed for 7 years seemed ~ to show "breakless increase". The difficulties in socialization, family and/or work place adaptation, stress situation were challenging the hospital to intervene in crisis by drugs /anxiolytics, milder antipsychotics and ~-ithdra%,-=l therapy/, qhe hospit~%lization and therapy of the heteroger~us subgroups with affective and sociopathic sy~t~irs indicated significantly negative predictor vari- ables /drug abuse, suicide behavior etc./. Hospital "Istvan" /Mer@nyi/ Dept. ">f Psychiatry H-1097. Budapest, Gy~li u. 17. Hungary. 33.01.02 33.01.03 ABSTRACT IS FAMILY HISTORY PREDICTIVE FOR TREATMENT RESPONSE OF Schizofrenia: The Brief Psychiatric Rating Scale (BPRS), AFFECTIVE AND SCHIZOPHRENIC PATIENTS Reliability and Validity studies. J. Hallmayer, W. Maier Andersen John, Korner Alex, Jens Knud Valid predictors of treatment response on affective Larsen, Vilhelm Schultz, Bjarne Meyer disorders and schizophrenia are rare. A large number of Nielsen, Ebbe Munk-Andersen, Kirsten Behnke, psychopathological or clinical features has been tested Niels Bjerum. but only a small number of them were found to be 103 patients (32 women, 71 men), 19 to 59 years of age predictive (e.g. delusions in depression for an (median 35 years), fullfilling the DSM-III criteria for unfavorable response to antidepressants). However familial schizofrenia were rated with the BPRS once weekly between loading with psychiatric disorders of patients has only 8.15 to 9.00 a.m. from august 1984 till july 1987. In been proved in a few studies for its predictive power for the used version of the BPRS each item is graduated from treatment response; this is especially the ease for treat- 0 to 4 with an explicit definition of each grade. ment with tricyclic antidepressants and neuroleptics. The group of raters consisted of 7. Each rater has seen To evaluate utility of family history for treatment no less than 50 and no more than 79 (median 73) of the response to tricyclic antidepressants and neurolepties we 103 patients. 31 of the patients were, furthermore, on carried out a family study in inpatients with depressive the same morning as the BPRS took place, rated globally and/or psychotic disorders. 40 patients with a current by a consultant using the Clinical Global Impressions major depressive disorder (RDC) and 40 patients with (CGI). schizophrenic/schizoaffective disorders (RDC) will The consultant did not attend the weekly co-ratings. receive standardized tricyclic treatment for depression The inter observer reliability (Rs) for the BPRS is 0.82 and standardized neuroleptic treatment for productive (0.74 to 0.88), for the B~RS 10 item schizofrenia- symptomatology during a period of 4 weeks after admission subscale;it is 0.85 (0.80 to 0.89). The concurrent to the hospital. First degree relatives are interviewed validity, the Global-rating versus the BPRS: R=0.64. personall~ using the SADS-L. The Global-rating versus The BPRS schizofrenia-subscale: Preliminary results from this ongoing study do not support R=0.66. the hypothesis that patients with sporadic occurrence of The B PRS item 6 (tension) and 16 (blunted affect) are the disorder are bad responders to treatment. responsible for disagreement between 5 and 4,respectively, Psychietrische Klinik der Johannes Gutenberg-Universit~t of the 7 raters. Mainz, Untere Zahlbacher Str. 8, D - 6500 Mainz 1 On 9 items there was agreement among all the raters. By comparing earlier interim results with the final result it is demonstrated that co-rating increases the inter-rater-reliability-coefficient for the scale as a whole as well as the agreement on the more specific schizofrenic symptoms comprising the BPRS subscale. 330 33.01.04 33.01.05 SUBGROUPS OF SCHIZOPHRENIA, CLINICAL .~ CLIniCAL SYMPTOi~TOLOGY,NEUROLEPTIC RESPONSE PHARMACOLOGICAL ASPECTS A}~ SERUM DOPAk~NE-BETA-HYDROXYLASE ACTIVITY M. Jarema IN FAMILIAL A~ SPORADI~ SCHIZOPHRENIA Gy. Bartk6,Gy. Z~dor,~&Arat6,Sz.Horvdth Different therapeutic response to neuroleptics The characteristic psychopathologic features, in schizophrenia may be caused by heterogeneity the neuroleptic response at the last episode, of schizophrenic population. The use of more detailed classification of schizoplnrenic serum dopamine-beta-hydroxylase /DEH/activity were studied in 32 schizophrenic patients psychoses may reveal more homogenous subgroups possessing a first degree relative with histo- of patients. ry of schizophrenia and 49 patients without a A cohort of patients who met the D~{-III-R criteria for schizophrenia has been s~adied. family histozoj. The family history positive pa- Negative/positive symptoms scale and DCR tients characterized by a more severe positive Nashville (Ban et. al, 1987) has been used. symptoms at admission.There was no significant DCR (Diagnostic Criteria for Research) is based difference in the severity of negative sympto- on European classification of functional matology between the two patient groups.Schizo- psychoses (Leonhard's classification, French phrenics with positive family history showed and Scandinavian schools of psychopathology). a nonsignificant tremd for greater improvement Therapeutic response to neuroleptics as well as over the 28 day neuroleptic treatment.There many individual and social factors (i.e. was significant reduced serum DEg activity im familial risk for schizophrenia, duration of the patients with positive family history in illness, length of present episode, season of comparison to patients with negative family birth, number of previous hospitalizations, history.The results support the validity of occupafional activity, and others) has been familim!/sporadlc distinction in schizophrenia. compared among schizophrenic subgroups. National Institute for Nervous and ~ental The differences bet,r various schizophrenic Diseases, t291 Budapest Pf.1.,Hungary subP9PUlations has been discussed. Department of Psychiatry, Medical Academy, Bronlewskiego 26, 71-460 Szczecin, Poland. 33.01.06 33.01.07 THE -JTILITY OF -~ZOPERIDOL PLAS:L~. ZE~.-s AFTER A SIGNIFICANCE OF PLASMA AND CSF HVA IN PSYCHI- TEST DOSE TO 7F-DiCT THE CLINICAZ RvSPONSE OF ATRIC PATIENTS BEFORE AND AFTER TREATMENT. ACUTE SC~ZO_=---~_=!~C PATIENTS TO I---=&2>~NT. J.l. Javaid, R. Sharma, K. Fault, and ~.M. Davis N. R. LouzR Zero*. F. Xiiller-Spai~-n. E. RGther~ J. Scherer Measurement of 3-Methoxy-~-hydroxy-phenylacetic acid Plasma level monitoring plays an =-portant role (HVA) has been used as an index of dopamine (DA) in psychiatric care. Besides its use during lit turnover. Recent evidence suggests that changes in thium and antidepressant therapies, there are plasma HVA may reflect central dopaminergic activity. numerous investigations about the relationship We studied plasma and CSF HVA in i7 psychiatric between neuroleptic plasma levels and clinical inpatients (11 schizophrenics, 3 schizoaffectives, 2 response to vreatment with controversial results bipolars, 1 paranoid disorder). After a washout period of (Baldessarini etal. Arch Gen Psychiatry 45:79- 19 days ( + 6 days), all patients underwent a baseline 9~, 1988). lumbar puncture. Nine schizophrenics and three In a double-blind study the plasma level of ha- nonschizophrenic patients underwent a second lumbar loperidol (EL) after a single test dose (0.05 puncture after /4 weeks of treatment. The schizophrenic mg/kg) was used to predict the resnonse of acu- patients were all treated with trifluoperazine. Blood was te schizophrenic patients (n=20, 7~C) to treat- drawn 15 minutes prior to each lumbar puncture. Plasma ment with a low (O.15 mg/kg) and a high (0.40 HVA was measured by HPLC-EC and CSF HVA was mg/kg) f~xed-dose of HL. Clinical response was assayed bY GC/MS. evaluated 8 and 30 days after the beginning of the treatment with the BPRS (Overall & Gotham Although there were no consistent changes across pa- Psychol Rep 1C:~99-812, 1962); _~ plasma level tients, alterations in CSF HYA after pharmacological was measured ~.#_th Eadioimmunoassay. treatment strongly correlated with changes in plasma The EL plasma level after the test ~ose had a HVA ( N= ll, r = 0.7/4, p = 0.009). The baseline plasma significant relationship (r=0.69, u{D.O3) with and CSF HVA did not eorreIate with baseline clinical the clinical improvement after 8 d&Vs of treat- measures. However, there was significant correlation mentfonly for the low-dose group. ~e improve- with a decrease in both CSF and plasma HVA and clinical ment after 30 days could not be ore~icted from improvement in schizophrenic patients. These results the HL plasma level after the test dose. suggest that improvement in certain psychotic symptoms These results could be due to the different after /4 weeks of treatment may be associated with a rate of the d~ag-induced clinical -'__-provement, reduction of DA turnover in the central nervous system. which decreases along the treatment (~avis et al. Psychopha-r~-acol Bull 21:48-5~, ~Ef). Illinois State Psychiatric Institute and Department of Psychiatric Clinic University of Zunich. Psychiatry, University of Illinois at Chicago, 1601 W. Nussbaumstrasse 9, 8000 ~t[uchen 2. FP.G Taylor Street~ Chicag%Ii 60612. *D#~D-Ee!low. lnstitut of Psychiav_~, 7niversity of S~o Paulc, ~razil. 331 33.01 .O8 33.01.09 INDICATION OF PSYCHOTIC AND PSYCHEDELIC STATES BY IMPAIRED DEPRESSIVE SYMPTOMS IN THE ACUTE PHASE OF SCHIZOPHRIINIA BINOCULAR DEPTH INVERSION AS PRI~ICIZIRS FOR RESPONSE TO ~LEPTIC q!~FATME~T H.M. Emrich, M.M. Weber, A. Wendl and J. Zihl Y. Lamer t T. Tl~l~t, N. Tamarin A three-component-model of the neuropsychological basis Data regarding the relationship between depressive of psychotogenesis is presented: it consists of Ist) a symptoms in schizoyhrenia and response to neuroleptics sensualistic; 2nd) a constructivistic, and 3rd) a "cen- is scarce and conflicting. Kolakowska et al. (Psychol. sor"-component of the system. It is assumed that in Med. 10, 335, 1980) found the subgroup of poor psychotogenesis the "censor-function" in relation to the responders to have lower depression scores. constrnctivistic component is weakened. Becker et al. (J. Clin. Psychiatry 46 (11, Sec 2), 26, Measurements of binocular depth inversion using a stereo- 1987), on the other hand, claim that the depression that scopic slide projection with polarized light were per- occurs in the course of schizophrenia is associated with formed in schizophrenic patients and in healthy volun- poor response to neuroleptic treatment. teers under cannabis. Since binocular depth inversion In the present study, 46 randcmly admitted patients who represents an illusion occurring in the perception of met RDC definite criteria for schizophrenia were rated objects with semantic relevance projected in a 3-D in- on the BPRS, Hamilton Depression Scale, and the EPI verted fashion, the hypothesis can be tested that psycho- Scale, at admission, and after six weeks of sis represents a state in which the human CNS is unable hospitalization. to correct implausible perceptual hypotheses. The data Neuroleptic treatment was prescribed by the therapist demonstrate a strong impairment of binocular depth inver- independently of two blind raters. Patients were divided sion in productive schizophrenia as well as in a can- according to their basal Hamilton soores into two sub- nabis-induced psychedelic state. groups: schizophrenics with depression (Hamilton>18) and Max-P]anck-lnstitut ffir Psychiatrie, Kraepelinstr. 10, those with few or no depressive symptoms (Hamilton <18). D-8000 Mfinchen 40 The tw~ groups of patients did not differ as to their basal BPRS scores, but at six weeks, the depressive schizophrenics scored higher on the BPRS. There was no difference between the two groups on the exti-apyramidal rating score, neither at admission nor at six weeks. The results support our previous findings (Lerner et al., Lithi~n CombLned with Haloperidol in Schizophrenic Patients. Brit. J. Psychiatry, accepted for publication) that the presence of depressive sympton~ during the acute y~ase of schizophrenia correlates with poorer response to neuroleptic treatment. 33.01.10 33.01.11 DES-~qKhwHAL~~ORPHIN : FdPrIHER EVIDENCE OF ITS ~UROLEPTIC-INDUCED HYPOTHER~ffA : A PERIPHERAL ANI~C ACTIVITY IALPHA-ADRENERGIC IhWOL%U~NT G. Boschi t N. Launay and R. Rips J.M.A. Sitsen and A.M.L van Delft Although neuroleptics are generally administered peripherally, their hypothermic effect has been said to Ever since the isolation and the identification of the involve the central nervous system, and more precisely endorl~ many investigators have been intrigued by the hypothalamus. However, the few data which provide their physiological and pathological functions. A role information regarding hypothermia produced by for these neuropeptides has been claimed in several psychiatric disorders, in particular schizophrenia. intracerebral administration of neuroleptics are Des-enkephalin-gamma-endorphin (Org 5878) is the controversial. We have therefore studied twelve shortest amino acid sequence derived from neuroleptics belonging to five chemical classes for gamma~r~hin retaining the behavioural activity, e.g. their ability to produce hypothermia when administered the facilitation of extinction of active avoidance ~utraperitoneally (ip) or intracerebroventricularly to behaviour in rats. Since antipsychotic drugs such as mice. The phenothiazines (chlorpromazine, haloperidol exhibit the same pharmacological effects, levomepromazine, thioproperazine, prochlorperazine, des-enkey~nlin-gamma-endorphin has been investigated in perimetazine and piportil) produced the strongest schizophrenic patients. hypothermia. The butyrophenones (haloperidol and In a trial comparing placebo, i, 3 and i0 mg of this droperidol), the thioxanthene (flupentixol) and the peptide per day in acutely exacerbated schizo~enic diphenylbutylpiperidine (pimozide) decreased the rectal patients on standard maintenance treatment, the patients temperature to a lesser extent. The benzamides receiving i0 mg showed a significantly larger reduction (sulpiride and sultopride) did not modify the in CPRS (Comprehensive Psychopathological Rating Scale) temperature except for sulpiride which produced scores than the other groups after 4 ~eks of treatment. hypothegmia at a dose inducing toxic effects (rigidity, A second cxmmparative trial of Org 5878 (3 mg i.m. per convulsions). Surprisingly, none of the neuroleptics day) versus haloperidol (5 mg p.o. twice daily) in administered icv induced hypothermia at doses which did schizophrenic patients not taking other antipsychotic medication showed a similar reduction of CPRS and BFRS not :produce toxic effects, suggesting that neuroleptics (Brief Psychiatric Rating Scale) scores. No act to elicit hypothermia via a peripheral, rather than side-effects that could be attributed to a central mechanism. Since most neuroleptics possess des-enkeyhalin-ganma-endoc~in ~re observed. In the alphs-adrenolytic properties, we attempted to second comparative trial patients treated with the antagonize the hypothermia with phenylephrine which endorphin had clearly less movement disorders than the activates peripheral alpha-adrenoceptors. Indeed, the haloperidol-treated patients. concomitant injection of phenylephrine (6 mg/kg ip) and The lack of sedative effects and the need for parenteral chlorpromazine (2.5 mg/kg ip) or haloperidol (4 mg/kg administration of Org 5878 are disadvantageous in the ip) suppressed the hypothermia supporting the view that treatment of acutely psychotic patients. However, the peripheral alpha-adrenoceptors may mediate former and the absence of extrapyramidal side-effects neuroleptic-induced hypothermia. may ~ii prove to be improvements on existing D~SERH, Pharmacologie, 17 rue du Fer ~ Moulin, 75005 maintenance treatment for schizophrenic patients. PARIS. Scientific Development Group, Organon International B.V., P.O. Box 20, 5340 BH Oss, ~ Netherlands. 332 33.01.12 33.01.13 A NEW CLUE IN THE PRECLINICAL PREDICTABILITY OF ACTION OF LOW AND HIGHT DOSE OF PIPOTIAZINE NEUROLEPTICS ON SCHIZOPHRENIC NEGATIVE SYMPTOMS. Y. Okazaki, N. Anzai, M. Setoguchi, T__t. Fukuda P. Robert, Y. Merdji, M. Touary, B. Bensmail, The clinical effects of neuroleptics are many and G. Darcourt. varied. The strong correlation between the clinical The aim of these study was to compare efficacy of low potency of a neuroleptic and its anti-dopaminergic and hight dose of neuroleptic (pipotiazine) in DSM III-R (DA) activity has been supported by many studies. schizophrenia catatonic type, disorganized typ~ Based on behavioural-pharmacological experiments, 14 undifferentiated type and residual type. neuroleptics known to have a variety of action After i0 days of neuroleptic wash out patients must characteristics, relative anti-NA/anti-DA, anti- present a minimal score of 75 at the scale for the 5HT/anti-DA, and anti-5HT/anti-DA ratio-values assessment of negative symptoms (SANS - ANDREASEN). adjusted to have a value equal to a chrolpromazine In these double blind study i0 patients received (CP) value of i were obtained. Values for each 0,I mg/kg of pipotiazine and I0 patients 0,5 mg/kg nenroleptic were plotted on a logarithmic during 8 weeks. Clinical course was rated each week coordinates' graphs with the origin at CP(1,1,1). using SANS, CPRS and MJtDRS. Pipotiazine blood ratio After considering the clinical effects reported from was evaluated after 4 days, 4 weeks and 8 weeks of each drug,findings important for the preclinical treatment. predictability of clinical effects in neuroleptics First results indicate that there is no signifiant were observed. difference between low and hight dose improvement rate. 1)Two significant axes crossing the origin (CP) at In the first 4 weeks action of low dose are more right angles were found and considered to effective but these initial better results is cancel characterize neuroleptics tested. by signifiant worsen score noted in the last 4 weeks. 2)One axes - the anti-5HT/anti-NA axis may relate to Clinique de psychiatrie et de psychologie m~dicale - sedative (anti-bHT>anti-NA)-disinhibitory (anti- H8pital PASTEUR - 30, avenue de la Vole Romaine - 5HT 33.01.14 33.01.15 PRESYNAPTIC DOPAMINE RECEPTOR AGONIST (B-HT 920) CLINICAL EVALUATION OF YM-09151, A BENZOAMIDE DERIVATIVE TREATMENT OF SCHIZOPHRENIA ON SCHIZOPHRENICS G. Lipka, K. Wiedemann, O. Benkert, F. Holsboer A.Sumiyoshi, M.Murasaki, A.Mori, R.Takahashi, B-HT 920 was administered in a dose range from 0.3 - 1.2 H.Kazamatsuri, G.Yagi, K.Kamijima, and T.Kariya mg/d for 21 days to 12 patients with schizophrenia, YM-09151 is a benzamide derivative which has been newly paranoid type, in order to examine whether presynaptic developed in Japan, having a differnt chemical structure receptor stimulation exerts antipsychotic effects as can from both sulpiride and sultopride. It has been shown to be assumed by therapeutic trials with low dose ad- have potent antipsyehotic effects in the preclinical ministration of apomorphine. From a pilot study which studies. was conducted at the Research Unit of the Dep. of In our phase 2 study of YM-09151 on schizophrenics, a Psychiatry, University of Mainz, the following results high quality of th@~inal global improvement rating emerged; (FGIR) has been obtained as shown in Table i. In 4 patients a significant amelioration (reduction of initial BPRS scores by more than 50~) of psychotic Table i: Final $1ohal improvement rating (%) symptomatology was observed. 8 patients remained without Improvement No change Aggravation Total any change of psychopathology. Psychomotor activation was +++ -H- + observed in six patients which prompted termination of 8 20 35 34 7 104 the trial in two cases. No other marked adverse effects (7.7) (19.2) (33.7) (32.4) (6.7) (i00) of B-HT 920 were noted. In agreement with pharmacology of B-HT 920, Prolactin plasma concentrations two hours after AS to the symptomatological parameters in BPRS, effective- oral application of a single dose of the drug were neSS Was ascertained in the terms of tention, hostility, significantly re4uced. and hallucinately behavior. Furthermore, relatively good It remains to be clarified whether B-HT 920 possesses results were obtained in the terms of anxiety, emotiona] antipsychotic properties. The activating properties of withdraw~l, and uncooperativeness, suggesting that YM- 8-HT 920 in o~r hand are interesting and should be 09151 might have the effect towards negative symptoms of inves#igated in further studies in a specifically defined schizophrenia, namely an activating action, as well as subsample of schizophrenic patients where negative posit$ve symptoms. symptoms predominate. The~nogt frequently observed side effect was akathisia Department of Psychiatry, University of Freiburg, noticed in 15.7%. Followed by appearence of tremor, Hauptstrasse 5, r~-7800 Freiburg, West-Germany muscular rigidity, slurred speech, and drowsiness were observed in over 10% respectively. It is the fact that the incidence of the extrapyramidal symptoms is reretively low in YM-09151. The global utility rating has been evaluated better than FGIR, shoeing the fact that YM-ogI51 is superior to the conventional antipsychotics used earlier in those schizophrenic patients. Department of psychiatry, Tokiwa Hospital,3439-2 Tokiwa, Machida, Tokyo, Japan, 194-02 333 33.01.16 33.01.17 GYKI-22 441, A NEW PHENOTHIAZINE ESTHER WITH INTERACTION OF THE NEW ANTIPSYCNOTIC RISPERIDONE WITH LONG-ACTING NEUROLEPTIC EFFECT SPONTANEOUS AND AMPHETAMINE-INDUCED MOTILITY IN RATS I. Kir~Iy, J. Borsy, M. Tapfer, S. Losonczy, A.A.H.P. Me~ens, F.H.L. Awouters, C.J.E. Nieme~eers and K. RAsky, L. Toldy and I. T6th P.A.J. Janssen In order to obtain depot neuroleptic effect the The effects of risperidone and haloperldol on spontaneous new 2-trifluoromethyl-phenothiazine esthers were and amphetamine-lnduced motility were studied in rats. synthetized by using sterically hindered acids Large motor movements were significantly reduced by low of lipophyllic character. doses of both risperidone and haloperidol (0.062 and Some compounds were administered intramuscularly 0.038 mg/kg, respectively). Progressively higher doses in depot injection and their pharmacological ef- were required to block smaller motor movements. The dose ficacy were compared to fluphenazine decanoate increment, however, was much larger for risperidone (up /Modecate/ as reference drug. to 2.80 ms/ks) than for haloperldol (up to 0.085 ms/MS). One of these compounds, GYKI-22 441 /2-trifluoro Also hyperactivity and stereotypy induced by low levels methyl-lO-~-[4-/@-ethyl/-l-piperaziny~ -propyl- of amphetamine stimulation were antagonized by low doses phenothiazine /4-chlorophenoxy/ isobutyrate/ Of the two compounds (0.02 to 0.0~ ms/ks). Normal moti- were selected for further investigation. Its pre- lity was completely restored at higher dose levels of clinical studies have already finished and the amphetamine stimulation too, but the required doses clinical trials are in progress now. diverged. To normalize motility induced by amphetamine In the pharmacological experiments the strong doses up to 5.0 ms/ks, the effective doses of risperldone and long-lasting antiapemorphine effects of the had to be increased rapidly (up to 0.50 to 0.96 mE/kS) compound were verified. It effectively antago- whereas a relatively small dose increment was sufficient nized the apomorphine-induced hypermotility, for haloperidol (up to 0.0~5 to 0.0Zl ~/kg). At still stereotypy and turning behaviour of rats and the higher amphetamine doses, the dose-normalization curves apomorphine-emesis of dogs. It had sedative and of risperidone and haloperidol were virtually parallel. cataleptegenic effect, as well as inhibited the It is concluded that risperidone and haloperidol are learning performance of rats. The pharmacolo- equipotent in controlling a low level of dopaminerglc gica& spectra and potency of this new depot phe- overactlvlty by partially occupying dopamine D2-receptors. nothiazine compound were similar to that of flu- Higher levels of functional dopamine antagonism up to phenazine decaneate. saturation of the D2-receptors, however, require much Its long-acting pharmacological effects were higher doses of risperidone than of haloperldol. There- supported by the pharmacokinetic studies, too. fore, the risk of dopaminerglc overblockade (and EPS in- Institute for Drug Research, Budapest, 1045. duction) is considered to be much smaller with risperldone Szabads~gharcosok u. 47-49., Hungary. than with haloperidol. Department of Pharmacolo&y, Janssen Research Foundation, B-2340 Beerse, Belgium 33.01.18 33.01.19 THE PHARMACOLOGICAL PROFILE OF THE NEW ANTIPSYCHOTIC PHARMACOKINETIC PROFILE AND NEUROENDOCRINE RISPERIDONE EFFECTS OF THE NEW ANTIPSYCHOTIC RISPERIDONE. C.J.E. NiemeKeers, K.H.L. Schellekens, F. Awouters and ~ANDEN BUSSCHE G.. HEY~_ANTS J. AND DE COSTER R. P.A.J. Janssen Risperidone (R 64 766) is a new benzisoxazol-derivative The in rive pharmacological profile of rlsperidone, a with potent central serotonin-S2 and dopamine-D2 receptor henzisoxazole derivative, was compared with that of blocking properties. The pharmacokinetic profile of rltanserln, a selective centrally actlnE serotonln S 2 risperidone was investigated both in volunteers and in antagonist, and with that of haloperidol, a classical psychotic patients. In single-dose kinetic studies in dopamine D 2 antagonist. volunteers with oral doses ranging from 0.5 to 4 mg, it Rlsperidone was found, like rltanserin, to be very active was demonstrated that oral absorption of risperidone was very rapid, with peak plasma concentrations (measured by in tests related to serotonln antagonism, and, llke a direct radioirmuunoassay) attained approximately 1 h haloperldol, in tests related to dopamlne antagonism. after dosing. The extent of absorption was as complete Peripheral serotonin antagonism was obtained at after intake of a ~ablet formulation as after a solution, 0.0011 mE/k E sc and central serotonin antagonism at and was not affected by a meal. Values of Cma x and AUC 0_ 0.01~ ms/ks sc, in tests in which tryptamine was used to 8h increased proportionally with the dose. Terminal half- induce serotonerElc overstimulation. Peripheral dopamlne lives, dependent of the dose, were between 20 and 30 h, antaKonism was obtained at 0.0016 mE/ks sc and central with a mean terminal half-life of 24 h. After chronic dopamlne antagonism at 0.056 mg/k E sc, in tests in which oral administration of i mg for 20 days in volunteers, amphetamine was used to induce overstlmulation. steady-state plasma concentrations were reached after 7 In contras~ to ritanserln and to haloperidol, risperldone, days, and the terminal half-life after the last 1 mg dose was a potent and complete LED antagonist (0.028 mE/ks, was 30 h. These linear pharmacokinetics were also sc). Furthermore manifestations Of dopaminergic over- confi-~ned in 15 chronic psychotic patients, who received blockade, such as catalepsy, inhibition of food-intake, increasing doses of risperidone during 4 weeks. The initial dose of 5 mg b.i.d, during the first week was and abolition of motor activity occurred with rlsperidone increase~ with increments of 5 mg each week, until a at significantly higher doses than with haloperldol. daily dose of 25 mg was reached during the fourth week of The mixed serotonin S 2 and dopamine D 2 antagonism of treatment. Plasma concentrations were measured on each risperld6ne is considered to be the pharmacological basis day o~ dose increase, just before intake of the morning of a new type of antipsychoties with major advantaEes over medication and 1 h thereafter. Mean peak- and trough classical neuroleptics, additional control of negative plasma levels of risperidone increased proportionally symptoms and EPS-free therapeutic doses. with increasing doses. In the same study and at the same Janssen Research Foundation, B-23~0 Beerse, BelEium time points, the following neuroendocrine parameters were measured: plasma T3, TSH, GH, LH, FSH, cortisol and prolactin. Plasma prolactin levels increased 7-fold after the first drug achninistration and remained at this level till the end of the experiment. The other parameters were not affected by the treatment with risperidone. Janssen Research Fou/~dation, B-2340 Beerse, Belgiu/n. 334 33.01.20 33.01.21 RISPERIDONE IN THE TREATMENT OF BEHAVIORAL THE IN VITRO AND IN VIVO BIOCHEMICAL PROFILE OF SYMPTOMS IN P SYCHOGERIATRIC PATIENTS : A RISPERIDONE, A NEW ANTIPSYCHOTIC ]~ILOT CLINICAL INVESTIGATION. J.E. Leysen, W. Go~eren, A. Eens, D. de Cbaffoy de -~synt~ens A.. Hevlen S.. Gelc]ers y.. and Vanden Bussche G. Courcelles, P.F.M. Janssen and P.A.J. Janssen In in vitro receptor binding and receptor mediated ~isperidone (R 64 766) is a new benzisoxazol-derivative functional studies risperidone was compared to the ~ith potent serotonin-S2 and dopamine-D2 receptor serotonin-S 2 antagonist ritanserin and to the dopamine-D 2 blocking properties. Previous single-blind trials in 120 antagonist haloperidol. The receptor binding profile chronic psychotic patients have demonstrated that revealed for rlsperidone high affinity binding (Ki-value , risperidone is a potent antipsychotic, which also nM) to serotonin-S 2- (0.16), dopamine-D 2- (3.13), a- I remarkably improves the negative symptoms of adrenergic (0.8), histamlne-H I- (2.23) and a 2 -adrenergic schizophrenia, without inducing acute extrapyramidal symptoms (EPS) . The present study was conceived to receptors (7.5~). The S 2 affinity was two-fold higher evaluate the effect of risperidone in a psychogeriatric than that of ritanserin and the D 2 affinity two-fold lower population with behavioral disturbances. Fourty patients, than that of haloperidol. Risperldone showed higher af- ~eeting the DSM-III criteria for "Dementias Arising in finity than the latter drugs for the adrenergic and hist- --he Senium and Preseniura" or for psychotic disorders in amine receptors. The signal transducing system coupled ~he elderly were selected. Selection criterion was the to S 2 receptors, measured as serotonin induced 32p-phos- presence of behavioral disturbances (agitation, phatidic formation in human platelets, was potently and agressiven~-ss, hostility, irritability, wandering, day specifically bloomed by risperidone and ritanserin (ICto and night disturbance, delusions, hallucinations), poorly values 0.5" and 1.6 ruM, respectively). Functional re- responding to conventional neuroleptic therapy. Patients sponses mediated by post- and presynaptlc D 2 receptors with major somatic diseases were excluded. The trial lasted for 5 weeks: a 1 week single-blind placebo wash- respectively, i.e. inhibition by dopamine agonists of out period, followed by four weeks of active treatment evoMed release of labelled acetylcholine and dopamine from -with risperidone. The starting dose of 0,5 mg b.i.d, was rat striatal slices, were both antagonized at nanomolar adapted whenever necessary, according to the achieved concentrations of risperidone and haloperidol. In in wive -_herap,eus effect or the appearance of side-effects. receptor labelling studies in rats, the occupation of D 2 Patients were evaluated on a weekly base, using a 15-item and/or. S 2 receptors in brain areas was investigated for behavioral evaluation scale, a Visual Analogue Line for rlsperldone, ritanserin, haloperidol, setoperone, plmo- the main target symptom, the Clinical Global Impression, ride, sulpiride and clozapine. Risperidone occupied and the Chouinard-scale for evaluation of EPS; side- frontal cortical S 2 receptors with an ID50 = 0.03 mg/kg, effects were assessed and vital signs checked. A pre i.e. 8 times more potent than ritanserln and strlatal D 2 versus post safety evaluation was performed, including ECG. At the end of the study a comparison was made with receptors with an ID50 = 0.63 mg/kg i.e. g times weaker the most successful previous neuroleptic therapy. The than haloperidol. The in vitro and in wive biochemical results of this pilot investigation suggest that properties of risperidone are in agreement with the in risperidone represents a new effective and well tolerated wive pharmacological profile. The potent S 2 and D 2 tool in the pharmacotherapy of behavioral symptoms in antagonism of risperidone may underlie its beneficial psychogeriat tic patients. clinical effects on both negative and positive symptoms ja~Issen Research Foundation, B-2340 Beerse, Belgium. of schizophrenia. Department of Biochemical Pharmacology, Janssen Research Foundation, B-2340 Beerse, Belgium 33.01.22 33.01.23 BEHAVIORAL PHA~,~ACOLOGICAL EVIDENCE OF 0PC-h392: A DOUBLE-BLIND, CROSS-OVER, COMPARISON OF CONTROLLED A DOPAMINE AUTORECEPTOR AGO~?IST AND POSTSYDA_~UIC ZDPkMINE RELEASE AND IMMEDIATE RELEASE FORMULATIONS OF REMOXIPRIDE RECEPTOR ANTAGONIST D. Tench, S. Semi and T. Ashwood T. Kikuchi~ S. Suzuki~ T. Hirose~ Y. Uwahodo and Thirty years of clinical experience have proved beyond K. Tottori doubt the efficacy of neuroleptics in controlling the The behavioral pharmacological effects of 0Pc-L3~2 (7-{3- symptoms of acute schizophrenia and in maintaining the [4-(2,3-dimethylphenyl)piperazinyl]propoxy}-2(iE!- patients symptom free. One of the major problems with quinolinone) on the central dopaminergic system were neuroleptic treatment is the high rate of non-compliance studied in mice and rats. amongst the schizophrenics for maintenence therapy. The Dopamine (DA) autoreceDtor ar activit?:= introduction of depot neuroleptics obviated this 0PC-4392 inhibited spontaneous locomotor activity e_nd difficulty but carried with it other problems associated climbing behavior in mice. The effects of 0Pc-L292 were with prolonged action and complications at the site of antagonized by low doses of DA antagonist which selectiVe- injection. One way of overcoming non-compliance without ly blocks DA autoreceptors. 0PC-4392 inhibited moth- relinquishing the advantages of oral medication such as amphetamine-induced locomotor activity in mice. ~ne effect ease of clinical control, is to use controlled release of 0PC-4392 was antagonized by low doses of DA ~n~agonist. (CR) formulations which need to be administered only No DostsvnaDtic DA receptor ar activit)'_. once daily. Remoxipride is a substituted benzamide which 0PC-4392 did not increase spontaneous motor acr in in clinical trials of the oraI immediate release (IR) reserpinized mice. 0PC-4392 did not enhance spontaneous formulatiop appears to be effective in the treatment of ipsilateraf rotation in rats with unilateral striatal acute schizophrenia. 3t follows, therefore, that to kainic acid lesions (KA-lesioned rats) and did nc~ induce improve compliance, a CR formulation would he of immense contralateral rotation in rats with unilateral seriatal benefit in the long-term treatment of schizophrenics. 6-hydroxydopamine lesions (6-0HDA-lesioned rats). This parer describes a study comparing the pharmaco- Postsyna~tic DA receDtor antagonistic activity. kinetics of a CR formulation of remoxipride with a con- 0PC-h392 inhibited apomorphine-induced locomotor acr vention~l (IR) formulation. The study was a double in reserpinized mice and apomorphine-induced szerect~rpy in blind, cross-over comparison of the two formulations in mice.,0Pc-4392 inhibited apomorphine-induced rc~azion in stabl~, chronic schizophrenic inpatients resident at KA-le~ioned rats and 6-OKDA-!esioned rats. Prestwich Hospital. The results suggest that OPT-h392 acts as an agcnist on DA A preliminary analysis of the data showed that the autoreceptors, does not act as an agonist on pcs~si,-~_.eptic fluctuations in the plasma concentration of remoxipride normosensitive and supersensitive DA receptors, an~ acts were less for the CR formulation than the IR formulation. as an antagonist on these DA receptors. Remoxipride CR appeared to fulfill the kinetic rationale Third Tokushima ~nst. of Hew Drug Res., Otsuka ~na.~--_aceu- for a CR formulation end from a kinetic point of view tical Co., Ltd., h63-i0 Kagasuno Kawauchi-cho Uc~ashima the drug can be g~ven once daily. However, clinical 771-01, Japan studies have to determine if there is a benefit regard- ing severity and frequency of adverse events during treatment with the CR formulation. Prestwich Hospital, N~nchester, U.K. 335 33.01.24 33.01.25 EX VIVO RECEPTOR OCCUPATION BY RITANSERIN AND RISPERIDONK LIGAND-BINDING PROFILE OF EMD 49980. A SELECTIVELY PRESYN- MEASURED USING AUTORADIDGRAPHY APTIC DOPAMINE (D2)-AGONIST WITH POTENT ACTIONS ON 5HT- A.G. Schotte and J.g. Leysen SYSTEMS Ex vivo receptor binding experiments were performed in C.A. Seyfried, H.E. Greiner, A.F. Haase and H. BSttcher rats with ritanserln and risperidone. Doses ranking from In in vivo neurochemical models, EMD 49980 (5-hydroxy-3- 0.0025 to 160 mg/kg body weight were injected subcu- (4-(4-phenyl-1,2,3,6-tetrahydrepyridyl(1)-butyl)-indole, taneously two hours prior to sacrifice. mesylate) proved to be a highly potent and selectively pre- The occupation of serotonin Sz-receptors in the frontal synaptic D2-agonist with a profile very similar to that of cortex, of el-adrenergic receptors in tbalamic nuclei and EMD 38362 (Seyfried et el., in Dopaminergic Systems and of dopamine D2-receptors in the striatum was investigated their Regulation, ed. Woodruff, MacMillan, London, 1986), for both compounds using ex vivo autorediographical tech- the hydrochloride of the identical base. Due to its higher niques. We used in adjacent horizontal 20 ~m thick solubility, we used EMD 49980 to study in vitro interac- brain sections: 0.2 nM [125I]7-amino-8-1odo-ketanserln tions with various ligands in rat brain membrane prepara- (with addition of selective displacers in the incubation tions. EMD 49980 was active in the nM range with respec~ medium) to label S 2- and el-receptors , and 0.2 nM [125I]- to D2-receptors (spiperone- and ADTN-binding:IC50=5x10- M), sulpride for measuring D2-receptors. slightly less ~ctive on<-, 5HT2- andS--receptors and inac- Ritanserln showed 50 % occupation of S2-receptors at tive (IC50>I0" M) on muscarinic and opiate receptors. Most 0.02 mg/kg and a total blockade of these sites at orominent actions were observed at hippocampal 5HT-IA sites 0.16 mg/kg, while ~i- and D2-receptors remained unoccupied (8-OH-DPAT-binding: IC50~"I0- M); in additi?~, 5HT-uptake until i0 mg/kg. 40 mg/kg ritanserin gave a 30 % occupa- was potently inhibited in vitro (IC50=2xi0- M) and in vivo tion of D2-receptors and g5 % occupation of el-receptor (ED50=0.17 mg/kg sc, inhibition of p-chloroamphetamine-in- binding. duced 5HT depletion). Other 5HT-uptake inhibitors,e.g, zim- Risperidone showed a higher potency for occupying all elidine, were inactive in 5HT-IA-binding studies, thus the three receptors. Dosages producing 50 % occupation were hypothalamic 5HT-transporter and the hippocampal 5HT-IA-re- O.00Z5 mg/kg for $2- , 0.16 mg/kg for ~i- and 2.5 mg/kg ceptor seem to have different characteristics. The possi- for D2-receptors. 100 % occupation of the receptors was bility that the dopaminergic actions of EMD 49980 (ED50= reached at 0.63, ~0 and 160 mg/kg, respectively. The 0.08 mg/kg so, inhibition of striatal L-dopa accumulation) findings using ex vivo autoradiography were in agreement are brought about by indirect effects via 5BT-systems can with in vivo binding data on S 2- and D2-receptors. For be ruled out since both, zimelidine and 8-OH-DPAT were in- the first time, demonstration of ~l-receptor occupation active in the L-dopa model (ED50>I0 mg/kg sc). Furthermore, measured ex vivo was achieved. For the latter receptor an a number of structural analogs of EMD 49980 with potent do- in vivo binding model is not available. Ex vivo autora- paminergic actions are devoid of 5HT-IA-binding and 5HT- diography, in contrast to brain homogenate techniques, uptake inhibiting effects, supporting the conclusion that allows an investigation of receptor occupation by rapidly in EMD 49980, dopaminergic and actions on 5HT-systems are dissociating drugs. independent properties. It is speculated that in addition Janssen Research Foundation, Department of Biochemical to its presumed antipsychotic actions due to presynaptir Pharmacology, B-2340 Beerse, Belgium inhibition of dopaminergic impulse flow, the effects of EMD 49980 on 5HT-systems might lead to beneficial antide- pressive and/or anxiolytic properties in the clinic. Biolog.Res.,Dept.Neurochem., E. Merck, 6100 Darmstadt, FRG. 33.01.26 33.01.27 TIOSPIRONE: POTENTIAL MECHANISMS OF ATYPICAL AMPEROZIDE - A POTENTIAL NEUROLEPTIC DRUG WITH ANTIPSYCHOTIC ACTION SPECIFIC EFFECTS ON LIMBIC FUNCTIONS D.P. Taylor~ D.K. Hyslop~ and J. Dekleva G. Andersson, E. Christensson, B. Gustafsson, Clozapine has become a benchmark in the search for new G. Pettersson and J. Svartengren antipsychotics because it has been shown to be effica- Amperozide is a novel psychotropic drug with atypical cious without the short- or long-term motor liabilities neuroleptic properties. It is characterized by a limbie associated with the "neuroleptics." One hypothesis ad- mode of action in several experimental models. Thus, vanced for clozapine's "atypical" profile has been its amperozide significantly attenuated amphetamine induced weak D-2 dopamine receptor blockade which occur~ in the hypermotility in mice. Furthermore, amperozide treatment presence of potent muscarinic blockade. Tiospirone (BMY caused an increased DA turnover selectively restricted 13859) is a new antipsychotic candidate which has demon- to the limbic forebrain of the rat. strated clinical efficacy with an atypical side effect Similar to antidepressant drugs amperozide is a very profile, i.e., devoid of extrapyramidal symptoms (EPS; potent (0.]5 mg/kg) inhibitor of spontaneous mouse- Jain et al., Intl. Clin. Psychephai-macol. 2:129, 1987). killing behaviour and the coni0ound significantly reduced Tiospirone was identified as an antipsychotlc candidate the ~bility time in the behavioural despair test. based on its affinity for D-2 sites and in vivo activity Amperozide exhibits a high affinity for 5-HT2 receptors in tests predictive of efficacy (Yevich e_!ta_!., J. Med. frcm rat cortex and these receptors are downregulated Chem. 29:359, 1986). However, its failure to induce during long-term treatment. In accordance with its effect catalepsy in animal testing,the preclinical predictor of on serotoninergic nerv transmission amperozide is a EPS, was not attributable to antimnscarinic effects in potent stimulator of the pituitary-adrenocortical axis. vitro or in vivo. We have investigated the interactions There is, however, no stimulation of prolactin release. of tios~irone and clozapine in in vitro receptor binding A~rozide also posses~-~ed potent anticonflict (=~xiolytic) at other sites which have been implicated in the action properties and of great interest is its remarkable thera- of atypfcal antipsychotics. These include D-I, sigma, peutic effect on the %~ting pig syndrome. This chronic PCP, 5-HTI, =I, and calcium antagonist binding sites. stress bondition is most probably caused by maladaptation The m~st notable affinity of both compounds is for the to environmental stressors. 5-HT 2 site. This was of interest sincebehaviorally re- The pronounced limbic mode of action on emotional par- levant doses of tiospirone did not inhibit ex vivo bind- ameters, its total selective effect on limbic DAturnover, ing of [3H] spiperone to D-2 sites in the rat striatum. the absence of extrapyramidal side effects in primates When this radioligand was used for in vivo binding and lack of stimulation of prolactin release makes studies specific radiolabeling at D-2 sites in striatum amperozide an interesting novel candidate for clinical was reduced 30% and completely eliminated at 5-HT 2 sites studies in schizophrenic patients with both positive and in frontal cortex. Similar observations have been made negative symptoms. with clozapine. These observations suggest an important role for serotonin in the pharmacologic profiles of tio- spirone and clozapine. CNS Biology, Bristol-Myers Co., PO Box 5100, Wallingford, CT 06492-7660, U.S.A. AB Ferrosan, Department of CNS-Research, P.O.Box 839, S-201 80 Malm~, Sweden 336 33.01.28 33.01.29 NEUROCHEMICAL C?_~CTERIZATION OF SOME NEW HALOGEN SUBST~ KC 9172 - A NOVEL AGENT HAVING ANTEPSYCHOTIC AND TUTED LYSERGOLS WITH ANTIPSYCHOTIC ACTIVITY ANXIOLYTIC POTENTIAL I. Laszlovszky, F. Auth, B. Kiss, E. Lapis B. Costall i , A.M. Domeney i , M.E. Kelly I , D.M. Tomkins* and H. Kr~hling 2 The pronounced dopamine (DA) agonistic activity of ergo- KC 9172, a new psychotropic agent, has been claimed re- lines as well as some of their 2-halogen derivatives such cently to possess antipsychotic and anxiolytic activity as bromocriptine and lergotrile are well known. Wachtel (Ruhland et al., and Kr~hling et al., Pharmacopsych., in et al. (Life Sci.33:2583 /1983/) provided the first ex- press). We have investigated these potential activities ample that bromination of ergoline skeleton at position in detailed tests using both rodent and primate species. 2 resulted in a DA-antagonist (e.g. 2-Br-lisuride). Antipsychotic potential of KC 9172 w-as established using A se~esof monc- (at position 2) and di-halogenated (at a model in which dopamine is infused persistently into position 2 and 8) lysergols were synthetized and screened the rat n. ac~ns to induce a phasic hyperactivity. using nenrochemical and psycbopharmacological methods. This behaviour is sensitive to inhibition by known anti- Our attempts undertaken to develop new ergolines provided schizophrenic agents. KC 9172 inhibited, without seda- further evidence for that not only bromination but also tion, the dopamine-induced hyperactivity at doses of chlorination (at position 2) could change the DA recep- i00 ng/ kg to 10 ~g/kg i.p.b.d. torial profile of lysergols. Surprisingly, the 8-halo- Anxiolytic potential was assessed in a mouse aversion genation of 2-halo-lysergols turned their DA antagonistic test, a rat social interaction test and a marmoset b,~n profile back co DA agonist direction. threat test. In the first of these tests naive mice are Three compounds, the DA antagonist 2-chloro-lysergol, taken from a dark home environment and placed in the cen- RGH-6141 and 2,8-dichloro-lysergol derivatives as DA tre of a white, brightly lit area of a test box having a agonists, RGH-L455 and RGH-1430 have been selected for black, darkened area simultaneously available. Vehicle further deveiopment and the neurochemical action of these treated mice spend must of their time in the black envi- drugs are briefly described here. They devoid of activity ronmentf KC 9172 (0.0001 - i00 mg/kg p.o), like known on D-I reneptors (on basal and DA-stimulated adenylate anxiolys agents, increases the time spent in the white cyclase activity) while all the three compounds displaced environment. This anxiolytic potential was confirmed in a with different activity 3H-gplroperidol in D-2 binding rat ~est in which naive animals from separate cages are experiments with IC-50 value in a range of 100-1000 nM. placed in an arena for measurement of time spent in so- The in vitro binding studies indicated their ~-adrenergic cial contact (e.g. grooming partner) which is increased and serotoninergic activity as well. RGH-614~, like by known anxiolytic agents, and in a human threat test haloperidol, markedly increased the biosynthesis and me- where the retreat of a marmoset from the threat, associa- tabolism rate of DA (but not that of serotonin) in pre- ted with characteristic posturings, is inhibited by known dominantly DA-ergic structures (striatum, limbie brain) anxiolytic agents. while RGH-4455 and RGH-1430, like bromocriptine had the Thus in our tests KC 9172 presents as an atypical anti- opposite action on both parameters. Interestingly, not psychotic having novel anxiolytic potential. only RGH-6141 (antagonist) but also RGH-4455 and RGH-1430 (agonists) showed antipsychotic activity in behavioural 1 School of Pharmacology, Bradford University, BD7 IDP,UK experiments. 2 Kali-Chemie AG, Pharmaceutical Division, P.O. Box 220, D - 3000 Hannover 1 Pharmacol. Research Center, Chemical Works of G.Richter Ltd., H-1475 Budapest 10, P.O.Box 27. Hungary 33.01.30 33.01.31 ANTAGONISM OF AP-5-1NDUCED STEKEOTYPIES LINKS KC 9172 CLINICAL EFFICACY AND NEUROENDOCRINE EFFECTS OF TO ATYPICAL ANTIPSYCHOTICS ZOTEPINE ~.J. Schmidt i , D. Bur~, S. Harrer i and H. Kr~hhling ~ A. WeiSbach, U. v. Bardeleben, O. Benkert and In animal models KC 9172 exhibits behavioural effects F. Holsboer predictive for antipsychotic and anxiolytic activity. Zotepine is a 2-chloro-ll-(2-dimethylamincmthoxy)di- However, unlike classical antipsychotics (e.g. haloperi- benzo (b,f)-thiepine with a seven-membered central ring dol), KC 9172 does not induce catalepsy and does not an- in contrast to conventional phenothiazines. To eluci- tagonize amphetamine-induced stereotypies (Ruhland et al. date clinical efficacy and neuroendocrine profile the and Kr~hling et al., Pharmacopsych., in press). Recently following studies were performed at the Department of we found that not only a stimulation of dopamine activity Psychiatry, University of Mainz, induces stereotypies but also a blockade of g!utamatergic I) In an open trial 23 inpatients with schizophrenia, transmission in the striatum using the NMDA receptor an- paranoid type (RDC). were treated with a mean dosage tagonist AP-5 (100 nM/0.5 ~i). AP-5 induced sniffing is of 200-300 mg/day for at least 21 days with the most antagonized not only by classical neuroleptics but also significant improvement during week I. According to the by atypical ones (e.g. clozapine). Possibly, AP-5-induced a priori defined criterion for response (BPRS total sniffing may prove to be an animal model corresponding score < 28) there were 17 responders and 6 nenrespon- more closely to antipsychotic efficacy in man than e.g. ders at day 21. There was a low incidence of dyskinesia amphetamine-induced stereotypy (Schmidt, Psychopharmacol. and parkinsonism. 90, 123, 1986). 2)In a double-blind controlled study enrolling 40 in- SNIFFING: KC 9172 (20, 10, 5 ~M/kg) did not change spon- patients ~ith schizophrenia (RDC) the antipsychotic taneous sniffing of rats, but the AP-5-induced enhance- effis of zotepine was similar to perazin, rio major ment of sniffingwas effectively antagonized at 20 and imbalance concerning frequency of side-effects was i0 ~M/kg~ These effects resemble the effects of clozapine noted. (30.7, 15.3, 6.1 ~M/kg). Haloperidol (0.26 ~M/kg) acts 3) In An open trial in 14 inpatients with endogenous differently in reducing spontaneous and AP-5-induced depression, psychotic subtype (RDC), 9 patients were sniffing. classified as responders supporting that zote~ine may GRCOMING. (additional parameter recorded in parallel): KC be ap alternative to combinations of neuro]ep~ics and 9172 neither changed spontaneous grooming nor did it re- antidepressants. store grooming suppressed by AP-5. Here the effects of KC 4) In 6 normal male controls 25 mg zotepine administer- 9172 differ from both, clozapine and haloperidol since ed orally in the morning induced a significant increase clozapine reduces spontaneous grooming and further sup- of plasma prolactin levels corresponding to the anti- pressed grooming reduced by AP-5. Haloperidol restores dopaminerglc action. Cortisol, LH, FSH, testosterone AP-5 inhibited grooming. remained unaffected. Plasma growth hormone increased 6 -CONCLUSION-: Sniffing induced by a blockade of gluta- hours after administration, possibly due to behavioral matergic transmission at the h~MDA receptor within the sedation. striatum is antagonized by KC 9172. The detailed beha- Department of Psychiatry, University of Freibu~g, vioural profile of KC 9172 links this substance to aty- Hauptstrasse 5, D 7800 Freiburg, West-Germany pical neuroleptics. 1 Biolog. Institut d. Universit~t, D - 7000 Stuttgart 80 2 Kali-Chemie AG, P.O. Box 220, D - 3000 Hannover 1 337 33.01.32 33.01.33 BECLAMIDE AS ADJUVANT IN THE NEUROLEPTIC TREATMENT CARBA~ZEPINE AS ADJUNCT OF ANTIPSYCHOTIC TREATMENT C. Roptis M. Dose, D. Garcio, D.E. Bremer, M.M. Weber, M. Dose, S. Apelt, D.E. Bremer, and H.M. Emrich and H.M. Emrich Anticanvulsonts have been used as adjuncts of neurolep- A recent study shovved the adjuvant effect of the anticon- tic treatment in patients with kEG-abnormalities or ag- vulsont carbamczeaine in the neuroleptic treatment of gressive behavior and putative temporal lobe epilepsy. acute schizophrenic psychoses (Dose & Emrich, 1987). However, controlled studies of a combined treatment with Since other cnticonvulsonts might hove similar applica- anticonvulsonts cnd neuroleptics in acute psychotic pa- tions the combira~ion haloperidol-beclamide was tested in tients without kEG-abnormalities or aggressive outbursts the treatment of acute paranoid psychoses. Beclamide has have not been carried out so for. Therefore, a placebo- been long used in the treatment of grand mal epilepsia as controlled, double-blind study was designed to study the well es in ]uverile behaviour disorders. efficacy of corbomazepine (CBZ) as an adjunct of halope- The combination of low dose haloperidol (HPD)/beclamide tidal (HPD) treatment in non-epileptic, acute schizophre- (BCM) vs. low dcse HPD/piacebo was tested using a double- nic patients without EEG-abnormalities. blind design in 24 patients with an acute schizophrenic 34 patients were randomly assigned to the CBZ- or place- or schizoaffective (non-manic) psychosis who had given bo-group. In both groups, patients initially received HPD their informed consent. In both groups patients initially (6 mg/d) which could be increased by 3 mg/d every 5 days received HPD 6 mg/d and either BCM (2 g/d initially, according to clinical judgement by the treating psychia- increased by ] g/d to 3 g/d) or placebo. Every seven days trist who was not aware of the additional medication with the treating psychiatrist was allowed to increase HPD by either CBZ (200 mg/d initially, increased by 100 mg/d to 3 mg/d if ~linicstly necessary. Chlarprothixene and bipe- serum lev61s of 8-10 pg/ml) or placebo. Biperiden end ride~ were at ncqd as additional sedative and anticholi- chlorprothixene served as additional medication. heroic medication. After 28 days 3CtA or placebo were Within 28 days o statistically significant improvement discontinued under constant HPD-doses and a final of occurred in the CBZ- and in the placebo-group. Discontin- weekly r~tings by IMPS, BPRS and EPS was carried out. uation 6f CBZ/placebo between day 28 and 35 under con- Results: Within 28 days the BCM- and the placebo-group stant HPD led to continuous improvement of the placebo- improved. The 5~.'-group, however, needed only 77% of the group while the CBZ-group deteriorated statistically HPD-dpsage comosred to the placebo-group, 46% of the significant. The CBZ-group, however, needed only 75 % of chlo~prothixene- and 66% of the biperiden-dasage. Extra- the HPD-dosage compared to the placebo-group, 44 % of the pyramidal as v,e!i as BCM-typical side-effects in the BCM- chlorprothixene- and 31% of the biperiden-dosoge. Ac- group were only 72,5%, in comparison to the placebo- cording to side-effects, extrapyramidal as well as CBZ- group. From =hose findings an adjuvant effect of the typical side-effects in the CBZ-group were only 38 % as anticonvu!sant ceclomide in antipsychotic treatment with compared to the placebo-group. HPD serum levels in the neuroleptics is suggested, which is, however, less pro- CBZ-graup were found to be 50 % of the placebo group with nounced to the adjuvant effect of acrbamczepine. equal HPD dosages. Max-Planck-lnszicut for Psychiatrie, Kreepelinstr. 10, From these findings an adjuvant effect of onticonvulsonts D-dOO0 MOnchen 40. in antipsychctic treatment with neuroleptics is con- cluded. Max-Planck-lnstitut for Psychiotrie, Kraepelinstr. 10, D-8000 MOnchen 40 33.01.34 33.01.35 SND 919 INHIBITS DOPAMINE RELEASE IN VIVO AND IN PHASE-I STUDIES WITH AMPEROZIDE, A NOVEL ANTIPSYCHIC VITRO. DRUG J. Mierau and W.D. Bechtel L. ~blander We studied the effects of SND 919 Y ((S)-2-amino-A~5, With the aim of developing compounds alleviating both 6,7-tetrahydro6-propylamino-benzthiazole-dihydrochle- positive and negative symptoms of schizophrenia, without ride) on the dapamine release by means of in viva and producing extrapyramidal symptoms, a series of diphenyl- in vitro trials. butyl-piperazine derivatives was synthesized. From this SND 919 Y exhibits a strong and dose-dependent attenu- program amperozide was selected. Amperozide represents a ation of the alpha-methyl-p-tyrosine induced reduction novel class of antipsychotic drugs by having a unique of dopamine content in rat brain estimated using HPLC type of combined activity on the dopaminergie system, with electrochemical detection. The ED 50 was found to selectively in limbic brain areas and on the seroton- be 0.04 mg/kg. This effect represents e marked inhibi- inergic system. tion of dapamine release in viva. According to N.E. Anloerozide has been given to normal adult subjects with Anden et al., Naunyn-Schmiedeberg's Arch. Pharmacol. the aim to study tolerance and acceptability and the 521~ i00 (1982) it can be attributed to s stimulation phar~acokinetics of amperozide after single oral and of presynaptic dopamine receptors. The inhibition of intravenous as well as after multiple oral administration. the dopamine release caused by 5ND 919 Y can be antago- Besides, the pharmacokinetics of one of the metabolites nized by h%Ioperidol but not by the selective 01 antago- of amperozide has been studied (after single and multiple nist SCH 23]90 suggesting a presynaptic agonistic oral administration of amperozide). The effects of activity of SHD 919 Y at D2 dopamine receptors. amperozide on the cardiovascular system during rest and From rat brain striatal slices in vitro SND 919 Y inhi- physical exercise have been studied. Long-term ECG bits do~e-dependently the electrically evoked ]H dora- recordings (Halter monitoring) have been performed during mine release. Thus, the results of the in vitro release ani0erozide steady state conditions. In none of the studies studies correspond well to those obtained in viva. there were clinically significant changes in vital signs, We conclude from the results presented that at least blood .~nd urine analysis. In all studies where ECG was the ~n viva effect of SND 919 Y is mediated via stimu- recorded there occured dose-dependent reversible pro- lation of presynaptic dopamine receptors resulting in a longation of the QT interval and T-wave amplitude changes. reduction of dopamJne release. This leads to a reduced No arrhythmias were recorded. Subjective complaints were availability of the neurotransmitter in the synoptic mainly related to the CNS system, ate-vestibular system cleft. Hence, the compound may be a useful tool in the and to a lesser degree the gastrointestinal system. treatment of schizophrenia. Boehringer Ingelheim KG, Department of Biochemistry, D-6507 Ingelheim, FR. Germany Depar~nt of Clinical Pharmacology Phar~acia LEO Therapeutics P.o. Box 839 MALMO Sweden 338 33.01.36 33.01.37 EFFECTS OF SAV0XEPINE ON IN VZVO [3-H]-SPIPERONE BINDING SAVOXEPINE, A NOVEL ANTIPSYCHOTIC AGENT.: INTERACTIONS TO PITUITARY DOFAMINE (DA) RECEPTORS AND ON PROLACTIN WITH NEUROTR~SMITTER RECEPTORS IN VIVO AND IN VITRO. (PRL) SECRETION S. Bischoff, H. Bittiger, J. Krauss, K. StCcklin, A. H~usler, S. Eischoff and L. Schenkel K. Hauser, M. Sills and H. Blattner. Savoxepine (CGP 19486A) is a novel DA antagonist with a Savoxepine (CGP 19486 A), a novel antipsychotic, has high preferential affinity for DA receptors in the hippocam- affinity for brain dopamine (DA) receptors. In vitro, it pus (IDb0 for inhibition of [3-H]-spiperone binding: was slightly more potent than haloperidol (HAL) on H- 0.04 mg/kg, ip) vs. striatum (IDb0:0.7 mg/kg, ip) in spiperone binding in rat striatum (IC5~ 0.5 and I nM male rats. Further it antagonizes apomorphine-lnduced resp.). In vivo, savoxepine inhibited H-spiperone bind- climbing in mice (IDb0:0.06 mg/kg, ip). In rat s, a dose ing in rat hippocampus at very low doses (ID50 0.04 mg/kg of 1 mg/kg (ip) inhibits pituitary [3-H]-spiperone i.p.), being 17 times more potent than in striatum (ID50 binding in vivo by more than 50% for at least 24 h. 0.7 mg/kg i.p.). In this test, HAL was also very active, Since blockade of pituitary DA receptors is known to but it was only 1.6 times more potent in hippocampus than stimulate PKL secretion, the effect of savoxepine on PRL in striatum (ID50 0.075 and 0.12 mg/kg i.p.). Kinetics of secretion was studied in rats in comparison with the DA receptor occupation by savoxepine were measured by in classical DA antagonist haloperidol. In vitro, the com- vivo H-spiperone binding at 0.I, 0.3, 1 and 3 mg/kg i.p. pounds were incubated with cultured pituitary cells for of drug. Again large differences were obtained between 4 h in the presence or absence of the DA agonist ergo- hippocampus ar.d striatum. At 3 mg/kg, binding was still cornine. In vivo, the DA antagonists were injected sc significantly ir~ibited in hippocampus 72 h after injec- and blood was collected either 2, 4 or 24 h after in- tion (-309), whereas in striatum the effect disappeared jection. PRL was measured by radioimmunoassay. In vitro, between 24 and 48 h. both savoxepine and haloperidol antagonized the inhibi- Savoxepine inhibited in vivo 3H-spiperone binding to 5- tory effect of ergocornine on PRL release in a dose- HT2 receptors in frontal cortex (ID50 0.3 mg/kg i.p.). In dependent manner. In vivo, doses of 0.3-1 mg/kg savoxe- vitro, it displayed the following affinities for ot~er pine and 0.i-i mg/kg haloperidol significantly elevated receptors (liqand, IC50 in nM). a ( H- plasma PRL at 2 h after injection. A dose of 1 mg/kg prazosi~,o 2) alpha-2-adrenergi ~ ( H-cIonidine, 280), savoxepine maintained this elevation for at least 24 h. 5rHTI (H-5-HT, 2607, 5-HT~A ( B-8-0H-DPAT, 92), 5-HTIB The ~same dose of haloperidol increased plasma PRL up to (• 1700), 5-HT2 (~H-~etanserin, I0), histamine 4 h, but not for as long as 24 h. HI (-H-doxepine, 34) andiH2 ( H-tiotid~ne, 710), and In conclusion, savoxepine is slightly less potent than cholinergic muscarinic (-H-QNB, 3500, E-Dioxolan, 2800). haloperidol in stimulating PKL secretion, but its dura- In conclusion, savoxepine is a potent and long acting DA tion of action is much longer. This corresponds well receptor blocking agent. Its strong preference for hippo- with its prolonged pituitary DA receptor occupation. campal vs striatal DA receptors is indicative of good However, these effects of savoxepine are exerted at antipsychotic potential in the clinic with low incidence doses which are higher than the IDb0s for blockade of of EPS as suggested by our new concept (Bischoff et al., hippoeampal DA receptors and antagonism of apomorphine- Prog.Neuro-Psychopharmacol. & Biol. Psychiat. (1988) 12, induced climbing, tests which are thought to be good in press). Res. Dept. Pharmaceuticals Div. CIBA-GEIGY indicators of antipsychotic efficacy in man. Ltd., 4002 Basel, Switzerland and Drug Discovery Dept. Res. Dept., Pharm. Div., CIBA-GEIGY Ltd., CH-4002 BASEL CIBA-GEIGY Corporation, Summit, USA. 33.01.38 33.01.39 EFFE~'~fS OF SAVOXEPINE ON DOP~Mih~ (DA) METABOLISM AND ON PSYCHOPHARMACOLOGY OF SAVOXEPINE DA AND ACETYLCHOLINE (ACh) RELEASE IN RAT STRIATUM L. Maitre, A. Vassout, A. Delini-Stula, R. Ortmann, P.A. Baumann, S.F. Bischoff and P.C. Waldmeier E. Radeke, M. Schaub, H. Blattner and S. Bischoff Savoxepine (CGP 19486A) increased the levels of the DA The pharmacological properties of savoxepine (CGP 19486A) metabolites, homovanillic (HVA} and 3,4- dihydroxyphe- a novel tetracyclic antipsychotic agent, have been as- nylacetic acid (DOPAC) 2 h after oral administration with sessed in various tests predictive for neuroleptic-like EDb0 value of 0.05 and 0.12 mgPKg, resp.; 2.5 h after i.p. activities. Thus, it antagonized amphetamine- and apo- administration, the corresponding values were 0.085 and morphine-induced stereotypies in rats (ED50 0.07 and 0.22 mg/kg resp. After 1 mg/kg p.o., the effect was maxi- 0.17 mg/kg i.p.) and apomorphine-induced climbing beha- mal at 6 h; both DA metabolites were still increased after vior in mice (ED50 0.06 mg/kg i.p.). In dogs, savoxepine 24 h, but not after 48 h. This time course is comparable diminished apomorphine-induced emesis (ED50 0.06 mg/kg to that observed with an equivalent dose of haloperidol. s.c.). In all of these tests, savoxepine exhibited a po- In the dose-range in which DAmetabolism was increased, tency similar to that of haloperidol (HAL), indicating po- no evidence for an alteration of the concentrations of DA. tent antidopaminergic properties. In contrast, savoxepine serotonin, 5-hydroxyindoleacetic acid and tryptophan, or was much less cataleptogenic: only 20 % at I0 mg/kg i,p., of the accumulation of 5-hydroxye_~yptophan after central whereas HAL reached an ED50 at 0.6 mg/kg i.p. 2 h after decarboxylase inhibition (a measure of serotonin synthes- drug injection. The excellent resorption of savoxepine is) was observed. The effect of savoxepine on rat striatal from the gastrointestinal tract is indicated by the al- HVA and DOPAC was greatly potentiated by amfonelic acid, most similar ED50 in the antagonism of amphetamine-in- similarl~to what is seen with haloperidol, but not with duced stereotypies by savoxepine given i.p., s.c. or p.o. atypical neuroleptics such as clozapine or sulpiride. Savoxepine exhibited also un unusual long duration of ac- The effect~ of savoxe~ne on the electrically induced re- tion. Apomorphine climbing was still antagonized by more lease of (-H)DA and (- C)ACh were assessed in vitro in than 50% 24 h after 1 mg/kg i.p. savoxepine. At a dose of preloaded, superfused rat striatal slices in the presence 2 mg/kg s.c., it produced still 30 % antagonism of apomor- of the DA uptake inhibitor, nomifensine. The stimulated phine-induced stereotypies 72 h after injection. Finally, release of both transmitters ~s enhanced in a eoncentra- in dogs, the anti-emetic effect of a single injection of tion-d~pendent manner from i0 -M upwards, but the effect 0.i mg/kg s.c. savoxepine lasted for 7-10 days. ~4 . . on ( C)ACh was much more marked; slmllar results were Savo~epine also antagonized the L-5-HTP-behavioral syn- obtained w~ haloperidol. Clozapine, in contrast, did not drome (ED50 1.8 mg/kg i.p.) reflecting blockade of cen- increase J C)ACh relase to a much more marked extent than tral 5-HT2, and possiby 5-HTI receptor subtypes. that of ( H)DA. These results su-gest that savoxepine, In conclusion, savoxepine is a strong, and long acting like haloperidol, has more potent effects on post- than on antidopam/nergic agent with a clear-cut dissociation bet- presynaptic D2 dopamine receptors Thus, although its side ween the potency in antagonizing DA-agonist-induced beha- effect profile in schizophrenic patients (particularly ex~ viors and in inducing adverse cataleptic effects. These trapyramidal effects) differ markedly from those of halo- pharmacological properties are fully in line with the af- haloperidol, savoxepine proved to have similar effects on finities of savoxepine for DA and other neurotransmitter DA metabolism. Therefore, the reason(s) for this differ- receptors, and its effects on DA turnover. ence are unlikely to be related to differences in effect (Bischoff et al., and Baumann et al., this issue). on presynaptic dopaminergic mechanisms. Res. Dept. Pharm. Div. CIBA-GEIGY Ltd. CH 4002 Basel. Research Dep. Pharm. Div. CIBA-~IGY Ltd. CH-4002 Basel 339 33.01,40 33.01.41 FG5803: A NEW POTENTIAL ANTIPSYCHOTIC COMPOUND COMPARISON OF ZOTEPINE AND PERAZINE IN SCHIZOPHRENIA E. Christensson, A. Bj@rk, B. Gustafsson, G. Pettersson, J. Svartengren and G. Andersson Zotepine is a new benzothiepine which blocks DA, NE and The neuropharmacology of FG5803, a butyro- 5-HT receptors, resembles chlorpromazine more than halo- phenone-l-piperazinecarboxamide derivative, peridol or pimozide (Puech et al., 1987). The unique phar- has been investigated and compared to haloperi- macological action of zotepine is I. a biphasic effect, dol and clozapine using both behavioural and 2. effectiveness in both, acute and chronic schizophrenic biochemical test models. patients and 3. low incidence on extrapyramidal symptoms FG5803 reduced amphetamine-induced hypermotili- (EPS) compared with other neuroleptics (Yamawaki, 1987). ty and exploratory behaviour. It also showed The low incidence of EPS is postulated to the strong anti- antiaggressive properties and reduced 5-HTP- serotonergic property of zotepine (Lai et al., 1980). Se- induced head-twitches. FG5803 did not induce dation, influence on positive and negative symptoms as catalepsy and was weak in antagonizing well as low incidence on EPS could be confirmed in an open amphetamine-induced stereotypies. clinical study (Dieterle et al., 1987). Bioehemically, FG5803 was found to have high In a double-blind study, zotepine and perazine were com- affinity for 5-HT 2 receptors and weak affinity pared for clinical efficacy, dose-dependent influence or, for D 2 and el receptors. Furthermore, the com- negative symptoms, influence on EPS and tolerability. pound increased the dopamine synthesis rate Methods: Drug administration was orally for 28 days, with and the ~opamine metabolism in rat limbic an-~n{tTal dose (150 mg Zotepine or 225 mg perazine) and forebrain and striatum. FG5803 also increased further on in a flexible schedule according to the clini- the plasma level of eorticosterone in the rat, cal requirement. Psychopathometric assessment such as BPRS but did not stimulate a prolonged secretion AMDP, SANS, WEBSTER and SIMPSON were done on days 0,3,5,7, of prolactin. 14,21 and 28. In conclusion, FG5803 is a psychotropic drug, Results: 39 hospitalized schizophrenics (group I=zotepine: which like clozapine and melperone exhibits a 20-patients; group II=perazine:19 patients) diagnosed ac- spec~flc atypical neuroleptic profile. This cording ICD=No.9 and DSM Ill were included; in group I, 4 property of FG5803 together with its favour- droppe4 out in case of worsening, 3 further in case of able endocrinological effects makes it marked improvement and discharge. In group II 6 dropped warrantied for clinical studies in schizo- out in case of worsening and 2 patients quitted the hospi- phrenic patients. tal. Diagnosis, mean age and manifestation of illness were comparable for both groups. In group II significant more sedative medication was required; administration of bi- periden was similar in both groups. The results of the psychopathometric scales showed no differences between the groups, however an earlier improvement in the group I. Psychiatrische Klinik der Universit~t MUnchen, NuBbaum- AB Ferrosan, Department of CNS-Research, strasse 7, D-8000 MUnchen 2 P.O.Box 839, S-201 80 MALMO, Sweden 33.01.42 33.01.43 RILUZOLE IMPROVES NEGATIVE SYMRT~IS IN SCHIZOPHRENIA OPEN RISING DOSE STUDY OF SAVOXEPINE (CGP 19486 A) IN F. Maillard*, J.P. Macher**, B. Musch*, J.P. Olie ~'* and ACUTE SCHIZOPHRENIA: THE PROFILE OF THERAPEUTIC ACTION J.C. Scotto**** D. Milovanovic and A. Delini-Stula 1 Riluzole (2-amino-6trifluoromethoxybenzothiazole, Savoxepine is a drug of novel tetracyclic structure PK 26124 or 54 274 RP) was found to interfere in exerting potent and long-lasting antipsychotic-Like glutamatergic neurotransmission and to increase slow-wave properties in a variety of animal models (Maitre et al. and REM sleep in rats and cats (cf. poster Stutzmann et this Congress). The most prominent feature of the drug al.). is, however, its ability to selectively block the D2 rec- Fifty-two patients under neuroleptic treatment and eptors in the hippocampus. It was therefore of interest suffering from schizophrenia (DSM III criteria) with to explore the therapeutic profile of action of this drug predominantly negative symptoms participated in an open in patients suffering from an acute episode of schizo- pilot study. phrenia. Oral neuroleptics were withdrawn and the patients were Ten acutely psychotic patients (5 males, 5 females) aged submitted to a single drug protocol with riluzole (50 to between 21 and 33 years fulfilling the ICD.9 criteria of 150 m8 per day) during 4 weeks. schizophrenic disorder were included in the study. After Patients were assessed by means of the Brief Psychiatric 3 days wash-out period the treatment with 0.1mg/day Rating Scale (BPRS), the Scale for Assessment of Negative savoxepine commenced. The dose was gradually increased in Symptoms (SANS), the Hamilton Anxiety Rating Scale (HARS) the following weeks. The mean daily dose at the end of 4 and the Nurse's Observation Scale for In-patient Evalua- weeks treatment period was 0.94 mg/day. tion (NOSIE) on days D.O - D.8 - D.15 - D.22 - D.29. In all patients an antipsychotic effect was evident after A check-list for somatic complaints was used on the same 3-4 days. At the end of the treatment 6 patients were days. very much or much improved, 3 patients moderately or After two week treatment with riluzole a marked improve- slightl~ improved, 1 patient did not improve. The initial ment of ~he negative symptoms was found especially in median total BPRS score of 45 (36-61) decreased by the those with blunted affect, apathy, hostility and poverty end of the treatment period to 13 (5-34). The analysis of of speech. Extrapyramidal symptoms or other side effects the ~PRS factors indicated that the regression of thought were ~ot observed. Durin8 the whole study the laboratory distOrbances was the most prominent effect. An anti- findings remained in the normal range in all of the anergic effect with amelioration of vital functions was patients. It is tempting to relate these clinical data also noteworthy. Few side-effects were observed: to the sleep modulatory effect observed in animals. sedation (n=2), hypotension (n=2) and general weakness The improvement of negative symptoms in schizophrenia (n=2). Most remarkablyr however, very few EPS were with a drug which is not a dopamine antagonist may be observed: 4 patients showed slight to moderate tremor and considered as a totally new approach to the treatment 5 slight to moderate rigor. Only 3 patients received of psychotic disorders. antiparkinSon medication. The results of this study ind- * Rh~ne-Poulenc Sant6, 20, avenue Raymond Aron icate rather specific antipsychotic action of savoxepine 92165 Antony Cedex, France a_.nd possibly its low EPS potential. ~-~ Centre Hospitalier Sp@cialis~, 68250 Rouffach, France Psychiatric Clinic, Faculty of Medicine, 11000 BelgradeiYU H6pital Sainte-Anne, 1 rue Cabanis, 75674 Paris 1Clinical Research and Development, CIBA-GEIGY Ltd. Cedex 14, France Basel/OH. ~-~-~*H6pital Sainte-Mar~uerite~ 13277 ~arsei]le France 340 33.01.44 33.01.45 CLINICAL AND BIOLOGICAL EFFECTS OF SAVOXEPINE (CGP A SINGLE BLIND STUDY OF CLOCAPRAMINE AND 19486 A), A NEW TETRACYCLIC ANTIPSYCHOTIC DRUG. SULPIRIDE IN CHRONIC SCHIZOPHRENIA. N. Bohacek, M. Jakovljevic, V. Plavsic, M. Korsic, S. YAMAGAMI r N. KIRIIKE AND K. KAWAGUCHI T. Brataljenovic, A. Delini-Stula I) Therapeutic efficacy and target symptoms with Savoxepine is a new tetracyclic drug which selectively clocapramine dihydrochloride were compared with blocks D2 receptors in the hippocampus and shows potent those of sulpiride by the single blind method in a total of 52 chronic schizophrenic patients neuroleptic-like effects in animal experiments. Open by administration for 8 weeks. The final glob- clinical studies in acute schizophrenic patients indicated al improvement rating showed no significant antipsychotic activity of this drug. Apart from this, difference between the two drugs, but the pa- little is known about other possible biological effects tients administrered clocapramine appeared to of the drug. Clinical neuroendocrinological, polysomno- have a more pronounced effect than sulpiride. graphic and biochemical investigations could provide some According to the improvement ratings in types insight into the overall profile of action of the drug. of schizophrenia, clocapramine tended to be We were therefore interested to study the effects of superior to sulpiride in disorganized, cata- savoxepine on various hormones, sleep and plstelet 5-HT tonic and undifferentiated types. In psychotic in schizophrenic patients. Ten acute schizophrenic pat- symptoms, clocapramine was superior to sulpi- tients were included in the study.Plasma TS,T4,TSH,GH,PRE, ride in motor retardation, delusion, hallucina- LH,FSH,cortisol, testosterone, oestradiol, as well as the tion and disturbance of self-consciousness, response to dexamethasone (DST) and the response of PRL, contact (attitude towards other persons), and TSH,GH, FSH,LH and TRH-GnRH stimulation were determined work or recreation. While improvement ratio of sulpiride was higher than that with clocapra- before and after the 4 weeks therapy with savoxepine. In mine in motor excitment, talkative, anxiety and addition, platelet 5-HT was measured. An all night poly- elation. In addition, frequency of side- somnogram was recorded in 5 patients. Therapeutic efficacy effects was lower with sulpiride than with of the drug was assessed by BPRS and GCI. The Simpson- clocapramine. Drowsiness and constipation Angus Scale was used for assessment of EPS. The mean daily occurred more frequently with clocapramine than dose of savoxepine was 0.31-0.60 mg. with sulpiride. Neither side-effect nor abnor- After 4 weeks of treatment 9 patients were considerably mal laboratory test results were severe enough improved and I patient was a non-responder. Of 4 previous- to terminate the trials. Clocapramine is ly unresponsive patients to a variety of neuro!eptics, 3 thought to be equivalent to sulpiride in terms responded favourably to savoxepine. No neuroendocrine or of antipsychotic effect in chronic schizo- sleep abnormalities specific for schizophrenia were phrenia. identified. Some appeared to be state-dependent markers Department of Neuropsychiatry, Osaka City and indicators of therapeutic response to savoxepine (DST, University Medical School, Osaka 545, Japan TRH-GnRH). In all patients savoxepine showed beneficial effects on sleep disturbances, even though it was given once daily in the morning. ~partment ofvPsychiatry.School of medicine, University of Zagreb, KispaYi~evs 12, YU-4100 1)Clinical Research & Developm.,CIBA-GEIGY Ltd., CH-Basle 33.01.46 33.01.47 PROPHYLACTIC EFFECTS OF NEUROLEPTICS IN SYMPTOM-FREE SCHI~ EFFICACY AND TOLERABtLITY OF FLUPHENAZtNE DECANOATE OPHRENICS: A COMPARATIVE DOSE-RESPONSE STUDY OF TIMIPERONE IN ELDERLY SCHIZOPHRENICS AND SULPIRIDE T. Nishikawa r M. T~naka, A: Tsudat I. Koga and Y. Uchid~ MC.Mauri, T.Girardi. B Panetta. A.C.Altamura Remitted schizophrenic outpatients were treated in order Neuroleptic treatment in elderly schizophrenic patients to prevent relapse with three doses of timiperone or sulpi- dictates caution in ChOOSing a psychopharmacologic agent. ride for 1 year in a double-blind controlled study employ- The choice is often based on the side-effect profiles of the ing a randomized design. The drug's ability to prevent relapse was evaluated by counting the number of subjects various agents. with different outcomes (remission, relapse, Overdose) 20 elderly schizophrenic in- patients, age ranging from 60 during the trial and/or the number of symptom-free days to 73 years, diagnosed as Chronic Schizophrenia according for each patient before any sign of relapse or overdose to DSM III were treated with fluphenazine decanoate (FD), appeared. Patients were randomly assigned to the follow- ing drugs orally administered once per day at night: 125 mg i.m with repeated administrations (every 21 days) placebo; timiperone 1 mg, 3 mg, 6 mg; sulpiride i00 mg, for six months 300 mg, 600 mg. Se.~um prolactin levels in each patient Psychopathological features were assessed by means of were estimated by radioimmunoassay. The data from a pre- BPRS at time 0 and then weekly. vious study using haloperido! and propericiazine were uti- lized as a retrospective placebo group and to compare the At O, 6, 12., 24, 36, 48, 72 hours and 7, 14 and 21 days after characteristics of four drugs for the maintenance treat- each administration, extrapiramidal side-effects were ment of remitted schizophrenic outpatients. Timiperone 3 evaluated by means of the EPSE and 6 mg or sulpiride i00, 300, and 600 mg reduced signif- FD was f.ound to be effective in the survey population. icantly the number of patients who relapsed compared to the placebo group. Timiperone produced an increased num- The most severe extrabyramidal side-effects occurred ber of signs of overdose relative to sulpiride. Analysis within t~he first two days of administration of FD, with a of variance of the number of symptom-free days revealed peak,around 36 hrs, possibly related to plasma peak no significant drug treatment effect. Only sulpiride 600 concentrations. The severity of these effects was reduced mg sighificantly prolonged the number of symptom-free days compared to placebo. Prolactin levels were elevated by after the fourth injection indicating a tolerance mechanism both timiperone and sulpiride dose-dependently, however a during chronic administration. flattening of the prolactin response was found with institute of Clinical Psychiatry, University of Milan, sulpiride. By comparing the dose-response curve of four Policlinico, Via F.Sforza 35, 20122 Milan, Italy. drugs tested in the same fashion, haloperidol and sulpiride were superior to propericiazine and timiperone for maintenance treat~.ent of remitted schizophrenic out- patients, from the point of view of having a wider "thera- peutic window". Department of Pharmacology, Kurume University School of Medicine, Kurume 830, *Seiwakai Nishikawa Hospital, Hamada 697, Japan 341 33.01.48 33.01.49 LONG-TE~ ~k~trROLEDAPIC ~_ OF CHI~NIC SCHIZOPHRE- BRDP OFTHE RATE OF HOSPITALIZATIONS AND RELAPSES IN NIC PATIL'NTS: CLINICAL AND BIblICAL EFFECTS OF WITH- PSYCHOTIC OUTPAT]ENTS WITH HALOPERIDOL DECANOATE. DRAWAL M. Su~rez Richa~ds; N~ M. Zelaschi K.Kamijim~a, Y.Tsutstmli, S.Murata and T.Mitsuhashi About a 50% of psychotic patients fail to follow their Five patients developed withdrawal symptoms treatment which lead at the reappearance of psychotic when long-term neuroleptic treatment was sto- condition. The importance of depot neuroleptics on the pped for seven days in 13 chronic schizophre- prevention of relapses and in the reduction the lenght of nics. the hospitalization period is also a fact well Gastrointestinal symptoms such as nausea, vo- established. In addition the therapeutic efficiency of miting, and anorexia were the prominent with- haloperidol decanoate (HD) has been proved in several drawal symptoms. studies, although%still scanty know the social aspects Large amount of neuroleptics and antiparkinso- related with the insertion of the patient into the nian drugs were responsible for the occurren- community. ce of withdrawal symptoms.Plasma level of pro- We have compared the clinical evolution of one group the lactin decreased significantly after 7 days of psychotic outpatients with oral treatment (OT) with other withdrawal and a significant positive correla- one of the same sex and age which was treated wi,th HD, tion was found between basal prolactin level (OT:n=15;M:9,~ age 30.9 - 3.6 - F=6,x age 26.2_ 3,6. and ~ prolactin level among the patients who HD: n=15;M:7, E age 35,3Z 4.5 - F=8,f age 33.5Z 2.5. manifested withdrawal symptoms. On the contra- sex: x~ = 0.30 NS; age: Mand F together t: 1.5 NS). ry, 3-methoxy-4-hydroxyphenylglycol(MHPG) in Both of them were also similars in graveness of the plasma, homovanillic acid(Hl~A) and vanillyl- pathology at the start of the study (BPRS score at week O: mandelic acid(v~) in urine elevated after 7 OT = 58.9, SD 0.29; HD=54,9, SD 3.2; t: 1,6 NS); the days.of withdrawal. These data suggested that complete ,follow-up period was of 3 years. increased turnover of dopamine occurred after The OT group showed a higher number of admissions (n=19) withdrawal. than the HD treated patients (n=l). Mann-Whitney test:r= Changes of plasma ?~PG, prolactin and other 4.13 ; p< 0.0001. monoaminergic variables broke the equilibrium The hi~her rate of hospitalizations in the OT group woul of autonomic nervous system and resulted in be imputed a the larger frecuency of relapses (6 times withdrawal symptoms. higher with OT) Mann-Whitney test (adjusted frecuency): ~= In our clinical practice, we shoud avoid the 2.73 p< 0.01. abrupt cessation of neuroleptics and to mini- 100% of the patients with OT relapsed at least one time mize sy-m~ptoms, antipsychotic drugs should be during the study , showing a clearcut difference with the tapered gradually, and patients on an antipar- HD group where never appeard signs of relapse in the kinsonian medication should continue if for at 73.33% of the cases. least a week after the antipsychotic drug is Departament of Psychiatry, School of Medicine; La Plata stopped. University, Argentine. 17 n~ (1900) La Plata. Dep.of Reuropsychiatry,KyorinUniv.School of ~dicine Argentine. 6-20-2 S~hirLka~Mitaka-shiTo~_kyo!8l JAPAN 33.01.50 33.01.51 ~EUROLEPTICS IN THE TREAT~iENT OF DRUG ~FULTIPLE K~E~SION SYSTEM OF PSYCHOTROPIC DRUGS IN THE TREATmeNT OF SCHIZOPHRENIA DEPEND~NCE Z~ SCHIZOPRENICS. l.Das and B.K.Gupta A STUDY WITH FLUPENTHIXOL DEC2uNOATE ( F.D. ) In the past few years, some literature reports on the R. Schilkrut, J.Cabrera~ E.~orales, L.Herrera acute psychotic and related illness following sudden withdrawal of long-term treatment of schlzophrenia.Cases In order to evaluate the long-term antipsychot- of rebound cholinergic supersensitivity as neuroleptic ic, antidepressant and stimulating properties withdrawal behaviour after long-term treatment of schi- zophrenia have also been reported. As such, in the pre- of F.D., twenty schizoprenics outpatients were sent study, the multiple emulsion system has been selec- treated during 12 month with F.D. Psychopathol- ted as a novel drug delivery system to formulate a suit- able dosage form of Trifluoperazine, wherein the rate & ogical symptoms were rated using the AMP and amount of drug delivered at the site of action can be the Hamilton scales. The global functional im- sustained or more accurately controlled compared to the conventional dosage forms. In this case, release is desi- pairment of the patients was assessed before gned to follow zero order kinetics to achieve control of and after the treatment. During the study psy- therapeutic plasma concentration for prolonged time peri- ods. Thus,. extreme fluctuation in Triflnoperazine plasma chopathological scores reduced progressively levels is avoided, the dose of the drug required to ob- and activation was observed in the patients. Sev tain a desired effect is reduced and as a result, the multiple emulsion system finds importance in the long- en patients used compulsively alcohol, marijua- term tr.eatment and the management of several symptoms of na, benzodiazepines and amphetamines before en- schizophrenia. Since Clozapine is reportedly less prone to precipitate extrapyramidal side-effects and has the try to the study. Six of them remainded comple- abilityto relieve symptoms of tardive dyskinesia,this tely abstinent from all abused drugs for 12 drug ~as also been formulated in a multiple emulsion sys- tem yielding promising results. month of F.D. treatment. The positive effect of We have followed the two-step procedure in the formula- F.D. on drug dependence behavior appears to be tion of the multiple emulsion(w/o/w & o/w/o). In the linked to its mood activating action. Our find- w/o/w emulsion, the first step is the preparation of an w/o emulsion and the second stage involves the transfor- ings suggest that F.D. appears to be an effec- mation of this to a w/o/w emulsion by mixing the w/o sys- tive therapeutic alternative for drug depend- tem with an aqueous continuous phase. In our investiga- tions, we have used sorbitan fatty acid esters as the ence associated with cronic psychosis. lipophilic emulsifier in conjunction with a non-ionic University of Chile. Providencia 365 Ap.41 surfactant. This drug delivery system holds a great pro- mise in the field of psychopharmacological investiga- Santiago de Chile tions and treatment. Dept.of Pharmaey,Jadavpur University,Calcutta-32, India 342 33.01.52 33.01.53 CIPAZO~API~TE - ~TFAP_vP-.ANIDAL SIDE ~?ECTS HALOPERIDOL DECANOATE IN MAINTENANCE Al~a Miha!jevi~,M.Jakov!jevi6 ~nd Maja ~e!ja THER.AI'Y OI = CHP.ONIC bCHIZOPI-II~.ENICS Dep ....m~n~ of Psychiatry,School of me ...... ~., University of Zagreb S.C. TIWARI, B.B. SETH1, V.P. MAHLA a CIPAZOXAPII~ is novel ne-;roleptic vh!:h is 30 adult chronic schizophrenics, diagnosed according claimed ~o have good antipsychotic.~ro}erties to RDC, were administered Injection HMopericlol and low extrapyr~midal potential.Anti;sychotic decanoate at monthly intervals for a period o~" six effects are connect@d primarily to their ability months in an open clinical trial. The e-fficacy and to block iopaminergic hj-per~ctivity in the hippo- side effects of the drug were assessed with the help c~_mpus ~d the assumption that selectivity of of Brief Psychiatric Rating Scale (BPRS), Clinical this action predicts the absence of extre2yr=~mi- Global Impression Scale (CGI), Dosage and Treatment d&l side effects. Emergent Symptoms Scale (DOTES) and Abnormal ~r s~ady investigated extrapyramidal sire Involuntary Movement Scale (AIMS). Laboratory effects in two groups of shizophrenios treated investigations were also done in each patient before with cipazo~apine s~d ph!u~hen~z~ne. "'e tried and afler the trial.The dosage ranged from 50mg-3.q0mg/ to com~_~e presentation of ~xtrapyramidsl side month of I/m injection; the majority (70,%) of patient effects in these two groups.~e used two =ethods bein'g maintained at week 2# with relatively lo'H dosage for registration side effects:~l. >y the rating of Haloperidol decanoate (l-2ml). There was statistically scale for extrap~am~dal side effects and 2. by significant clinical improvement measured on Severity the electronic inst~imemt.Mea~oring inst~ments of Illness CG! sub-scale, at week 2/4 in comparison measure and ~nalyze side effects objective!y and with that at week 0(p/_ 0.01). The same was true ratihg scales are dependent on ~h~.... ra~_r~= ' s ~ab- for BPRS and its three sub-scale - The Depression jeetive judgement.$1e &Iso trie~ to compete the Sub-Scale, Thinking Disorder Sub-scale and Anergia u~'~e~s= ....~" ~ese me~.~ods~ ~0~~ the registration Sub-Scale. Significantly less side effects, at week of~ extrapyramidal side effects in clinic?! pra= 20 .k 2/4 in comparison to those at week 2, were observed. ct%ee. TD was observed in m;~d form in 3 patients and 19 Our results indicated that cipazoxapine's extra- pat,ents showed other abnormal involuntary movements, pyramidal potential had some specific ch~acteri- albeit in mild to moderate form~. The findings are stirs comparing to phluphenazine. discussed and it is concluded that haloperidol decanoate Tremor registration by electronic inst~ments iS effective and safe in maintenance therapy of chronic could be ve-~y 6cod for observation of side schizophrenics. effects in clinical practice. 33.01.54 33.01.55 SIDE'EFFECTS IN SCHIZOPHRENIC PATIENTS UNDER RELATI(iN~IP B~lq KXTRAPYRAMIDAL SYMFIDMS AND TREATMENT WITH DEPOT NEUROLEPTIC DRUGS:A FOLLOW- SERUM ANTICHOLINERGIC LEVELS IN C}IRONIC SCHIZOPI~R~qICS. UP OF*FOUR YEARS. SOM D. SONI, J. S. BAMRAH, JANET KRSKA. Psychiatric Research Department, A.Ch~nchj[la;M.Vega;P.Sanchez;F.Lana;L.Jorda;M.Camarero Hope and Prestwich Hospitals, Salford, M6 8HD. Hospita~ Ram6n y Cajal. Servicio de Psiquiatria. MADRID.SPAIN. The neuroleptic induced extrapyramidal symptoms can be relieved by anticholinergic agents, such as 25 schizophrenic patients who have undergone procyclidine. In clinical practice, the effect of such treatment with Depot Neuroleptics over a period agents is monitored with gradual, sequential increases of 4 years were followed.The main side effects in the dosage until the desired therapeutic response is and their evoZution;influence on the patients' work and social adjustment and noncompliance are obtained. Based on an iK~A assay method, we have earlier studied. reported an inverse correlation between serum AnCh and the presence or absence of EPS in treated chronic The most significant results are:e~,trapyramidal schizophrenics (B~mrah et al 1986). We have now disturbances are most evident in the first year, systeratically investigated various relationships that diminishing proportionally and becoming almost might affect serua AnCh and neuroleptic induced EPS. imperceptible in the last year[acute dystonic re- Sixty Nine chronic schizophrenics %~o had been actions in 32% and tremor in 40%,both during the stabilised on a single neuroleptic at a fixed dose for ffrst year,andfin the fourth year tremor only in over 6 monYhs and a single anticholinergic, prescribed the 4%;no cases of Tar~ive~Dyskinesia were found~ for EPS, for a minimt~, of 4 weeks participated in the amenorrhea increasing according to the evolution study. Serum neuroleptic and anticholinergic levels time up to 28%;permanent weight gain in 20 to 24~ were measured by the P~I method. The patients were also dysthymics between 16 and 20%;loss of motivation rated on the Extrapyramidal symptom. mainly in the first year {64%) decreasing in ti- Serum anticholinergic levels showed a significant me and,maintained subjetive cognitive deficits inverse correlation with ~S but did not appear to be in 20 to 30%.These were the most common side ef- dose related in any of the three anticholinergic drug fects found. groups. Percentage binding to proteins was Noncompliance rate was between 4 to 8%. significantly less with benztropine than either The results are clinically correlated with the benzhexol or procyclidine. Serum free antichoiinergic syndromic form, symptoms,personal and family his- levels correlated significantly with total serum levels tory of psychiatric disorders and with the type in the benzhexol and procyclidine groups but not in the of Depot Neuroleptie used. benztropine group. At senlm levels above 4.5 pmoles/ml atropine equivalents, EPS was significantly less than at levels Oelow that. We discuss the implications of this finding and suggest clinical applications of measurement of serum anticholinergic levels. 343 33.01.56 33.01.57 PLASMA DETERMINATION OF REDUCED HALOPERIDOL AND ITS NESSUREMENT OF HALOPERIDOL PLASNA-LEVELS: RELEVANCE TO CL!NICAL OUTCOME IN SCHIZOPHRENIA A TOOLE TO OPTINIZE NEUROLEPTIC TREATNENT K. Meszaros, G. SchOnbeck, W. Sieqhart, H. A.C.Altamura, M C Mauri, R.Cavaltaro, S.Bareggi Aschauer, A. Bu#neq Although haloperidol (HL) is probably the most widely used neuroleptic, few studies have attempted to quantitate its active metaboh~e, reduced haloperidol (RHL), evaluating its It has been shown that treatment with halo- peridol can be optimized by taking into con- clinical signihcance sideration haloperidol plasma-levels (HPL) in HL, RHL plasma levels and RHL/HL ratio were studied in 36 addition to dose. Especially in patients with schizophrenic ~rl-~atients diagnosed according to DSM Ill poor treatment response and/or intolerable side effects, HPL-messurement revealed either and treated with HL (5-21 mg daily; mean 12.34 + 0.70) for a to high or a to low level according to the six weeks. hypothesis of a "therapeutic window" (1). Clinical outcome, extrapyramidal and antichotinergic side- To test this hypothesis in daily routine of effects were evaiuated by BPRS, EPSE and ACS at time 0 psychiatric inpatient care, a study has been performed with a possibility to adjust daily (basal values), i (3rd week) and 2 (6th week). haloperidol dose according to plasma-levels Plasma determination of HL and RHL were made at time 2 by in poor responders. both liqLlid-chromatographic and mass-spectrometry Recovery has been defined as a 30 % amelio- electron impact a~_says. ration in BPR8, RIA-Assay has been used for HPL messurement. Diagnostics according to After three weeks of treatment there was no correlation DSM~III have been performed. between'HL, RHL oiasma level or RHL/HL ratio and clinical The hypothesis of a "therapeutic window"could outcome (evalua~.eO as % of amelioration at BPRS). be confirmed in 146 patients, i.e. signifi- But there was a negative correlation between RHL plasma cantly more patients recovered when HPL have been in the range of the postulated 16-27 !evel$ or RHL/HL and clinical improvement after s~x weeks ng/ml after adjustment of dose. of treatment. No correlation was found between HL, RHL plasma levels and Literature: side-effects 1) Plasma concentration of haloperidot and prolactin in acutely psychotic patients. The results of ,ms study are consistent with the hyDothesis Aschauer H., et al (Pharmacopsychiatry, that RHL makes a significant contribution to chnlcat in press). outcome in sch~z0pnremc DaQents could have a Dred]ctlve value on the c;m~cal response to HL treatment Psychiatrische UniversiC~tsklinik Wien, W6hringer GOrtel 18-20. A-1090 Wien institute of Ci~n',cai Psychiatry, University of Milan, D0l]climC0, Via F Sfcrza 35, 20!22 Milan, Italy 33.01.58 33.01.59 EFFECTS OF MIANSERIN ON NEGATIVE SYMPTOMS IN SCHIZOPHRENIA CLUZAPINE iN THE THEATMENT OF NEGATIVL bYMPTOM~ IN Y. Mizuki, N. Kajimura, M. Yamada, ~. Tanaka and SCHIZOPHRENAA K. Inanaga V. R. Paunovic t M. M. 3a~ovic-Ga~ic~ M. R~ Bo~danovic and The efficacy of mianserin as a supolement in treating S. 0. Totir chronic schizophrenics was tested by monitoring the Brief There is some evidence that clozapine, a dibsnzodiazepine, Psychiatric Rating Scale (BPRS) and the monoamine metabo- is superior to standard neuroleptics for the treatment of lites in plasma (HVA, MHPG and 5-HIAA). Twenty inpatients nearly all categories of schizophrenic symptoms. The re- with schizophrenia were administered fixed doses of neuro- sults of numerous studies~ concerning this matterj demon- leptics during the study. A control BPRS scoring and blood strata this superiority~ particularly in diminishing emo- drawing from the venosus mediana were done before mianse- tional withdrawal and blunted affect, that are considered rin administration. The fixed doses of 60 mg/day of mian- as negative schizophrenic symptoms (A. J. Gelenberg, 3. C. serin for 2 weeks and the flexible doses for 4 weeks were poller, 3. Clin. Psychiatry 40, 23B-240, Ig?g). However, given orally in an open trial for 6 consecutive weeks, and studies of E. Guirguis etal. (Curt. Therapeutic Has. 21, no treatment followed for I week. BPRS scoring was carried 707-719, lg7?) reported that clozapine and chlorpromazine out once weekly, and blood samples were obtained after had similar efficacy in treating negative symptoms. mianserin treatment. The concentration of HVA, MHPG and This study deals with the effects of clozapine and halope- 5-HIAA was measured by high-performance liquid chromato- ridol for the treatment of schizophrenic syndrome with graphy (HPLC). prevailing negative symptoms. Two statistically homogenous The total BPRS scores decreased by mianserin administra- groups of male schizophrenic in-patients, defined by the tion as compared with the control values. In each item, RDC, with prevailing negative symptoms, were randomly ass- scores for anxiety, emotional withdrawal and motor retar- igned to clozapine ~at median doses 200-250 mg per dayJ or dation decreased as compared with control values, respec- haloperiOol (at median doses 20-40 mg per dayJ for a tively. In clinically, mianserin treatment ameliorated 6-week p~riod. Clinical assesment was done on the 1st day clearly the negative symptoms in 11 patients out of 20 of addmission and at the end of the 3 and 6 weeks of treat. schizophrenics. The HVA and 5-HIAA concentrations after men,, with the Brief Psychiatric Bating ~cale ~BPRS) and mianserim treatment in the patients who showed improve- the Positive and Negative Symptom Scale (PANSS). Reduction ment pf their clinical symptoms increased as compared with in th~ negative schizophrenic symptoms was noted in both the control values, however, the MHPG contents in this groups, particularly in diminishing emotional withdrawal, group indicated no significant differences as compared to blunted affect and motor retardation, but clozapine was control values. Laboratory findings did not reveal any superior to haloperidol by its efficacy and by the patients abnormalities. These results suggest that the negative subjective report of the improvement. The results are symptoms of schizophrenia are oartly improved by mianse- discussed in the light of specific action of clozapine on rin treatment, and that the DAnergic and 5-HTnergic the mesolimbic dopaminergic system and its interaction neuronal activities might play a role in the amelioration with the serotonergic and alphl-adrenergic neurotransmi- of some negative symptoms. ssion. Dept. of Neuropsychiatry, Yamaguchi University School of Department of Psychiatry, ~chool of Medicine, Clinical Medicine, 1144 Kogushi, Ube 755, Japan Center, University of Belgrade, Pas~erova 2, ii000 Beograd Yugoslavia 344 33.01.60 33.01.61 CL!~ICAL ~-~ALUATION OF CLOZAP!~TE T~ET[',~T IN CLOZAPINE PLASMA LEI~LS DETERMINED BY HPLC AN~ MEN T~ DISORDERS UV-DETECTION A. KIEJNA Ch.Humpel, Ch.Harin~ B.Auer. A.Saria, Clozapine is a neuroleptic differing from the Ch.Barnas? W.F]eischhaeker T H.Hinterhuher hitherto known ones by chemical structure, For highest selectivity of measurement of mechanism of action and absence of typical side c]ozapine (S-chloro-ll-(4"-methy])-piperazino-5 effects. !t ez~ibits a strong antipsychotic dibenzo(b,e)(1,4)-diazepine) ~n plasma a three effect, however fraught with a risk of undesired step extraction procedure was developed. This effects, esq?eoial!y of haematolegie ones, which Drocedure invo]ved a pre-extraction of the requires further observations of the drug. acidified plasma to eliminate acidic and In our study a ouestionnaire method ~.ras used to uncharged organic contaminations. C]ozapine was collect an~mnestie and clinical data from 111 extracted by two treatments of the alkaline clozapine treated patients. The examined group plasma with n-hexane. The average recovery rate consisted of 76 women and 35 men, mostly with of c]ozapine from plasma was 61.7 + 6.~r To the diagnosis of long lastinghistory of schizo- compensate for irreproducible losses during the phrenia. In 65% of them clozaoine was used with complicated extraction-procedure fluphenazine lacking improvement and after other neuroleptic~ was used as interna] standard. Recovery of Oral and parenteral routes were adopted with f]uphenazine was found to be similar to that of divided doses, some patients received a single clozapine. (56.1 + 14.5~). These results could night dose. ~e mean initial, as well as main- be confirmed by ~xtraction with radioactive taining doses was 190 mg daily, the maximal f]uphenazine. Reversed Phase (octy] silica; doses amounted to 350 mg daily (from 25 to 800 5 ~m, pore size 10 rim) high performance liquid mg) was aonlied on average for 27 days. chromategraphy was carried out with a single- ~-k~ll remission was obtained in 22.5% patients, piston-pump. The chosen e]uent (10~ water, a satisfactory improvement in 34.2%, slight 90g acetonitrile, 0.25 mM ammonium acetate) and improvement in 22.5%, no improvement in I~% and the f]ow rate of 0.5 m] per mfnute provided deterioration in 2.~%. optimml separation from plasma. For absorbance Amon~ the most frequent side effects and compli- ~easurements a [W-detector (f~lter 254 nm) was cations there were: hypersalivation in 3T%, used. Ouantification was performed by ~o, hypersomnia in 5~, hypotonia in 10. 8,o, hyper- integration of peak area and peak height thermia in ~.3%,~ exogenous syndromes in 3.6,o~ and measurement. Although the capacity of the gastric symptomes in 2.7% of the patients. Two detector was not fully exhausted, the lower patients with mania mhowed an inversion into detection limit was 5 ng/m], demonstrating the depressive phase; leukopenia occured in 10.0% high sensitivity of this method. of patients. UniversJtitsk]inik fiir Psychiatrie, The results obtained were evaluated statistically Neurechemisches Labor. AnichstraBe 35, Department of Psychiatry, Medical Academy, 50-229 A-6020 Innsbruck. Austria. ~roclaw, Kraszewskiego 25, Poland 33.01.62 33.01.63 RESULTS OF THE LONG-T.~R~ TREATI~ENT WITH CLOZA- UNSUSPECTED INTRACEREBRAL PATHOLOGY IN OLDER PINE. CLINICAL A]~ ELECTRO~CEPHALOGP~&PHIC SCHIZOPHRENICS STL~Y W~_~-_Hoff~an~ M. Burry, and D. E. Casey H.Hanu~, M.Zaolet~lek, V.KuSera and ~.Kuba Evaluation of patients for extrapyramidal Clozapine is an efficient neurolepticdrug, syndromes (EPS), such as tardive dyskinesia (TD) that has a marked antipsychotic effect and only and drug-induced parkinsonism (DIP), can be a scarce incidence of side effects. The purpose complicated by the presence of other conditions of our study is the clinical and EEG assess- which cause or exacerbate EPS. Twenty-six ment of a group of patients on the long-term schizophrenic patients over age 55 underwent clozapine treatment. At our clinic there have non-contrast computed tomographic (CT) been 30 patients on a long-term therapy. In evaluation as part of an examination of EPS in some of them the treatment had been finished older schizophrenics. Patients with a previous for a full adjustment of their state, in some diagnosis of stroke were excluded. TD and DIP others it had to be broken off for other rea- were rated on the Abnormal Involuntary Movement sons than a relapse or a side effect; in Scale and the Sct. Hans Rating Scale for Extra- others the therapy was substituted by other pyramidal Syndromes, respectively. The CT scans medication after a relapse. We assessed also a were read by a neuroradiologist who was blind to group of 12 schizophrenic patients, who were patient identity and clinical data. Presence of treated v~th clozaoine for l0 years in average stroke was rated on a 0 to 3 scale (none, (range l~14 years,'median lO years). In the questionable, probable, and definite). Eleven course of the treatment with clozapine there patients (42%) were rated as none, 7 (274) as were maintained good remissions of the psycho- questionable, 4 (154) as probable, and 4 (154) sis. There were no serious side effects.In one as definite. In addition, one patient was found patient we have seen a transitory leu_kopenia. to have'idiopathic basal ganglia calcification. During the longitudinal EEG recording only one There was no significant difference in either patient had completely normal EEG. All the AIMS or Sot. Hans scores between the patients other patients had generalized mild changes or with strokes (probable or definite) and those dysr~ytmic changes of the recordings. Nine pa- without (none or questionable). A patient with a tients had their visual evoked potentials exa- large, left hemisphere lesion involving the mined. It was surprising to find shorter la- lenzicular nucleus also had severe right sided tency of the evoked response in comparison to hemi-parkinsonism. The patient with basal normal recordings. There was no sign of the ganglia calcification had moderately severe latency prolongation as described after other orofacial dyskinesia which persisted despite neuroleptic drugs. discontinuation of neuroleptics. Psychiatric Clinic,500 36 Hradec Kr~lov4,~SSR These older schizophrenics had a high prevalence of unsuspected intracerebral pathology. In two cases, ~his pathology contributed to the sever- ity of EPS. Implications of %hose findings for research and clinical practice will be discussed. 345 33.01.64 33.01.65 FRONTAL DYSFUNCTION AND SCHIZOPHRENIA FRONTAL AND TEMPORO-HIPPOCAMPAL IMPAIRMENT IN T. Kojima*, H. Ando*, E. Matsushima*~ SCHIZOPHRENIA: NEUROPSYCHOLOGICAL CORRELATES K. Ando*~ R. Takahashi*and Y. Shimazono.** A. Mucci, S. Galderisi, M. R. Solla, A. Giacco Our earlier studies with the eye camera method and M. Maj. indicated that chronic schizophrenic patients Several neuropsychological investigations have with negative symptoms have dysfunction of the shown an impairment of performance in visual perception process. schizophrenic patients in tests involving Furthermore, our previous study on frontal and temporo-limbic functions. It is schizophrenics and patients with frontal lobe still controversial, however, if this finding is lesions using an eye camera and maze tasks related to a left hemisphere or to a bilateral suggested that schizophrenia is not produced by dysfunction. a frontal lobe lesion alone, but by a frontal The present study was designed to clarify this lobe lesion in a setting of more extensive issue by using a neuropsychological test cerebral dysfunction such as limbic system, battery in a sample of 13 male DSM IIl thalamic nuclei and association areas. schizophrenics and 14 matched healthy controls. From how schizophrenics looked at the last The fronto-hippocampal functioning was blind alley in maze, they were classified into evaluated by means of the Spatial Conditional two groups, the perplex type and the haphazard Associative Learning task (SCAL), the Non type. The- former was a patient group that viewed Spatial Conditional Associative Learning task the last blind alley several times and took (NSCAL), and the Self-Ordering Pointing Task longer times before starting drawing. This (SOP) for high imagery words and for abstract type was seemed to be confused and poor to drawings. The temporoThippocampal functioning utilize'a cue. was tested by using the Hebb's Recurring Digit The latter was a patient group that started task (HRD) and the Corsi's Block Tapping task drawing without caution and viewed the last (CBT). The performance of schizophrenics was blind alley for the first time while drawing significantly impaired with respect to normal near the blind alley. This type indicated an con t~-ols for both SCAL and NSCAL. On SOP, impairment in planning and programming and a patients performed significantly worse than poverty of the ability to look foward. normals for the "high imagery words". The correlation between our two types and CT As to the tests for the temporo-hippocampal findings, maze performances, psychological functioning, the CBT did not detect tests, IQ score, drug dosis and clinical Oifferences between patients and controls. On features will be discussed on 37 schizophrenic HRD, the performance of schizophrenics was subjects diagnosed according to DSM-III. significantly poorer than that of normals. *Dept. of Neuropsychiatry, Tokyo Medical and These results suggest a bilateral frontal Dental Univ. 1-5-45, Yushima, Bunkyo-ku Tokyo lobe dysfunction and a left 113, JAPAN, **National Center of Neurology and temporo-hippocampal impairment. Psychiatry, 4-1-1, Ogawahigashicyo, Kodaira-shi, Department of Medical Psychology and Psychiatry, Tokyo 187, JAPAN First Medical School, University of Naples, Italy. 33.01.66 33.01.67 ERPABNORMALITIES IN SCHIZOPHRENIA: RELATIONSHIP INCREASED SACCADIC DISTRACTIBILITY IN TARDIVE TO POSITIVE AND NEGATIVE SYMPTOMS. DYSKINESIA (TD): A PUTATIVE GABAERGIC MECHANISM S. Galderisi, M. R. Di Gregorio, N. De Marchi, G.K. Thaker~ J.A. Nguyen~ B. Buchanan and C.A. G. Ionta and M. Maj. Tammin6a A reduction of the Late Positive Complex (LPC) An abnormality of basal ganglia GABAergie effents has has been reported by some authors in been hypothesized to play a role in pathophysiology of schizophrenia and reIated to a dysfunction of TD. Dysruption of these nigrotectal neurons produces the limbic system. The present study was carried increased saccadic distractibility in monkey. We out in 14 male drug-free DSM Ill schizophrenics studied the control of saccades in schizophrenics with and in 19 matched healthy controls. and without TD. Results from our first study show a Event-Related Potentials (ERPs) and reaction two-fold increase in saccadic distractibility in TD time (RT) were recorded by using a visual target compared to non-TD schizophrenics thus suggesting a detection paradigm in which consonant pairs were decrease in nigrotectal GABAergic transmission in TD. presented centraliy and to the right (RVF) or to A second set of studies were carried out in our labora- the left (LVF) visual field. In the central tory to further evaluate the saccadic control in schiz- condition, the LPC peak amplitude was lower in ophrenic patients with and without TD and its relation- schizophrenics than in controls and inversely ship with the smooth pursuit eye movement (SPEM) per- correlated with the global score on Andreasen's formance. Method: Thirty-two schizophrenic patients scale for negative symptoms. For the lateral (20 with TDI participated in different eye movements: conditioQ, the LPC peak amplitude was higher for saccade (look at the target jump), anti-saccade (look RVF than for LVF stimuli in normals, whereas in away from the target jump), fixation (fixate the gaze schizophrenics no visual field effect was found in presence and absence of fixation light) and SPEM for this component. In contrast, SW and P320 (follow,a target with a sinusoidal motion, 0.5 hz). amplitudes were higher for LVF than for RVF Infra-red technique was used. stimuli in schizophrenics and did not show any Results replicated our initial finding of a two-fold visual field effect in normals. Moreover, in increase in saccadic distractibility in TD patients schizophrenics, SW and P320 scores for LVF competed to the non-TO patients. Multiple regression stimuli were positively correlated with global analysis revealed that saccadic distractibility was the score on CPRS positive symptoms. As to only oculomotor measure significantly associated with behavioural data, faster responses were observed TD (partial r:0.59); other measures including SPEM in controls for RVF stimuli, while no visual score showed negligible correlations with TD score. field effect was detected in schizophrenics. SPEM score, however, was significantly associated with These data support the existence of LPC other non-localizing neurological deficits. In conclu- abnormalities in schizophrenia whose patterns, sion, we observed a distinct oculomotor abnormality however, seem~ to be different depending on the (i.e. increased saccadic distractibility) associated predominance of positive and negative symptoms. with TD in schizophrenic patients. We hypothesize that this abnormality is secondary to the previous chronic Department of Medical Psychology and Psychiatry, neuroleptic treatment and consequent changes in basal First Medical School, University of Naples, ganglia GABA function. Maryland Psychiatric Research Italy. Center, P0B 21247, BaLtimore, ~ 2]228, USA 346 33.01.68 33.01.69 EN~NTIOMERS OF 3-PPP SUPPRESS NEUROLEPTIC-INDUCED PR_~'_I~E OF TARDIVE DYSKI~SL~ VARIANTS IN JAPAN PERSISTENT ABNORMAL MOVEmeNTS IN CEBUS APELLA MONKEYS D. Clark*, P. LeWitt and B. Kovacic T. Inada. K. 0hnishi, M. Kamisada. S. Nakajisa. S. Kanbe, Following withdrawal from long-term administration of ~. Takamiya, K. Kamijima. 6. Yagi neuroleptic agents, Cebus Apella monkeys can display Recent tardJve dyskinesia studies have moved from classical oro- various persistent abnormal movements (PAM). These movements, which resemble human dyskinesias, are facial dyskinesia to subtyping of clinical variants such as limb temporarily alleviated by neuroleptic agents but this is accompanied by Parkinsonian-like symptoms. We have dyskinesia, dystonia, akathisia, and so forth. We examined preva- recently investigated the effect of the enantiomers of the lence of involuntary movements in psychiatric patients between dopamine (DA) agonist 3-PPP (0.5-8.0 mg/kg) in three Cebus Apella monkeys with PAM induced by withdrawal from long- Oct. through Dec. in 1987. term administration of fluphenazine. (-)-3-PPP temporarily abolished the PAM in two monkeys without The sub,ants comprised 706 inpatients and 49 outpatients, who producing any Parkinsonian-like symptoms. One of these received psychiatric therapy for at least one year at Sakuragaoka monkeys was also tested with (+)-3-PPP; a dose-dependent alleviation of PAM was observed. A biphasic reaction was mental hospital in Tokyo. The clinical diagnoses of the patients apparent during the time that PAM were abolished by the included schizophrenia (n=~43), mental retardation (n=64), epile- highest drug dose. The animal initially showed amphetamine~like stimulation, followed by a period free psy r and so forth. of PAM and motor stimulatory effects. Neither enantiomer of 3-PPP reduced PAM in the third monkey. (+)-3-PPP Ye identified tardive dyskinesia in ]45 patients. Ten variants of produced hyperkinesia and tongue protrusions when the tard/ve dyskinesia could be distinguished: classical oro-facial monkey was in a restraining chair, but not when tested in the home cage. These findings confirm the earlier work dyskinesia (]4.8~), limb dyskinesia (2.1%), trunk dyskinesia of Baggatrom and colleagues that the 3-PPP enantiomers can reduce neuroleptic-induced PAM in monkeys, an effect (0.~'. respiratory dyskinesia (0.3~), dystonia (0.9~), akathisia which is likely related (at least in part) to their (0.~.Tourette llke syndrome (0.]~), rabbit syndrome (2.0~), ability to reduce DA function by stimulating DA autoreceptors. The amphetamine-like symptoms produced by ,yen]orms (].7~), choreoathetosis (0.7~). (+)-3-PPP are probably mediated by stimulation of postynaptic DA receptors. The present work supports the ~e found similar prevalences of tardive dyskinesia variants in contention that (-)-3-PPP and drugs with a similar Japan and the West, despite cross-cultural differences in psychi- pharmacological profile might be effective as symptomatic treatments for tardive dyskinesia, with little chance of atric practice. inducing acute extrapyramidal dysfunction. Dept. ~europsychiatry, Keio [niv. Med. School. 35 Shinanomachi, Dept. Neurology, Lafayette Clinic, Wayne State University School of Medicine, Detroit, U.S.A., and *Neuropsycho- Shisjuku-ku, Tokyo, 160, Japan. pharmacology Lab., Dept. Psychology, University of Reading, U.K. 33.01.70 33.01.71 MORTALITY RATE IN SCHIZOPHRENICS WITH TARDIVE DYSKINESIA ANALOGICAL TESTS AND PSYCHOTIC DISORDERS. L.Bourrelly, M. Ohayon M.Takamlya, G.Yagi, M.Kamisada, S.Kanba, A.Tanoue, The authors present the ciinicai stage of a research program about tre mooel]- K.KamizLma, T.Suzuki, S.Kaizawa, F.Saito zation of normal and Psychotic analogical processing. The cognitive abilities of psychotic patients are always grossly upset, t~ougn IO We exsb~,.1.~,~mortality rate in between schizophrenics with .s often subnormal. Thought disturbances are more obvious Ouring re actwe (n=63) end wzthout(n=75;age and sex matched controls) tar- phases than in remissions. dive dyskinesia(TD), during the average of I 0 years. Our hypothesis is that analogical reasoning is the basis of cognition and lear- Relationshlp was also examined between the mortality rate rang: on the ground of me likeness of a new object with something a reaoy and the clinical variables. ,~nown, one will put it mto the same ctass. Finding differential proderties will ~ead to more class links. Language is involved in this process, as it provioes "pointers" The TD grsup had a significantly higher mortality rate :o ctasses, and ready-made object and class links. (41%), as compared with the control group(20%, p<.05). The Therefore, the authors built, a set of "analogical puzzles", designed as fa}~mvs: average of s'~u~vival years from the beginning of the inves- Ill ",4" becomes "B", what about "C'? Are you pleased with your ansv,,er ~ tigation in the deceased patients of the TD group(~6 years A/B conversion and A/C likeness may be graphical, semantic, or a biend of both. ) was shor-_er than that in the control group(~7 years). :-he answer patterns elicit the ability in: 1) finding out implicit AfB convers=on ru- The mortal'_ty rate in the TD group was not related to any ,es, 2) applying them to "C'. 3)managing compromises between cons'u'au'Tm, 4) of the clinical variables such as severity and clinical estimating one's work. course of UD, presence of physical complications, duration The rating includes 3 stages: 1) is the C/D conversion analogous In A/B c~,'wer- and course of pharmacotherapy, etc. In the female TD group s=on according to the imolicit rules?, 2) which kind of transformation was orion- , the deceased patients were significantly older than the sad?, 3) is the auto-valuation accurate? surviving patients when antipsychotics were first given Psychotic patients usually find out a C/D link disregarding A/B and their auto- as well as TD appeard. A prevalence rate of hypertension valuation takes no account of the value of the analogy. It seems It-~atthe ma~ dis- was alsc higher in the former group. ~rbance is in the lack of reliability of the )udgment about their own proOuctions. When c~-,,p,ared causes of death, we found that respiratory The result Is that not only their analogies are Inadequate, but also and cerebrovescular diseases were more predominant in the that t[3ey applle them as a knowledge. The nevrotic or depressive Pa- tients make correct analogies. In depression, the auto-valuation is usually low, TD group[the fermer;5vs3, the latter;4vsl ). obsessionals often choose the graphical ru~es while hysterics stress the seman- The.,org~nzc fragirity which may exist in the TD patients, ~c associations. The Dsychotic disturbances are permanent, even dunng remis- especialiy in ~he females, was discussed. sions. The pseudo Tudng test (test-based diagnosis/clin~.al diagnosis) is s'Jikin- g~y accurate, and was able to detect genuine psychotic patients in our "normal" sample. D1ceased r22 DI 1 c4 i ! Laboratoire de Tra~tement des Connaiss&nces, CHU Sainte-Marguerqe. 270, sur',-lvlnct 32 ! 56 1 2 Bou!evard de ate-Marguerite, 13009-Marseille (FRANCE) t~tal 63 I 75 I 2 ; P<" 05 Takamzya Hcspltal ,! 961 Yesh!muracho-oomachi ,Miyazaki, 880 JAP.~N 347 33.01.72 33.01.73 A STUDY OF RABBIT SYNDROME: FOCUSSING ON THE COMPARISON OF THE CLINICAL EFFECTS OF LITHIUM LINGUAL COMPONENT AND SLEEP EEG CRITERIA CARBONATE AND CARBAMAZEPINE ON EXCITED SCHIZO- PHRENICS Utpel GoswamI, R. Sundararaian, B.N. Gan~adhar, M.Kamisada,M.Tateyama,Y.Nakano,Y.Kawachi,Y.Fujii P. Satish Chandra S.M. Cbannabasavanna, ,A.Tanoue,M.Takamiya,S.Nakajima,K.Sakuma, E. Frecska, M. Arato and A ndras Perenyi E.Oguchi,G.Yagi In !972, Villeneuve first coined the term "Rabbit Syndrome" A total of 30 inpatients (aged 21 t0 57) of ICD- to describe a tardive, neuroleptic-induced hyperkinetic 9 schizophrenic psychosis were administered syndrome characterised by rhythmic, 5 to 5.5 Hz involuntary lithium carbonate (LT), carbamazepine (CB) or movements of the perioral and mesticatory musculature placebo (PL).Patients were included if they were resembling the chewing movements of a rabbit. Later rated as moderate or more in "tention", "man- 5ovner and DiMaseio (1977), 3us et el. (1979) and Todd nerisms and posturing" or "excitement" of BPRS. et el. (1985) confirmed that the syndrome reversed with The doses of real medications were on the dou- anticholinergic challenge and/or neuroleptic withdrawal. ble-blind fixed-flexible method for 8 weeks" (start at 400mgs/d,upper limit at 1200mgs/d). The Canadian investigators proposed two other features Other antipsychotics,if administered concomi- as the integral part of this syndrome - (i) sparing of the tantly, was fixed throughout the study period. tongue and (ii) persistence in sleep - throughout the stage [ NREM sleep until the onset of stage I] NREM. The findings were as follows; ~)Backgrounds of patients:more frequently cata- During the .past 8 years, working in four centres, 11 cases of Rabbit Syndrome were identified, of which seven patients tonic PL~CB. (p<0.1). consented for the present study. After 3 days of habituation 2)General Improvement Rating:PL~LT(p<0.01). PL>CB(p<0.1) in the sleep EEG lab, spontaneous night sleep EEG was 3)Global Usefulness Rating:PL>LT,CB (p<0.05). done on . day 4, in addition to polygraphic recordings 4)Overall Safety Rating:CB>LT,(p<0.1). of labial and lingual movements. The records were blindly end independently evaluated by two authors with standard 5)Side effects:two cases on 600mgs/d of CB dev- staging procedure by Kales and Rechtschaffen. Except eloped diffuse skin rashes with fever in weeks 2 for on,e patient, the 5.5 Hz movements disappeared with thenfthe medication was ceased. 6)Although no difference appeared among the tree the onset of stage I NREM and not stage [I NREM as groups in improvement expressed by the decrease was claimed by the Canadian group. Also 5 of the seven of the total BPRS score or the activitation subjects showed definite presence of a lingual component synchronus with periorel-masticetory movements. The score,the thrapeutic effects occured more rapid- ly for the LT group. It has been speculated that syndrome subsided with intravenous promethazine challenge, temporarily. It naturally follows that the syndrome is neither LT rapidly ameliorates the psychiatric symptoms tongue-sparing nor does it persist in sleep.as stated earlier. of exitable schizophrenics. Inogashira Hospital. 4-14-1 Kamirenjaku Mitaka- Jswshsrla] Institute of Postgraduate Medical Education and shi 181 Tokyo Japan. Research, Pondicherry-6OS006; NIMHANS, Bangalore; CMC, Vellore, INDIA end National Institute for Nervous and Mental Diseases, 1281 Budapest 27, Pf 1, HUNGARY. 33.01.74 RISPERIDONE VERSUS HALOPERIDOL IN CHRONIC SCHIZOPHRENIC PATIENTS : A 12 WEEK MULTI- CENTER DOUBLE-BLIND PARALLEL STUDY. Cuvper H_. Malfroid H.. Peuske~s J.. Bo!l~n J. and Eneman M. Risperidone (R 64 766) is a potent combined serotonin-S2 and dopamine-D2 antagonist. In previous studies in chronic psychotic patients it was demonstrated that this substance combined an effective antipsychotic action with a significant improvement of negative symptoms, without inducing acute extrapyramidal symptoms (EPS) , while existing EPS were reduced significantly. TO confirm these results, 40 chronic schizophrenic patients (according to DSM-III-R criteria) were selected for the present study, after informed consent was obtained. They all presented positive, negative and/ or ext rapyramidal symptoms although the neuroleptic medication was optimalized repeatedly. This study lasts for 15 weeks. The first 2 weeks, (from day -21 till day -7) the patients are evaluated with the existing treatment kept unchanged; then all neuroleptic and antiparkinson medication is stopped, and they have a single-blind placebo wash-out period of 1 week (day -7 till "day 0) . On day 1 the double-blind medication is started, with an initial dose of 1 mg b.i.d., both for risperidone and haloperidol. According to the achieved therapeutic effect or the appearance of side-effects, this dose is adapted whenever necessary, with a maximum dose of 10 mg b.i.d, for the first half of the trial. For the next 6 weeks, i.e. from day 43 on, the dose of the doubLe-blind medication is kept unchanged untill day 84, end-point of the study. Patients are evaluated by means of the SADS-C (on day -21, 0 and 84) and the pANSS, NOSIE-30, CGI, and Chouinard EPS-rating scale on day -21,-14,-7,0,7,14,28,42,56,70 and 84. On the same days, a target symptom and 4 sleep-parameters are scored with visual analogue lines, vital signs are recorded and side- effects noted. A complete safety-screening is done on day 0, 42 and 84. At the end of the study a comparison is made with the previous therapy, both by the investigator and the patient. The preliminary results are discussed. Univ. P =sychiatr. Centre Sal~ Mater, 3042 Lovenjoel, Laurel, Belgium. 348 33.02.01 THE EFFECT OF LEVOPROTILIN ON THE BASIC SYMPTOMS OF EATING DISORDERS F. Faltus, G. Wendt In the course of therapy of some cases of depressive POSTER states with levoprotiline its favourable effect on appetite regulation, hunger feelings and stabilisation PRESENTATION of body weight was observed. Therefore we decided to apply levoprotilin in patients with different types of 33.02 eating disorders. In patients suffering from anorexia nervosa repeated ratings were done in basic symptoms: enhancement of appetite and feeling of hunger, improvement of attitude to eating, increase of body weight. In patients suffering from bulimia nervosa we studied the effect of levoprotiline on regulation of feelings of hunger, on purging, and stabilisation of Anorexia Nervosa and body weight. In both treatment groups we evaluated the effect of levoprotiline on emotional stability, on Bulimia occurence of anxious and depressive symptoms and on self esteem. Detailed results will be presented and discussed. Psychiatrische Klinik, Medizinische Fakultgt d. Karls-Universit~t, Ke Karlovu 11, CS 12821 Praha 2 33.02.02 33.02.03 CONTROLLED TRIAL OF FLUVOXAMINE AND BEHAVIOR A OOMPARATIVE EVALUATION OF THE BEHAVIOURAL THERAPY IN THE TREATMENT OF DEPRESSED OBESE AND ANTIPSYCHOTIC EFFECTS OF CENTBUTINDOLE D.O. Nutzinfler, M. de Zwaan, G. Sch6nbock, IN RHESUS MONKEY (MACACA MULATTA) A. BuQnar, R. Macura, S. CayiroQ1u, P. Berqer, G. Palit, C. Nath, M.B. Gupta, R.C. Srimal, B.N. Dhawan G. Aschauer-Troiber, A. Kiss, S. Meryn. and G.P. Gupta There is a close interrelation of appetite and CentbutindoJe (CB), a new antipsychotic drug developed emotions. This fact is of particular importance at Central Drug Research lnstitute~ Lucknow, India, was in the treatment of depressed obese, where studied ior its effects on behaviouraI patterns and ampheta- dieting is often linked with deterioration of mine induced psychosis in rhesus monkey, and compared depressive symptoms. The use of traditional with standard antipsychotic drugs (haloperidol and chlorpro- therapeutic approaches is limited in this sub- mazine). group as conventional antidepressants (AD) com- Centbutindole (12.5-50 ~ug/kg im) produced a dose-dependent monly cause weight gain respectlively dietary decrease in social behaviour patterns (social groom, approach, management (DM) alone or in a behavior therapy body jerk and reactivity). In solitary behaviour, the sponta- setting takes the risk of a high drop out rate neous motor activity (SMA) was markedly decreased, auditory due to aggravation of depressive symptoms. response and sell groom, were suppressed. Larger doses In our study we have chosen an innovative ap- of CB (100-200 ~g/kg im) produced a marked cataleptic proach to these problems: Fluvoxamine(F), a new posture. Haloperidol produced similar extrapyramidal eIIect AD with weight reducing properties combined with but in lower doses (#0-80 ~g/kg im). Amphetamine (t~ mg/kg cognitive - behavior therapy(BT). In a double- ira) produced checking, stereotypy and suppression of feeding, blind, four-cell study design we compared four drinking and grooming behaviour which were blocked by treatment modalities: F and BT, F and DM, pla- prior treatment with CB (20 ~ug/kg im), haloperidol (40 jug/kg cebo and BT, placebo and DM. Sixtyfour obese im) or chlorpromazine (1 mg/kg ira). In equipotent anti- women aged 19 to 54 with present or past amphetamine doses, chlorpromazine caused more marked Depressive Disorder according to DSM-III-R were sedation and decrease in SMA than CB and haloperidol. randomly assigned to one of the four treatment Thus, the profile of behavioural eflects ol CB is similar conditions. Their body mass index at baseline to that of other antipsychotics with lesser propensity to rang&d from 29 to 47 kg/m 2 (median 36). The cause extrapyramidal effect than haloperidol. treatment lasted 24 weeks with weekly group Neuropharmacology Unit (CDRI), Department ol Pharma- therapy sessions through 12 weeks, followed by cology, King George's Medical College, Lucknow-226003, 8 weeks of placebo controlled drug treatment India alone and further 6 weeks of placebo adminis- tration. Subjects were assessed at regular intervals throughout treatment. Blood samples for measurement of F wore taken pro-, mid- and post- treatment. Follow-up assessments are planned 8 and 12 month after treatment phase. Results will be presented. Psychiatrische UniversitAtsklinik Wien, W&hringer G~rtel 18-20, A-1090 Wien 349 33.03.01 THE PSYCHOPHARMACOLOGY OF RITANSE~IN: DIFFERENTIATION WITH CHLORDIAZEPOXIDE T.F. Meert, F. Awouters and P.A.J. Janssen Ritanserln, a central 8erotonln 5-HT 2 antagonist with POSTER complete LSD-antagonist properties, was compared with the benzodlazepine ehlordiazepoxide (CDZ) in different animal PRESENTATION models of anxiety. In conflict procedures using electric shock as an inhibitory stimulus, a dose related dlsinhi- 33.03 bition was observed with CDZ but not with ritanserin. In different other anxiety tests involving more natural aver- sire stimuli, riteunserin dlsinhlbited exploratory behav- iour over a broad dose range while CDZ was marginally active. The differences between ritanserin and CDZ were also clear in drug discrimination test procedures. CDZ but not Biological and ritanserln had intrinsic discriminative properties. Furthermore, ritanserin did not generalize with CDZ nor Pharmacological Aspects with fentanyl, LSD, cocaine, d-amphetamine and 8-OHDPAT. These results indicate that ritanserin is unlikely to of Anxiety Disorders possess abuse potential. Unlike the benzodiazepine, ritanserin did not induce motor incoordination or seda- tion, was devoid of interaction with alcohol, produced no stmte dependency, w~s not self-administered and did not affect basal corticosterone plasma levels. On sleep, ritanserin is known to increase SWS and CDZ to affect REM sleep. These ~xperimental studies indicate that ritanserin pos- sesses anxlety-reducing effects with a mechanism of action different from that of the benzodiazepines. The clinical effects of ritanserin in dysthymic and anxiety disorders are considered to be based on a neurotransmitter interac- tion that avoids the limitations of classical anxiolytic drugs. Department of. Neuropsychopharmacology, Janssen Research Foundation, B-2340 Beerse, Belgium 33.03.02 33.03.03 PERSONALITY DISORDER IN PANIC DISORDER PATIENTS RITANSERIN-AN ORIGINAL THYMOSTHENIC-IN THE TREATMENT OF GENERALIZED ANXIETY DISORDERS. J.L.Ayuso, A. Rivera and S. Alfonso A. A. I. Jansen ~nd E. A. Pangalilia-Ratu Langi. In a double-blind trial, 22 patients treated with The aim of this study was to measure the inciden 5 mg b.i.d, of the selective serotonin-Sz antagonist ce of personality disorder in panic disorder pa- ritanserin for 4 weeks were compared with 26 patients treated with placebo for generalized anxiety disorder tients and examine the relationship of persona- (DSM Iii: 300.02). Symptoms were assessed using the lity disorder and clinical variables and treat- Hamilton Anxiety Rating Scale (HARS) and the Visual Analog Mood Rating Scale (Noris, Bond and Lader). ment outcome. Patients were further evaluated by means of a clinical global impression. The present treatment was The sample consisted of 90 consecutive referrals also compared with the previous treatment for who met DSM-III R criteria for panic disorder generalized anxiety disorder. At the end of the treatment ritanserin was significantly superior to and were evaluated and treated on a outpatient placebo in its effect on the psychic cluster of the basis. HARS, es#ecially for the items insomnia (already after 1 week of treatment) tension and depressed All subjects were screened by means of the Ss mood. According to the Mood Rating Scale, the ritanserin-treated patients rated themselves as tured Clinical Interview for ....nS~-TTT~ ..V ~fCP~tzer calme~, more energetic and more relaxed. This and Williams,1985) including Axis-If version. significant symptomatic improvement with ritanserin was confirmed by the clinical global impression and Probands with or without personality disorder in the comparison with the previous treatment, both al~o significantly in favour of the were, compared in regard to age of onset, dura- ritanserin-treated patients. As only one side-effect tion of illness and avoidance behavior. was reported in the ritanserin group versus 5 in the placebo group, it may be concluded that ritanserin Treatment outcome after 6 months was assessed provides a novel and very well tolerated therapy for outpatients suffering from generalized anxiety in both groups by means of Global Assessment disorder. Scale, Physician Global Improvement Scale and Janssen Pharmaceutica B,V.,dept. of Clinical Research, Patient-rated Global Improvement Scale. P.O.Bo• 90240, 5000 LT Tilburg, The Netherlands. Hospital Universitario San Carlos, 28040 }ladrid 350 33.03.04 33.03.05 MEDETOMIDINE, A POTENT AND HIGHLY SELECTIVE ALPHA-2- FUNCTIONAL INTERACTION OF NOVEL ~NXIOLYTICS WITH ADRENOCEPTOR AGONIST HAS ANXIOLYTIC PROPERTIES IN RODENTS 5-HT - AND ADRENERGIC RECEPTORS lA * E. MacDonald, A. Haapalinna, R. Lammintausta & R. Virtanen T. GIaser, L.A.A. van Rooiien and J. Traber Medetomidine (MED) is an imidazole derivative, recently Recent evidence strongly supports the existence in introduced for veterinary sedation in cats and dogs etc. brain of at least five subt}~es of serotonin (5-HT) It is a potent a2-adrenoceptor agonist, with no major receptors named 5-HT - 5-HT 5-HT - 5-HT - and IA ' IK' iC ' 2 binding affinity to any other studied CNS receptors. MED 5-HT3-receptors. Especlally the o-HTl~-receptor subtype caused a dose-dependent inhibition of noradrenaline (NA) seems to be involved in mechanisms ~6hderlying anxiety turnover as assessed by levels of NA metabolite or inhibi- (Traber and Glaser, Trends Pharm. Sci. 8, 432-437, tion of a-methyl-p-tyrosine induced depletion of NA levels 1987). The aim of the present study was to compare on a in brain. MED also inhibited the turnover of dopamine and biochemical level the novel 5-HT.]A-receptor related 5-hydroxytryptamine (5-HT). The effects on these other anxiolytics buspirone, gepirone and-zpsapirone as well biogenic amines were blocked by prior treatment with the as the 5-HTiA-receptor ligand 8-hydroxy-2-(di-n-propyl- a2-antagonist, atipamezole (ATI, 1.0 mg/kg). amino)tetralYn (8-OH-DPAT) in respect to their func- The doses of MED used in the above experiment (30-300 ug/ tional interaction with 5-HTIA- and a-adrenergic r e- kg) caused sedation, at the higher doses even complete ceptors. loss of the righting reflex. Lower, non-sedative doses of MED (I-5 ug/kg) had clear anxiolytic properties in several The four compounds bound in the rank order 8-OH-DPAT > rodent anxiety tests. In rats, a considerable increase in ipsapiro~e > buspirone > gepirone to hippocampal 5- punished dfinking was seen after MED. In mice, rearing be- HTiA-recepters. 8-OH-DPAT acted as a full agonist on haviour in the staircase test and an increase in the num- these receptors as measured by inhibition of forscolin- ber of transitions from lighted to dark chambers in the stimulated adenylate cyclase. The intrinsic activity of two compartment test, this latter effect blocked by ATI, buspirone, gepirone and ipsapirone was" considerably were indicative of anxiolytic activity. lower than that of 8-OH-DPAT. At higher concentrations Treatment Dose Transitions Activity ipsapirone, but only marginally buspirone could anta- (~g/kg) (no. per 10 min) (counts per 10 min) gonize the agonist-induced inhibition of enzyme activi- Salin~ (5) 19.6• 594• ty. 'Ipsapirone interacted with a higher affinity than MED (5) 2.5 36.4 • 1.2"* 711 • 29 buspirone, gepirone or 8-OH-DPAT with central al-and ATI (5) 50.0 28.6 • 2.6 712 • 12 ~2-adrenergic receptors. Functional in vitro studies MED + ATI (5) 2.5+50.0 20.1• 558• revealed ipsapirone to possess antagonistic or agonis- **=statistically different from control, P 33.03.06 33.03.07 &NTI-ANXIETY EFFECTS OF THE 5-HT~ RECEPTOR ANTAGONIST EFFECT OF BUSPIRONE AND ITS METABOLITE I- ~ 205-930 AND D!AZEPAM IN THE PLACE AVERSION PYRIMIDINYLPIPEP_&ZINE (I-PP) ON STRIATAL DOPAC IN VIV0 OTNDITIONING IN RATS. F. Crespi K. PanD. Buspirone is a novel antianxiety agent devoid of Evidence from experimental and clinical studies has anticonvulsant, sedative and muscle relaxant activities ~ointed to the rmle of central 5-HT, and 5-HT= receptors which are associated with the benzodiazepines. as target sites for new non-benzodiazepine compounds with Pharmacological and biochemical studies indicate that putative anti-anxiety properties. In the present paper buspirone modulates the activity of dopamine (DA) and the anti-anxiety effects of ICS 205-390, an antagonist of serotonin (5HT) neurones. While buspirone directly 5-ET3 receptors and diazepam (DIA), were studied in a affects the serotonergic system by interacting with the place aversion conditioning test. The obtained results 5HT I . subtype of the high affinity 5HT. receptor show that when one of two distinctive and previously (J. ~raser & T. Giaser, TIPS 8, ~32, I~87), some studies preferred compartment was associated with an inescapable suggest a minute of agonist and antagonist effect on DA fsmtshock (eightl-mA shocks, applied throughout a 20-min synapses (L. Eiblit et al, J.Clin.Psychiatry ~3, 11, session for 3 consecutive days), a conditioned aversion 1982). This complicated pharmacology on the DA system developed and control animals did not enter that may be partially attributable to the metabolism of compartment in the post-condltioning test. DIA (I.0 - 4.0 buspirone to I-PP which rapidly accumulates in brain ~/k~ i.p.), given 60 mln before the post-conditioning tissue after buspirone administration (S. Caccia et al, test, increased in a dmse-dependent manner the amount nf Xenobiotica I_~, 147, 1983) and, like buspirone, shows time spent by animals in the conditioned compartment activity %n certain animal conflict tests (D. Taylor, (F(3,20)=9.896; p 351 33.03.08 33.03.09 NEW EXPERIMENTAL ANXIETY MODEL: EFFECT OF BUSPIRONE ON A COMPARISON OF THE 5-HT RECEPTOR P~ELATED ANXIOLYTICS GASTRIC LESION INDUCED BY THE COM~UNICATIO~ BOX METHOD BUSPIRONE, GEPIRONE, IPS~IRONE, SM-3997, THEIR COMMON IN MICE METABOLITE I-PP AND DIAZEPAM IN ANIMAL MODELS OF ANXIETY C. Hara and N. Ogawa J. Traber T. Sehuurman and U. Benz The communication box (CB) method was introduced by Ogawa Four second generation anxiolytics, buspirone (B), ge- and Kuwahara (1966) to induce the experimental anxiety pirone (G), ipsapirone (I) and SM-3997 (S), which exert using the intraspecies emotional communication. The at least part of their anxiolytie effects via interaction animals (responder,"R") receiving the e/ro~ional cues with the 5-HT subclass of central 5-HT receptors, their A (EC) from the animals (sender,"S") exposed to electric common metab~ite I-PP and the reference benzodiazepine shock (ES) preceded by conditioned stimuli (CS) were anxiolytic diazepam (D) were compared in different animal leaded to the anxiety state. "R" was reported to have models of anxiety and in motor function tests. These con- gastric lesions (GL) in mice. However, only CS also flict and anxiety tests were the shock-suppressed drin- elicited GL. Therefore, the present study exa~ined whether king (SSD), Geller-Seifter conflict, conditioned emo- only EC from "S" without CS could elicit GL to "R", and tional response (CER). social interaction (SI) and ultra- did the possibility for the tool evaluating anxiolytics sonic vocalisation (USV) test, all with rats. The data using buspirone (BSP). show that D, B, G, I and S disinhibit punished behaviour Male ICR mice were used. The CB with the grld floor to in the SSD and Geller-Seifter test. Rank order of potency deliver ES, consists of 36 small compartments divided was D > G ~ I > B > S. In the CER test rats were trained by transparent plastic walls. Eight "R" were individually to press on a lever for food reward (FR I0). One day be- placed in the compartments shielded from ES. Sixteen "S" fore drug testing, delivery of each food pellet was com- were arranged in the compartments surrounding the "R" bined with footshock. This shock session was signalled by compartments. Influences of single and repeaned exposures a tone and a light. On the next day, tone and light were to EC on incidence of GL in "R" were examined. "R" were presented again, resulting in a reducion of lever press- fasted for 24 hr before the final experimental day. "S" ing. D and the serotonergie anxiolyties disir~ibited were daily renewed to intact animals in the repeated lever pressing. In the USV test ultrasonic vocalisation exposure. The experiment was startd at 7:00 PM. After of rats was elicited by footshocks. All test substances completing the ES period, the stomachs of "R" were decreased the amount of 22 l~Hz vocalisation. Furthermore, inspected GL visually. BSP was tested in the repeated D, B, G and I increased the duration of social inter- exposure to EC. 0.2, 1.0 and 5.0 mg/kg of BSP were actions between rats paired in a brightly illuminated administered i.p. to "R" once a day 15 min before the test arena, whereas S and I-PP were inactive. Interest- experiment. ingly, prosocial effects of I but not of D, B or G were "R" exposed to the 3 Day exposure to 3 hr EC exerted also observed under less stressful test conditions (low 100% incidence of GL. BSP 0.2 and 1.0 mg, but not 5.0 illumination of test arena). I-PP was active in a few of mg, significantly prevented GL. the ar~xiety models, potency being lower than that of the The results suggest that the CB method wlthout CS is parent compounds. Finally, it was demonstrated that D a valuable model to study psycho-social factor implicated affected motor function of mice more strongly than B, G, in peptic ulcer and to induce anxiety psycholog=cally. I and S. Ehime University School of Medicine, Dep~rtment of Neurobiology Department, Troponwerke, Neurather Ring I, Pharmacology, Shigenobu-cho, Onsen-gun, Ehire 791-02, 5000 K61n 80, FRG JAPAN. 33.03.10 33.03.11 THERAPEL~IC EFFICACY OF NEW ANTI-ANXIETY DRUG, BUSPIRONE CLINICAL PHASE II OPEN TRIALS OF BUSPIRONE IN HOKKAIDO ON NEL~OSIS. AREA, JAPAN M. Ni~hizono as a representative of 30 institutes. I. Onodera, F. Okada~ K. Itoh, Y. Asano and I. Oka The anxiolytic properties of a new nonbenzodiazepine anx- Clinical phase II open trials of a new nonbenzodiazepine iolytic "buspirone" with a unique Pharmacologic profile anxiolytic buspirone with a unique chemical structure were were assessed at 30 institutes in the Western Japan area. performed at 20 institutes in the Hokkaido area. The study population consisted of 136 adult neurotic The study population consisted of i01 adult neurotic pati- patients (Male:68, Female:68) with an age range of 16-66 ents (male: 36, female: 65) with an age range of 15-75 years. The drug was administered orally with 5 mg tablets years. The drug was administered orally with 5 mg tablets to a maximum dose of 25 mg t.i.d. The administration to a maximum dose of i0 mg t.i.d. The administration peri- period was ]-70 days with 22 days the mean period. od was 2-55 days with 23 days the mean period. Patients were evaluated at 0,1,2,3 and 4 weeks, according Patients were assessed at 0, I, 2, 3 and 4 weeks, accord- to the Psychoneurosis Rating Scale for Symptom (PNRS-S), ing to the Psychoneurosis Rating Scale for Symptom (PNRS), the Symptom Rating Scale for Neurosis (SRSN), Japan and Japan and the Hamilton Rating Scale for Anxiety (HAM). the Hamilton Rating Scale for Anxiety (HAM-A). The amelioration rate on final global improvement ratings The Amiiioration Rate on Final Global Improvement Ratings (AR) for the i01 patients is 65 %. By type of neurosis, (AR) for the 136 patients is 73.5%. By type of neurosis, the AR for anxiety neurosis (N=50) is 67 %, for depressive the AR for anxiety neurosis (N=54) is 74%, for depressive neurosis (N=I3) 84 %, hypoehondriasis (N=I8) 66 %, for neurosis (N=20) 65%, for phobic neurosis (N=19) 65%, for other neurases 43-100 %. By previous severity, the AR for obsessive-c6mpulsive neurosis (N=I0) 80%, for other neuro- moderate severity (N=55) 67 %, for severe severity (N=41) sis 76%. By previous severity, the AR for slight severity 66 %. By previous medication, the AR for fresh cases is is 62%, for moderate severity 73%, for severe severity 81%, 88 %, and for cases previously treated with henzodiazepine By previous treatment, the AR for fresh cases is 84%, and is 26 %..This phenomenon may be concerned in withdrawal for cases'previously treated with benzodiazepine or others s~ptoms from benzodiazepines. ~ne AR increases gradually is 66%. By dosage of final administration corse, the AR by administration period as follows: 50 % (-i week), 30 % with a 5 mg t.i.d.(N=79) is 73%, and for a i0 mg t.i.d. (2 weeks), 50 % (3 weeks), 82 % (4 weeks) and 92 % (over 4 (N=32),is 72%. On the alteration in H.~M-A and SRSN scores~ weeks). On the change in Ii4_M scores, the reduction of tot- the reducation of total scores in fresh cases was signifi- al scores in fresh cases was significantly better than cantly improved than cases previously medicated with benzo- cases previously treated with 5enzodiazepines. Adverse diazepines. Adverse reactions appeared in 3S% of the reactions appeared in 21% of the patients and included patients and included drowsiness (Ii%), iight-headedness drowsiness (7 %), dizziness (8 ~), nausea (5 %) and other (8%), nausea (8%) and other minor reactions. minor reactions. Abnormality of clinical laboratory find- Abnormality (GOT:23~45, GPT:53+71) of clinical laboratory ings with probable relativity to the drug was not shown. findings with relativity to the drug was shown in one of Our phase II open trials suggest that huspirone will have the patients. Our clinical open trials in patients with higher effectiveness for cases ~ith more than 4 weeks of neurosis have shown that buspirone may have equivalent administration period, with a lower incidence of adverse efficacy to benzodiazepines without causing euphoria, reactions, and for fresh cases ~ithout prior benzodiaze- functional impairment and alcohol interaction. pine treatment. Department of Psychiatry, Fukuoka University School of Sapporo Okamoto Hospital, Japan, 060 }~ed~clne. No.7-45-] Nanakuma Jonanku, Fukuoka City, Japan. 352 33.03.12 33.03.13 Ipsapirone in the treatment of generalized anxiety dis- Treatment of Anxiety Neurosis with Ipsapirone. orders. Results of a phase II US-multicenter trial. M.Beneke, B.Kfimmel, I.S.Roed, H.Spechtmeyer B. Kuemmel, M. Beneke, G. Krol*, G. Schoellnhammer, Ipsapirone, a pyrimidinylpiperazine derivative, H. Spechtmeyer exhibits strong anxiolytic properties (Brain Ipsapirone a specific 5-HT IA receptor agonist is a Res. Bull. 12,741-44) in animal models without substance in a new class of anxiolytics/antidepressants interacting with the GABA-receptor complex, and representing a possible new therapeutic principle for thus resulting in lack of side effects, i.e. se- anxiety and depression. dation, ataxia and muscle relaxation.- Neurobio- In a randomized, placebo-controlled, parallel-group logical findings confirm high affinity binding study the efficacy and safety of Ipsapirone was investi- sites at 5-HT receptors for ipsapirone, while I gated in a total number of 267 patients with moderate to developing predominantly serotonin agonistic severe generalized anxiety (DSM III: 30o.o2) in dose properties (Brain Res. 358,129-136).- In several ranges of 2,5 mg; 5,0 mg and 7,5 mg Ipsapirone t.i.d. randomized double-blind clinical trials conduct- over 28 days. The primary efficacy variables in these ed in the FRG the therapeutic efficacy of ipsa- studies were the Hamilton Anxiety Scale (HAM-A) and the pirone compared to placebo in anxiety neurosis Zun~ Anxiety Scale, the safety aspects were detected and neurotic depression (ICD-9:300.0, 300.4) through laboratory routine and listing of adverse re- treatment were assessed.- Patients - recruitment actions. The improvement in HAM-A scores was signifi- option: HAM-Ami n score = 20 - were treated with cantly greater in the 5.o mg Ipsapirone group than in a fixed dose per centre allowing dose titration the placebo group at all visits. The mean HAM-A score depending on the occurence of side-effects and wa% 24.2 at baseline. Improvements in scores of 5.8, the degree of therapeutic effect (2.5-10mg/tid). 8.2, 9.8 and 1o.9 were seen following each consecutive - Analysis based on pooled data of 124 male and week of treatment. In the 14-item Zung scale a greater female patients treated with either medication improvement relative to placebo was observed over the showed a significant superiority of ipsapirone treatment course with 5.0 mg Ipsapirone with a signi- with respect to clinical variables (STAI-Xl/X2, ficance at week 3. The laboratory data were within HAM-A,HAM-D) and global ratings (global improve- normal ranges and did not significantly differ from ment, safety, utility). When compared to placebo tho~e of the preexamination test. The most frequently ip~apirone developed a higher rate of adverse reported adverse experiences (% of patients) are: effects which is in accordance with phase-I headache (Ipsapirone 2o.3 %; Placebo 28 %); Nausea findings, and mainly characterized by dizziness, (Ipsapirone 16 %; Placebo io %); Dizziness (Ipsapirone dazed feelings, and 'soft' or unsafe feelings 45 %; Placebo 17 %); and Sedation (Ipsapirone 15 %; in the legs.- Global analysis indicates that ip- Placebo 6 %). with regard to the primary efficacy sapirone improves as well symptoms associated variables Ipsapirone proved to be an effectiv treatment with depressive states. It is judged to have of anxiety disorders. nearly equivalent safety when compared to pla- Medical Department, Troponwerke, Neurather Ring I, cebo and to be an extremely useful drug in the D-5ooo K61n 80, FRG treatment of anxiety. *Biochemical Department, 4o0 Morgan Lane, West-Haven, Medical Department, Troponwerke, Neurather Ring I, CT 06516, USA D-5000 K61n 80, FRG 33.03.14 33.03.15 TOIZRANCEANDPHARMACOKINETICS OF ZOLPIDEM IN,HE ELECTROPHYSIOLOGIC.~_ AND BEHAVIORAL ASPECTS OF ETHYL- HEALTHY VOLUNTEERSUSING ~-BLINDMANNER ESTHER OF BETA-CARBOLINE 3-CARBOXYLIC (OR BETA-CCE) ACID Y. Kudo, H. Suzuki, Y. Nakamura and T. Kudo IN RHESUS MONKEYS. A FIRST APPROACH. The tolerance and pharmaeokinetics of zolpidem, a new D. LAGARDE (I), C. MILHAUD (I), J. LAL-RF.ET (2), H.J. AUBIN imidazopyridine hypnotic, were investigated in healthy (1), L. GAYET (1) and D. DELVlLLE (1) male volunteers. The single and nmltiple dose studies Beta CCE is usually considered as having an affinity for were designed in a double-blind manner. benzodiazepine receptors and as an inverse agonist of ben- In the single dose study, the subjects were randc~ly zodiazepines. Administered alone it can induce convulsions allocated to each of two gr~aps; the ist group censisted or anxiety. The first approach made in our laboratory was of 8 subjects(6: receiving zolpide~ 2.5 and 7.Smg, 2: designed to observe the effects of the administration of placebo). Zolpidem was well tolerated in all the three increasing doses of Beta-CCE (0.5-1,0-2mg/kg in IV) subjects at all dose levels. A marked hypnotic activity on heart rate (HR), EEG signal and power density spectrum, was observed at the dose levels of 5-10r~ and there were and behavior of four male rhesus monkeys (mean b.w. 10kg). some changes in clinical signs, objective expressions Heart rate was studied by measuring R-R.intervals. The and psychological parameters, which were attributed to power density spectrum was obtained after automatic EEG the pharmacological activities of the compound. (FFT) processing from a left parieto-occipital lead. Beha- The plasma concentrations were dose-dependent and the vior was observed off-line, on a video tape, noting the peak concentration(Cmax) and the area under the plasma frequency and duration Of behavioral criteria. Administra- concentration curve (AUC) were linearly dose-related. tion of increasing doses of Beta-CCE induces EEG, ECG and The plasma concentrations declined with mean half-lives behavioral hhanges. High doses of Beta-CCE (1 and 2 mg/kg) (tl/2) of 1.8-2.3 hours. Excretion of unchanged zolpidem administered alone triggered a convulsive crisis in one in the urine accounted for less than 1% of each given subject. The spectral analysis evidenced increased power dose. on fast frequencies. The very high increase in HR and the In the multiple dose study, nine subjects were randcmly development of unusual, even abnormal behaviors seem to allocated to receive either 10n~ zolpidem(6 subjects) or reflect a neurovegetative effect, maybe even anxiety. It placebo(3 subjects) once a day for 7 consecutive days. can therefore be suggested that Beta-CCE is a molecule Zolpidem was well tolerated. A marked hypnotic activity which ~an induce convulsions and anxiety in Primates. was ~bserved during the dosing period with zolpid6~n. If sudh properties were confirmed, this molecule could be As well as in the single dose study, there were same used to create an anxiety model. changes in clinical signs such as equilibrium on standing one leg, facial expressions, and psychological parameters (l) Centre d'Etudes et de Recherches de M~decine A~rospa- (Flicker, Line-drawing and Fmller-lyer test) . tiale. Division de Neurophysiologie, 5 his, ave de la The plasma concentration profiles, Cmax, time to reach Porte de S~vres 75731 PARIS CEDEX 15 F~ECE. the peak concentration(Tmax), AUC and tl/2 on day 1 were (2) ROUSSEL UCLAF ROMALNVILLE 93230 F~;CE similar to those on day 7. less than 1% of the given dose was excreted unchanged in the urine on day i, 4 and 7. These findings indicated that zolpidem is well tolerated and is expected to be useful for patients with insc~a. Aino Institute of Clinical Pharmaeol~. 353 33.03.16 33.03.17 THE DISCRIMINATIVE STIMULUS PROPERTIES OF THE PHARMACOLOGICAL PROFILE OF ALPIDEM, A NOVEL ANXIOLYTIC B-CARBOLINE ZK 95 962: A NON-SEDATIVE BENZO- DRUG OF IMIDAZOPYRIDINE STRUCTURE DIAZEPINE-RECEPTOR LIGAND WITH ANXIOLYTIC-LIKE G. Perrault, E. Morel, D.J. Sanger, D. Joly, 8. Zivkovic PROPERTIES and K.G. Lloyd J. S. Andrews and D. N. Stephens Alpidem (6-chloro-(4-chloro-phenyl)2N-N di-n-propyl Benzodiazepines (BZ), although effective in the imidazo [ 1,2-a] pyridine acetamid~ binds the w sites treatment of anxiety possess many unwanted side of the GABA-A receptor complex as do benzodiazepines effects, in particular strong sedative and (BDZ). In contrast to BDZs alpidem is highly selective musc!e-relaxating properties. The 8-carboline for the m I site and has a very high affinity for the ZK 95 962 has been identified as a partial peripheral BDZ ( m 3) recognition site. In accordance agonist at the BZ receptor. ZK 95 962 genera- with this binding profile alpidem exerts anticonvulsant lises to chlordiazepoxide (CDP) in drug-discri- and anxiolytic activities but unlike BDZ it fails to mination procedures, has anticonflict and induce sedative and myorelaxant effects. Moreover, antiepiieptic properties, but is non-sedating. after repeated treatment less tolerance develops to The interoceptive properties of CDP and ZK 95 the anticonvulsant effects of alpidem than to those 962 were compared using a drug-discrimination of BDZ. In tests predictive of anxiolytic action, alpi- procedure. Rats were trained to discriminate dem shows a potency similar to that of chlordiazepoxide. either CDP (5 mg/kg) or ZK 95 962 (i0 mg/kg) In mice, it inhibits burying, a defensive behaviour, from veh&cle in a standard 2-1ever drug-dis- (MED = 3. mg/kg ip) and increases food intake in an crimination procedure (Stephens et al., Psy- unfamiliar environment (MED = I0 mg/kg pc). At these chopha_~macology 83, 233, 1984). Following dose~, alpidem does not interefere with the acquisition training, differences between the two cues were of conditioned fear, indicating a lack of memory impair- investigated using a series of BZ receptor ment. However, in rats, the general anxiolytic profile agonists and antagonists. CDP and ZK 95 962 differs'from that of BDZ. Alpidem exerts an anticonflict genera!ised to one another with similar poten- action in the punished drinking paradigm (MED = 30 cies. In general full BZ agonists behaved mg/k9 ip) but fails to produce a benzodiazepine-like simi!arily in each of the cues; one exception inte~oceptive stimulus. Moreover, alpidem appears more was the B-carboline ZK 93 423 which generalised efficient in tests requiring high degree of motivation. to CDP but neither generalised nor antagonised This could explain the large difference between the ZK 95 962. However, BZ antagonists and partial doses of alpidem inducing a decrease in spontaneous agonists behaved differently, e.g. RO 15-1788 locomotor activity and an impairment in rota-rod perfor- and ZK 93 426 antagonised the CDP cue but mance. These results indicate a good anxiolytic poten- generalised to the ZK 95 962 cue. Phenobarbital tial for alpidem with minimal central depressant acti- generalised to CDP, but not to ZK 95 962. The vity. results suggest that the removal of sedative effects of BZ ligands alters the discrimina- Laboratoires d'Etudes et de Recherches Synth@labo tive-stimulus properties. (L.E.R.S.), 23-25 ave Morane Saulnier, 92360 Meudon-la- For~t, France Department of Neuropsychopharmacology, Schering AG, D-!000 Berlin 65, F.R.G. 33.03.18 33.03.19 FTuNDLING HABITUATION MODIFIES ~ EFFECTS OF BENZODLg-~z~-- EFFECTIVITY OF CAVAIN IN TRANQUILIZER INDICATION PINES ON SHUTTLE AVOIDANCE ACQUISITION BUT NOT ON ~.~??.?I- A. Klimke, E. Klieser, E~_Lehmann r W.H. Strauss COSTERONE RESPONSE.* There is a problem in treating patients who A. Fernandez, R.M. Escorihuela, F. Boix and A. Tobeff=. suffer from anxiety and psycho-reactive dis- The acquisition of two-way shuttle avoidance orders with drugs like Benzodiazepines because (40 trials) was used to test the anxiolytic ac- of addiction and other undesired effects. There- tion of diazepam (2 and 4 mg/kg) and alprazelem fore Cavain, a drug derived from natural sub- (1.25 mg/kg) vs. vehicle in rats which had pre- stances, which did not produce such undesired viously received one of three different treat- side-effects, seems to be indicated in these ments: acute, acute with previous handling ha- patients. bituation for 15 days and chronic combined with At the university psychiatric hospital in handling habituation for 15 days. Both the pre- DUsseldorf a double blind placebo-controlled and post-test corticosterone levels were also study was conducted in order to record the measured. The acute treatment showed a compara- influence of Cavain on anxiety states and ble anxiolytic effect of diazepam and alprazc- psycho-reactive disorders. The therapeutic lam, reflected through an improvement in avoi- effectiveness was rated by the global appraisal dance acquisition. After handling habituation, of the doctor, the Hamilton-Anxiety-Scale no effect on shuttlebox was obtained in the (HAMA) and the Adjective Check List (EWL) on rats treated acutely. When handling habituation days 0, 14 and 28 of treatment. Side-effects was combined with chronic treatment, the drug's were also checked in a global rating on days anxioly~ic action persisted. The two acute tre- 14 and 28. atments provoqued an enhancement of the ccrzi- We found a statistically significant difference costerone basal levels, but a decrease was ob- in favour of Cavain in reducing ~he neurotic served after the chronic treatment, both in the symptoms. basal'and after the shuttlebox session. On the basis of MMPI and life history question- Those behavioral results are discussed in naire (LAZARUS) before treatment, responders relation to the emotional changes induced by and nonresponders are described in more details. the, procedure of handling, and they are tem;a- Department of Psychiatry, University of D~ssel- tively linked with possible changes in the doff, Bergische Landstr. 2, D-4000 DUsseldorf 12 functionality of GABA neurotransmission at the (F.R.G.) level of the GABA-BZ receptor complex, which has been associated with handling habituation in some studies. These results also showed a lack of relationship between the anxiolytic ac- tion of the benzodiazepine treatment and the plasmatic levels of corticcszerone. *Work supported by a CAICYT gr~nt n.1839/82 and Up~,o~ SA. Dept. of Pharmacology and Psychiatry. Medical Psychslc~ Unit. School of Medicine. Universitat Aut6noma de Barce- lona. 08193 Be!laterra. Spain. 354 33.03.20 33.03.21 EVALUATION OF ANXIOLYTIC EFFECTS OF KETAZOLAM SEDATIVE ACTION OF ALPROZOLAM AND DIAZEPAM AS MEASURED USING EEG FREQDT/qCY ANALYSIS BY EWL AND TWO DIFFERENT FLICKER FUSION METHODS C. Almenar, E. Estivill, C. Pinet, M. Casas, C. A. Frei, W. Mollenkopf~ H.J. Gaertner Udina, J. Conill, E. Alvarez. In a double-blind pharmacopsychological experiment ap- proved by the Tuebingen Ethics Commission, 20 healthy volunteers each (total, I00) received diazepam (10 mg or 5 Computerized e lec troenc ephalography (CEEG) has mg), alprazolam (I mg or 0.5 mg), or placebo. been used mainly in pre-clinical studies in Flicker fusion was determined at 30-minute intervals with order to determine the central brain properties two different devices (ZAK automatic flicker fusion tester, of new compounds such as the beginning and Metabo visual stimulator). At measurement, blood samples duration of their effects and their effective were taken for determination of plasma alprazolam and doses. diazepam levels, and the EWL-N was completed (JANKE and All psychotropics produce systematic and DEBUS 1978). Measurements were made before drug administ- significant changes in bioelectric brain ration and 9 times thereafter. Only female volunteers be- activity, which are detected by a CEEG; being tween the ages of 18 and 35 were entered in the trial. directly related to the pharmacological family Whereas the ZAK device measures critical flicker fusion and dose, and also being similar in other (CCF) (i.e, flicker frequency is increased until flicker is substances with a different chemical composition no longe~ percieved), the Metabo device measures percep- but with the same clinical effect (therapeutic tion threshold (i.e., constant light is added to a certain equivalent ). selectable flicker frequency until flicker is no longer We have" studied i0 patients with generalized perceived [de Lange curve]). We expected the Metabo device anxiety disorder who were treated, as out to be more sensitive for registeration of fatigue. patients, with ketazolam and, in general terms, Our findings show that dose-dependent sedation is demon- we aim to evaluate the following: strable by EWL; significant differences, however, were es- - The n~inimum effective dose. tablished for the tested drugs. Findings obtained by - Begiruning and duration of CNS action. flicker fusion methods corresponded well with those ob- - CEEG evaluation of hypnotic and aruxiolytic tained by EWL. The two methods, therefore, did not differ ef~[ects. as expected with respect to the information they provided, We " also tried to determine the possible since measurements with the Metabo device appears to be predictor role in clinical effectiveness after a more sensitive, but their scatter is broader. single oral dose of the drug. These devices for measuring the sedative action of benzo- The authors describe the methodology used in the diazepine do not depict dose differences any better than present study and suggest its use in clinical than the rating scales. psychopharmacology as a convenient and non- invasive technique. Department of Psychiatry (Director: Prof. Dr. H. Heimann), Servicio de Psiquiatria, Laboratorio de University of TObingen, Osianderstr. 22, 74 TSbingen Cronobiologia y Unidad de Toxicomanias. Programa Sant Pau-CITILAN. Univ. Aut6noma de Barcelona. Hospital de ia Santa Creu i Sant Pau. Avda. Sant Antoni M. Claret, 167. 08025. Barcelona. Spain. 33.03.22 33.03.23 EFFECTS OF ISAZOTANE (CGP 361 A) IN MONKEY GROUPS, EXPERIMENTAL INVESTIGATION OF ANXIOLYTIC EFFECT AND GROUPS OF HEALTHY VOLUNTEERS, AND IN PATIENTS WITH SPEECH BEHAu IN HEALTHY VOLUNTEERS ON BETA BLOCKER CHRONIC ANXIETY SYNDROME CGP 361A OR PLACEBO J. Jaekel, R. Kohnen, H. P. KrUger, A. Delini-Stula, I. BOscher and H.J. Gaertner K. D. Stoll The drug CGP 361A, a water-soluable hydrochloride, has a Isazotane, a phenoxypropanolamine derivative shows anti- phenoxypropanolamine structure typical os beta blockers. neophobic, anxiolytic as well as antiaggressive proper- Behavioral-pharmacologic experiments, e.g., on rhesus ties in classical animal models in relatively low dosages. monkeys, have shown that CGP 361A dosages, lower than In much higher dosages isazotane exerts ~-blocking that required for peripheral beta blocking action, change effects. general and social behavior. This finding suggests a cen- a) In rhesus monkey groups both alpha- and omega-animals trally mediated anxiolytic effect for CGP 361A. In his were integrated into group interactions (i.e.grooming) "Monkey Observation Test," JAEKEL (1986) observed an in- with isazotane more than usually, under placebo duction or intensification of positive social contacts at conditions, or with other psychotropic drugs. lower dosages. _ - b) A series of psychopharmacological group experiments In a field study with healthy volunteers, KOHNEN and with healthy students was able to detect positive KROGBR (1986) found that speech behavior of subjects who influences on social stress reactions, social inter- had classified themselves as "socially handicapped" actions and speech processes. Results of those studies differed markedly under CGP 361A as compared to placebo. with new experimental models are, as far as 90 heslth~ male volunteers participated in a placebo- comparable, in good parallel with the findings of the controlled double-blind study to test the effect os CGP monkey studies. 361A on anxiety and social behavior. Speech behavior on c) The first multicentric clinical trials, a placebo the Thematic Apperception Test was used to operationalize cont,rolled dos e finding study favouring a daily dose social Behavior. The tests were videotaped and later of 4 mg and a comparison of 2 and 4 mg/day with analyzed. Anxiety, mood, and personality characteristics diazepam (5 mg t.i.d.), were able to demonstrate the were rated by additional scale& The pulse rate served as anxiolytic effects of the drug by using repeated physiologic correlate. The data were evaluated by an ffatings with HAMA and SDS. analysis of variance. Results of animal studies, experiments with healthy volunteers, and clinical studies will be presented and Department of Psychiatry (Directo~ Prof. Dr. H. Heimann), discussed with focus on parallelisms, possible social University of TObingen, Osiander~tr. 22, 74 TObingen implications of anxiety, and consequences drawn for a now running placebo-controlled clinical trial in chronic anxiety syndrome: degree of social problems (family, friends, job) for stratifications as well as repeated ratings of social components of anxiety are used in addition to usual characterizations of patients resp. to classical anxiety scales (HAMA, SDS). CIBA-GEIGY AG, Neurobiochemie, CH 4002 Basel 355 33.03.24 33.03,25 PREVENTION OF "LEARNED HELPLESSNESS" IN THE RAT NEuRoPSYCHOLOGICAL STUDIES IN OBSESSIVE-COMPULSIVE BY HYDROXYZINE DISORDER F.N. Neziroglu, F.I. Penzel, J. Vasguez and C.E. Giurgea1, P. Martin2. A. Lend,re 3. S. Froma~e3 and R.D. P0rsolt3 J.A. Yar~ura-Tobias The effects of hydroxyzine (8, 16 and 32 mg/kg i.p.), administered either 30 The present study was made of 17 patients diagnosed as minutes before exposing rats to a series of inescapable shocks ("stress") or during having obsessive-compulsive disorder (DSM-III-R), using the subsequent aeqnlsidon of a shuttle box avoidance response, were investigated. the Halstead-Reitan Neuropsychological Test Battery and In these conditions untreated rats, previously exposed to stress, show a marked encephalography (EEG). Nine of the 17 were on psycho- increase in escape failures in the shuttle box when compared with non-shocked tropic medications at the time of testing. Routine blood control animals (qearned helplessness'). Control experiments examined the effe.cls chemistries, liver and thyroid profiles were normal. of hydroxyzine on memory (p~ssive avoidance test) and on electric shock Complete physical examinations were within normal limits. sensitivity. Diazepam (2 mg/kg i.p.) was used as a reference compound. Of 15available EEG's, two evidenced non-specific abnormal. ities, and two seizure disorders. Analysis of group data Hydroxyzine, when administered before "stress', dearly decreased at 32 mg/kg indicated more than half were at or below the borderline the number of escape failures observed but was without effect when administered range for consistency of organic impairment on the after "stress" during the subsequent shuttle box avoidance learning. Similar results Halstead Impairment Index. Twelve of the patients showed were observed with dlazepam. Unlike diazepam, hydroxyzine at 32 mg/kg induced impaired performance on one aspect of the Tactual no amnesia in the passive avoidance test whereas dear amnesia was observed with Performance Test (TPT), eight on another, and 15 on a diazepam. Neither compound altered the rats' sensitivityto shock. third, which is suggestiveof tactual-spatial impairment. Eight patients performed within the brain-damaged range These results suggest that hydroxyzine decreases the effects of "stress" and that on the Category Test, possibly indicative of logical- these effects cannot be attributed either to impaired memory for the aversive analytical reasoning deficits. Deficits were also stimulatiofi or to diminished shock sensitivity. detected on the Finger Oscillation Test in 12 patients, which might be indicative of motor impairment. Addition- ally, longer than expected performance times were seen in 1 : Dept. Psychopharm, Univ. Cathol. Louvain, 1348 Louvainla Neuve - Belgium ii patients on the Tactile Form Recognition Test, 2 : Fad. Med. Pifi~-Salprtri~re, 91 Bd de l'H6pital, 75013 Paris - France suggestive of tactile sensory deficits. A comparison of 3 : I.T.E.M.-Labo, 93 Avenue de Fontainebleau, 94270 Kremlin-BicEtre - France impaired versus non-impaired scores showed no significant relationship to either the presence or absence of medica- tions. As a group, these scores point to a concentration of deficits in the anterior regions of the brain - the frontal and parietal lobes, and the inferior motor strip between them. Further, these findings would seem to replicate the results of two previous studies, which reported frontal lobe dysfunction in one case, and spatial perception deficits as measured by the TPT in another. Bio Behavioral Psychiatry 935 Northern Boulevard Great Neck, New York 11021 33.03.26 33.03.27 BLOOD ;f.iE~ PROFILE IN OBSESSIVE C~ULSIVE DISORDER DRUG RESPONSE AND BIOLOGICAL VARIABLES IN OBSESSIVE J.A. Yaryura-Tobias, W. Essrein, F. Neziroglu and COMPULSIVE NEUROSIS B. Lindeel. J. Ananth, A. Djendredjian, R. Polland, A. Kaur, J. Based cn the serotonergic theory of Obsessive Co~oulsive Garb~r and R. Gamal Disorder (OCD) a blood amine profile, Serotonin, (5-HT), 45 patients diagnosed as having OCD on DSM III 5-Hydroxyindolacetic acid (5-HIAA), Dopamine (DA) , criteria for over two years were treated with Epine/nrine (E~I), and Norepinephrine (NE) ,was studied Clomipramine in a dosage of I00 to 300 mg daily. The in 102 ounpatients. Patients were classified according patients who had schizoid personality, head injury, to the D~r III-R, as OCD (N=-56), Generalized Anxiety drug history and seizures, were excluded from the Disorder (GAD), (N=I9), and [~jor Affective Disorder study. The patients were assessed periodically by a (:&AD) ('.~=27). All patients were drug free for at least structured clinical interview on the basis of which 2 weeks. A control group (N=48) without mental illness family history, Yale Brown Scale for OCD and Clinical was used for cc~parison. Multiple t-tests, and a Global Impression Scale were completed. Initially, BEHRE{-FISI~ZR test with Welch degrees of freedom were Neuropsychological Test Battery, MMPI, and Brain computed. Overall results indicated lower neurotrans- Electrical Area Mapping (BEAM) were conducted once, mitter levels in OCD. The OCD as compared to the GAD while laboratory tests, electrocardiogram and biochemical tests were conducted periodically for one group_ had significantly lower 5H-T levels (pf0.05). year after the initiation of the study. Response to Sis differences in inter and intracorrelations Clomipramine was assessed by Group vs period ANOVA were primarily observed in the OCD group. Also 16% of 0CD patie_nts had 5-HT levels that fell bel~ t/~e 95% technique. Neuropsychological Test Battery results inter~Ll of the control group, 11% in the [~AD, and did not differentiate the drug treated group from the unmedicated group. Initial severity score correlated 5% in the GAD. This study indicates that 5-HT may not be the only biological marker for OCD, but one indicator with the'final response. Patients Self Ratings for a subset. Finally the presence of strong inter- correlated with the Yale Brown Scale Scores. There correlations arsDng its neurotransmitters suggests a more were two groups of patients with and without family cc~plex biochemical disorder to exq31ain OCD history of OCD. Responseto Clomipramine was significantly correlated with T-I values for right physi +opatholoqy. frontal white matter. Prolactin increase also Bio Behavioral Psychiatry correlated with positive response. As a group, OCD 935 Northern Boulevard patients BEAM revealed higher alpha index in the Great f$eck, New York 11021 frontal lobe. Side effects did not predict response except that those who initially had severe agitation could not be continued on the study. Detailed analysis of these various biological variables and their significance in the prediction of Clomipramine response in the treatment of obsessive disorders will be discussed. Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, California 90509 USA. 356 33.03.28 33.03.29 CLINICAL EXPERIENCE AND EXPERIMENTAL RESULTS WITH CCIrPARIS0~ OF THEP_~PEUTICAL EFFECT OF TOFLAZE-- LORMETAZEPAM IN A NEW SUBLINGUAL WAFER FORff,ULATION PATE CGNT~ARY TO BROEAZEPAM Bischoff,R.C., Ott, H., Rohloff, A. V e n z o v s k y E.,S o u k u p o v a E. Research Laboratories of Schering AG Berlin/Bergkamen, FRG Authors present the results of treatment of 60 patients with loflazepate.The patients were di Lormetazepam is a benzodiazepine derivative with an effect- vided into two groupe of 30 subjects,one group ive duration of approximately 6-8 hours and a terminal was treated with lof!azepate and the othergro- half-life of I0 hours. In the tablet fonT. it has been on up with bromazepam. The therapeutic results we the market for 6 years. The lormetazepam wafer is a new re evaluated by Hamilton scale of depression. formulation which consists of a small cellulose "stamp" From the diagnostic point of view the patients into which the benzodiazepine has been e=~edded. Lormet- were diagnosed as neurotic and anxious states, azepam, which is absolutely tasteless, is released when fcbic disorders, masked depressions and sexu- the wafer is placed in the cheek or under the tongue. al insufficiencies. The therapeutic results The main advantage of this form of application is that the were with both groups very good. But with the wafer leads to a faster r~se in plasma levels compared to group of patients, %rested by loflazepate was the tablet administration .Secondly this application route therapeutic effect better / 84 % of improved is advantageous for the many people who have difficulty sub~Jects / than with the group ,treated by bro swallowing pills. Thirdly the gastrointestinal tract is mezepam / 77 % of improved sub~ects /. The the not involved, an advantage in various medical conditions raoeutic effect of loflazepate was particular- including the use of benzodiazepines as pr~edications ly excellent with masked depressions and from before surgery or for diagnostic procedures. this point of view loflazepate represents a Various experimental and clinical studies will be des- v~iu~ble additiens~or their therapy for its cribed, qhe results of experimental studies involving EEG clear antidepressive / non psychotic / fea- and a psychometric test battery showed that the sublingual t-~res.-Loflazepate is produced under the na- route of application is preferable to the buccal route me V i c t a n / Clin - ~{idy, Paris / and from the pharmacodynamic point of view. bromszepam as L e x o t a n i 1 / Hoffmann - The use of the wafer in sleep disturbance (n=60) as a Le Roche, Basel /. sedative for diagnostic procedures (n=49) and as a pre- Psychiatric University C!inic,Sverdlovska 80, medication before surgery (n=40) have all indicated a very 323 18 Pilsen, Czechoslovakia. high rate of acceptance by the patient (75-80% of patients preferred the wafer to traditional tablets). IT~uber U., et al., Plasma levels of lor~etazepam after sublingual and oral administration of I mg zo humans. Drug Development and Industrial Pharmacy 10 (10) 1587-1596 (1984). 33.03.30 33.03.31 1S IT POSSIBLE YO~A~JR~.&NTICIPATORY AXIETY IN ANI~ALS? LEVOPROTILINE - TREATMENT OF ANXIETY STATES F. Borsini, A. Lecci and A. Meli G.-E. KUhne, U. Binz, G. Wendt During exnerL~ents aimed at determining the effect of Levoprotiline is the R-(-)-enantiomer of the racemate drugs on rectal temperature in mice, it was casually obser oxaprotiline, the hydroxylated derivative of the anti- depressant maprotiline. red that, among animals of the same cage, those removed The pharmacological profiles of the three drugs are later had a higher tenmerature as compared to those remo- comparable, but in contrast to maprotiline and oxaproti- ved earlier. It was noted that this ~henomenon a) could be line, levoprotiline is completely devoid of NE-reuptake observed by reversin~ the order of removal of the animals inhibition. from., the cage; b) persisted, at least, over 5 days; c) was A series of double-blind clinical studies vs. standard present regardless the number of the animals in each cage antidepressants revealed both antidepressant and anxiolytic efficacy as well as superior tolerability of and d) was independent td~ether the animal which has been levoprotiline. taken was transferred to a different cage or again alloca- A new study was aimed at the anxiolytic effects of ted in the same cage. levoprotiline in patients with anxiety states (i.e. These findings, together ~dth the observation that the mice generalized anxiety syndrome, social phobia sensu remoVed earlier~.hec~me h}~erthermic~ ~ken a~ain immetliat~ DSM III). A broad spectrum of scales was used to find ly after the removal of the last one, could be interpreted out the possible anxiolytic profile of the drug: self as indicati~,e of a state of anticipatory, anxiety. This ratings with Erlanger Anxiety Scale (EAS-S), an Interaction-Anxiety-Test (IAF), and the KUSTA, and the could be also substantiated by the fact that this rise in physician's rating scales HAMA, HN4D, ASI and CGI. rectal temnerature was prevented by diaze~ administered Additionally, sleep quality was repeatedly rated with either orally (2.5 and 5 mg/kg, 30 min) or intracerebro- a newly developed short scale. First analyses of the ventricufarly (O.IO and O.17 mg/kg, IO min), but not by data gave clear evidence of sleep improving properties imipramine (15 and 30 mg/kg, po, 60 min) or haloperidol and anxiolytic effects in both somatic and psychic (0.5 and 1 mg/kg, po, 60 min). symptoms as well as in social aspects. Detailed results will be presented and discussed. Presunfably, this rise in rectal temoerature is not attrib- utable to the physical exercise due to an attempt to es- Klinik fSr Psychiatrie und Neurologie "Hans Berger" Bereich Medizin, Friedrich-Schiller-Universit~t Jena cape, since a) there is no correlation between motor acti- Philosophenweg 3, DDR 6900 Jena vity (open-field) and rise in rectal temnerature and b) rise in rectal temnerature was also observed in mice seda- ted by haloperidol. This model could renresent a new tool for studying the neurobiolo~" of anticinatory anxiety. '~. Menarini" s.a.s. Pharmaceuticals, Research Division, Via Sette Santi 3, 50131 Firenze, Italy. 357 33.03.32 33.03.33 EFFECTS OF A NEW BENZODIAZEPINE DERIVATIVE, ETHYL MIDAZOLAM, TRIAZOLAM AND TEMAZEPAM RESIDU- LOFLAZEPATE (CM6912), ON THE AROUSAL LEVEL OF NORMAL AL EFFECTS UPON VISUAL SEARCH BEHAVIOR AT HUMANS: ASSESSMENT BY THE AVERAGED PHOTOPALPEBRAL REFLEX INTERSECTIONS DURING AN URBAN DRIVING TEST H. Isozaki*, M. Tanaka*: Y. Mizuki*** and K. Inanaga**** Ih Quasten, w.J. Riedel, C. Hausen and J.F. O'Hanlon The averaged photopalpebral reflex (PPR) is a reocord of Benzodiazepine hypnotics can have residual sedative the mean of summated reflexive contractions of orbicularis effects on driving performance that last throughout the oculi muscle in response to periodically applied photic day following nocturnal ingestion. Studies until now stimuli. The peak latencies of PPR have been reported to have concentrated upon the occurrence of such effects be sensitively shortened and prolonged according to in one particular driving environment; i.e. during elevation and lowering of the arousal level of the prolonged, uninterrupted high-speed operation on subjects, respectively (M. Tanaka et al., Folia Psychiat. highways. The question remains whether driving would Neurol. Jpn., 3__77, 67, 1983). In the present study, we be equally impaired during low-speed operation in busy investigated the effects of a new benzodiazepine urban traffic. The present study was designed to answer derivative, ethyl loflazepate (CM6912), on the arousal this question. level of normal male humans by use of PPR for assessing Sixteen shiftworkers were treated subchronically (5 the arousal level of the subjects and predicted the days) ~dth hypnotic drugs and placebo according to a 4- possibility of the drug as a hypnotic and/or anxiolytic. way, double-blind design. The doses were midazolam 15 The ten university student volunteers, ages from 20 to 24 mE, trlazolam 0.5 mg and temazepam 20 mE, d.d., p.o. years were subjected to the study. Four doses of ethyl After the Ist and 5th successive doses the subjects loflazepate, i.e., 2 mg, 4 mg, 6 mg and 8 mg, and a slept during the day within sleep-lab facilities and were plcebo were administered to each subject 30 min after awakened for testing which began six hours after tablet lunch according to a double-blind, crossover design. ingestion. The driving test consisted of operating a Ethyl loflazepate significantly prolonged both latencies specially instrumented vehicle under an experimenter's of PPR with a dose-dependent manner. The dose-response supervision around a 9.3 km urban circuit. Subjects' eye curve for both latencies, derived from the maximum movements and fixations were measured using a NAC-4 prolongation, showed a definite and linear dose-response eye mark camera and video recording system. The relationship. The drug action occurred within I hour, analysis of these data was confined to locations along peakdd at 2.5-3 hour and continued slightly even 4 hour the route where traffic conflicts were likely to occur; after medication. In the subjective assessments, i.e. at intersections. Failures to seek visual information vagueness of thought, sleepiness, and weakness were only indicating the potential presence of approaching vehicles slightly observed. These results suggest that ethyl were the prime performance measures. In addition, the loflazepate could be a potent hypnotic and/or anxiolytic safety of the subject' driving performance was rated by which possesses a relatively rapid onset of action with an expert using a standard check-list. moderate duration and has no severe side effects. Results ~dll be presented at the conference. *Clinical Laboratory, ** Department of Pharmacology and Institute for Drugs, Safety and Behavior, University of ****Department of Neuropsychiatry, Kurume University Limburg, P.O. Box 616, 6200 MD Maastricht, The School of Medicine, and ***Department of Neuropsychiatry, Netherlands Yamaguchi University School of Medicine, Ube 755, Japan. 33.03.34 33.03.35 ASSESSMENT OF THE ANTIAGGRESSIVE EFFECTS OF LONG TERM COMPATIBILITY OF LOW DOSE TREATMENT A PUTATIVE ANXIOLYTIC, CGP 361A, VERSUS THOSE WITH FLUSPIRILEN (FLU) IN OUTPATIENTS - PRELI- OF DIAZEPAM AND PLACEBO IN HUMANS USING A MINARY RESULTS NOVEL EXPERIMENTAL APPROACH M.Osterheider and G.Reifschneider C. van Leeuwen, W. Riedel, H. Hamers and J.F.O'Hanlon There is a change in the drug management of pa- A recently developed propranolol derivative, CGP 361A, tients with psychosomatic and phobic disorders was found to have both conventional antianxiety effects among general practitioners and psychiatrists. and unusual antiaggressive effects in studies employing Drug dependency under Benzodiazepine (B) treat- animal models of emotional behavior. It seemed ment has become a severe problem. Alternative important to confirm the latter in humans but methods prescription of low dose neuroleptics (NL) be- for reliably eliciting aggressive feelings and objectively comes more favored. Main topics are focused on measuring the same appeared to be lacking. side effects of NL-especially on extrapyramidal The first purpose of this pilot study was to develop a symptom (EPS); specific abnormal involuntary method and then apply it in a comparative study of CGP movement (AIM). There is a lack of information 361A's, diazepam's and placebo's effects upon controlled about severity and frequency of neurological aggression. Parallel groups comprised of 12 or 13 young impairment in this group of patients. males who expressed positive interest in violent Outpatients with minimum three years under contact sports were studied during separate 1-hour continous or interval treatment with FLU onl~ presentations of a control video film and one showing a are compared with patients under B without any particularly violent boxing match. Respective groups NL treatment in their history. Diagnostic crite- were treated with oral doses of CGP 361A 2 rag, ria include DSM III 300, 307, 309, 316 and ICD diazepam 10 mg and placebo 1 hour before the latter 300, 306, 309 categories. Standardized diagno- presentation. Various physiological, subjective and stic i~ formed by using rating scales of SIMPSON psychomotor parameters were measured before, during (EPS), AIMS (NIMH), Akathisie schedule (TEGELER) and after both presentations. Most revealing were UKU and WEBSTER-scale. Psychopathometric evalua- catecholamine excretion rates determined for urine tion includes FPI, CGI, HAMA, STAI and SDS. The sam!~les collected over presentation periods. rate'of AIM and EPS under FLU shows only a mild Diazepam blocked both the pronounced subjective tendency to rise compared with spontaneus oc- effects of watching the violent presentation and the curence, 300% + (p<.001) rise in adrenahne excretion which The diagnostic tools have to be improved for occurred comparably in the two other groups. Simple a correct evaluation of these side effects. sedation could not have been responsible for the diazepam effect since the drug had little influence on Psychiatrische Universit~tsklinik WOrzburg psychomotor performance. The test seems sensitive to FOchsleinstra6e 15, D-8700 WOrzburg the effects of anxiolytics on induced emotional states in man. Institute for Drugs, Safety and Behavior, University of Limburg, P.O. Box 616, 6200 MD Maastricht, The Netherlands 358 33.03.36 33.03.37 In the course of open medication trials with social HYPNOTIC AND ANTIANXIETY EFFECTS OF ZOPICLONE VS phobics, we observed two types of socially anxious NITRAZEPAM patients. The first had discrete fears of one to V. Manna, N. Martucci and A. Agnoli several situations, such as speaking, writing, or The effects of zopicIone (7,5 mg per os at bedtime), a eating in public. These patients usually had normal new non-benzodiazepine drug, on anxiety levels, time of interpersonal relationships. In contrast, a second sleep induction, hours of sleep, number of nocturnal group had pervasive avoidance of or severe anxiety arousals, quality of sleep and quality of daytime during most or all activities involving social arousal were evaluated by using psychometric ratings. A interaction. These generalized social phobics led random double-blind cross-over study versus nitrazepam severely restricted or nonexistant romantic and social (5,0 mg per os at bedtime) was performed on 20 patients i ives. (8 M and 12 F, mean age 38,2 +.2,1 yrs) affected by Patients with DSM III social phobia entering a insomnia and Generalized Anxiety Disorders (DSM III). double blind controlled trial of phenelzine, atenolol The treatments lasting 2 weeks were intervalled with a and placebo were prospectively classified as having week of placebo administration. The effects were the generalized or discrete subtype. To d~te 56 evaluated by using HRSA, a time-signed semiquantitative patients have completed the acute 8 week treatment scale for anxiety and the Tolouse-Pieron Attention Test. trial. At week 8 five of the 20 (25%) patients on Time of sleep induction (p/-,O,OOl), quality of daytime placebo, 5 of 18 (28%) on atenolol, and 13 of 18 (72%) arousal (p~O,Ol), HRSA scores (p~,.O,OS), daytime on phenelzine were considered responders; these rates anxiety levels (p~O,OOl) and Tolouse-Pieron Attention of response differ significantly (p =.02). Phenelzine Test results significantly improved after zopiclone than was significantly more effective than placebo (p = after nitrazepam administration. .Ol) and atenolo! (p = .02), which did not differ. The results of the trial confirm the effectiveness of Response rates among the 41 generalized social zopiclone in the treatment of insomnia with effects phobics were 79% (11/14) for phenelzine, 15% (2/15) similar to nitrazepam on quality and duration of sleep for atenolol, and 21% (3/14) for placebo (p < .001). and number of nocturnal arousals, but superior in all the other parameters. Phenelzine was significantly more effective than both atenolol (p = .001) and placebo (p = .003), which did I.N.I. - 00046 Grottaferrata - Roma - Italy not differ. Among the 15 discrete social phobics, 1 out of 4 (25%) of patients on phenelzine, 3 out of 5 (60%) on atenolol, and 2 out of 6 (33%) on placebo were judged responders (N.S.). Phenelzine is showing a trend toward being more effective (p = .08) in generalized than discrete, and atenolol more effective (p = .i0) in discrete than generalized, social phobia. ABS880001 33.04.01 RANDOMIZED PLACEBO-CONTROLLED DOUBLE-BLIND 5- PERIOD CROSSOVER STUDY ON ANALGESIC PROPERTIES OF THREE ACUTE ORAL DOSES OF CM 40907 AND ASA - EMPLOYING CO2-LASER FOR NOCISTIMULATION POSTER W. Klausnitzer*, K. Schaffler* A randomized, double-blind crossover study was run with three PRESENTATION acute oral dosages (600, 900 and 1200 mg) of CM 40907 - a newly developed anticonvulsant drug, which chemically is a 6- 33.04 (2'chlorophenyl)-3-(4'hydroxypiperidino)-pyridazine - vs ASA (1000 rag) and placebo in 12 male healthy volunteers to compare analgesic potencies. CO2-1aser radiant heat emission, which - with high selectivity - stimulates nociceptive A-delta and C-fibers, was employed for no- cistimulation. Objective algesimetry was done by means of CO s- laser somatosensory evoked potentials (LSEP). Effects on vigilance Pain and were screened by auditory evoked potentials (AEP). There was a simultaneous control of vigilance alterations with regard to both Psychopharmacology types of evoked potentials by means of an adaptive pursuit tracking task (APTT). Subjective pain intensities were measured by post- LSEP pain ratings. Subjective sedation, excitation and anxiety were screened- by visual analog scales. Blood pressure, heart rate (supine and upright) and tolerance ratings were recorded in addition. All dosages of CM 40907 showed an analgesic effect in the laser model, with. significant reductions of P2-LSEP-amplitudes. With regard to this component the effect of 1200 mg CM 40907 was mo- re marked than that of ASA, which was also effective in the NI- component. Like ASA CM 40907 reduced pain as measured by sub- jective rhtings. Subjective sedation was decreased, however AEP- findings cued a decrease of vigilance after CM 40907. Excitation and anxiety were not significantly altered after CM 40907. Blood pressure and heart rate were not significantly raised after CM 40907, which was in general well tolerated. The onset of action was somewhat slower after CM 40907, when compared with ASA. There were cues that CM 40907 (1200 rag) is active till hour 6 after dosing with a peak effect within hour 1 and 2. With regard to the majority of measures CM 40907 showed a li- near dose-efficacy. * Institute for Pharmacodynamic Research, Chamm~nsterstr. 4a, D- 8000 Munich 82, FRG 359 33 04 02 33.04.03 WHAT IS CHRONIC ADMINISTRATION OF ANTIDEPRESSANTS IN ANTINOCICEPTIVE EFFECT OF THE TRIAZOLOBENZODIAZEPINE ANIMALS ? ILLUSTRATED BY THE STUDY OF THE ANALGESIC ALPRAZOLAM ON EXPERIMENTAL PAIN. ANTAGONISM BY R0-15.1788 BUT NOT BY NALOXONE. EFFECT OF CLOMIP~MINE IN MICE. J.A.Mico, M.C.G6mezTCama , J.Casas, I.Leonsegui, A. Eschalier, J. Fialip, 0. Varoquaux, M.C.Makambila, R.Maldonado, R. Fernandez and J.Glbert-Rahola. H. Marty, P. Bastide. The benzediazepines (BZP) in general have shown mixed The pattern of repeated administration of antidepressants results with respect to their ability To increase noci- ceptive thresholds. Although some studies report no in animals varies from one study to another making compa- effect,others have reported mild antinociceptive effects rison of results difficult. The aim of the present work in man and in animals. Moreover, the mechanism of this is to propose standardized pattern of administration effect is not clear. The aim of this study was to investigate the influence based on animal pharmacokinetic parameters, to be close to of alprazolam (ALPZ) on experimental pain and to attempt clinical use. Therefore, chronic administration should elucidation of the mechanisms of action. correspond to injections repeated every plasma elimination The experiments were carried out on OF1 mice lhot plate test and acetic acid test) and Wistar rats (tail flick half-life i.e. 130 min for clomipramine (CMI) in the Swiss test). The doses of ALPZ used were: in the acetic acid CD] mice used, though daily administration, so often used test, 0.007/ 0.015/ 0.031/ 0.062/ 0.125/ 0.25/ 0.5 and in-rodents, is merely repeated acute administration.The ] mg/kg i.p. In the hot plate test and tail flick test, 0.5/ 1/ 2 y 4 mg/kg i.p.In another experience the effect antinociceptive action of CMI(10 or 20 mg/kg,i.p.) varied of chronic ALPZ (0.5 mg/kg, tree days} on the acute according to the pattern of administration used : the effect of morphine (0.25 mg/kg s.c) was investigated. effect obtained after an acute injection was increased Finally, t]se mediation of opioid and BZD-receptors was evaluated. The results were analyzed with the Kxllskall- twofold after 5 chronic injections ; closely-repeated Wallis tes~ (H} and Mann-Whitney U test. injections (every 40 min) gave a more marked effect than ALPZ alone in the doses used did not affect significan- chHonic administration, and daily administration (for 3-8 tly The nociceptive responses of mice in the hot plate test (H=3.322) and rats in the taJ] f) ick test at any or 16 days) was ineffective. The antinociceptive activity time(30 rain. H=6.063t 60rain. H=1,8501 90 rain. H=5.334; was correlated with blood and brain levels of CMI and of 120 min. H=3.605l. These two tests are freqQently used its demethylatedmetabolite, independant of any modifica- to dete6t potent narcotic analgesics. Similarly, in the hot plate test, chronic ALPZ treatment did not affected tion of motor activity (especially after 5 chronic injec- significantly the effect of morphine given acutely tions), and was suppressed by naloxone. These results (H=4.500). However, in the acetic acid test, ALPZ elici- emphasize the importance of the pattern of administration ted ~ntinociceptive properties at very small doses (0.031 mg/kg, U=41.5 p~=.05) with a good dose-effect and' of pharmacokinetic data, often overlooked, for pharma- correlation {y=3.58+4.99b, r=0.665 p~=.O5}. The specific codynamic studies in animals which therefore will better BZD-antagonist Ro-15.1788 inhibited in a dose-dependent predict effects in humans. manner the antinociceptive effect of ALPZ (20 mg/kg U=28.5 n.s; 40 mg/kg U=9.5 p~=.01l.The opiate antagonist naloxone (0.5 and I mg/kg} was completely i,effective. Laboratoire de PharmacologieM~dicale, INSERM U195, In conclussion, this study has revealed that ALPZ like Facult~ de M~decine, 63001Clermont-Ferrand C6dex. France. other clasic BZD induces antinociceptive test-dependent properties and that this effect could be mediated by BZD-recept ors. Department of Neuroscience. Faculty of Medicine. Plaza de Falla, 11003, Cadiz (SPAIN}. 33 04 04 33.04.05 EFFECT OF MU OPIOIDS ON SYNAPTIC MEMBRANE DEVELOPMENT OF CONTROLLED RELEASE DRUG (Na§ ACTIVITY FROM RAT CEREBRAL CORTEX DELIVERY SYSTEMS CONTAINING DIAZEPAM IN THE PRESENCE OF SEVERAL DIVALENT CATIONS. T. Nishikawa, T. Teramoto and S__~.Shimizu S.C.Chaicta~aj, S.K.Da~, S.K.Gho6~ and B.K.Gupiza It has been reported that opioids inhibit the enhanced release of several neurotransmitters in The most prominent CNS effects of diazepam are sedation, the central nervous system. However, the hypnosi% anxiolytic, muscle relaxation and anticonvulsant biochemical mechanism of their inhibitory action activity. The distributive (alpha) half-life of diazepam has not been elucidated so far. In the present is about 2.5 hours which requires frequent administration experiments, effects of opioids were studied on of the drug in anxiety neurosi% psychosomatic disorders, the synaptic membrane (Na++K+)-ATPase activity muscu]o-skeletal spasm in order to maintain the effective from rat cerebral cortex in the presence of therapeutic concentration of the drug in blood. The aim biolo~ically impoltant divalent metal ions such of this study was to develop drug delivery systems capable L+ Z+ Z+ ~+ as Ca , Fe , Cu = and Zn . Mu opioid agonist~, of maintaining the plasma level of diazepam for a prolonged morphine (I0-=-I0 -u M) and dynorphin A 3-8 (10 -~, period thus increasing the therapeutic potential of the 10- M) but not k~ppa ags dynorphin-(1-8)- drug with much lesser side effects. octapeptide (10 -=, 10 -~ M), stimulated the suppressed sy~aptic membrane (Na~+K+)-ATPa~e Drug delivery systems were fabricated adopting the principles activity by ~e (10- -10- M) or Fe plus Zn of microencapsu|ation, pelletization and gastric retention (10 -~, 10 -v M _) in the iDcubation ~edium systems. Physicochemical characterisation of the dosage containing I0-b-2.2 x 10 -! M free Ca z+. MU forys were carried out to have reproduceable delivery opioids, however, failed to stimulate the syst-ems. In ~/tro drug release profile was studied using (Na++K+)-ATPase activity in the absence of Fez the USP methods. In vivo bioavailability of the drug delivery and sc%rcely ~ffec~ed the suppressed enzyme systems were assessed in experimental animals. activity by Cu z+, Zn z+ and Fe2+ plus Cu 2+. The Satisfactory drug level was maintained in the blood for stimulatory effect of mu opioids was antaggnize ~ 24 hours with single administration. Prolongation of sedation by specific opioid antagonist naloxone (10-=-I0 TM time was also observed. M). 'The concentrations of the synaptic ~embrane bound Fe, C~ and Zn were 3.2 + 0.4 ~ 10 -~, 3.9 + Such drug delivery systems for diazepam would be highly 0.4 x 10-" and 7.0 ~ 0.6 x I 0-" mol eq. /g efficacious in maintaining the optimum CNS activity. membrane protein, respectively. The dosage forms also serves the requirements of patients These results indicate that mu opioid corn pliance. agonists may stimulate the suppressed ~(Na++K+) - ATPase activity by interacting with Fe z+ at its Division of Pharmaceutics, Department of Pharmacy, 3adavpur University, Calcutta - 700 052. India opioid receptor sites and inhibit the cell depolarization through their stimulatory action on this enzyme in the brain. Department of Pharmacology, Kagoshima University, Dental School, Kagoshima 890, Japan 360 33.04.06 THE ANALGESIC PROPERTIES OF SOME SUBSTITUTED AMPHETAMINES L M. Beaton. F. Beningon and R. D. Morin. We have previously shown that two amphetamine analogues, the alpha-methyl and alpha-ethyl derivatives of methylenedioxymeth- amphetamine, have potent analgesic properties. We believe that the analgesic action of these agents is due in part to their substituents in the para position. Therefore, a series of amphemmlne analogues, substituted in the para position were synthesized and tested for their ability to induce analgesia in mice. The compounds tested were amphetamine, 2,5-dimethoxy-4-methyl-amphetamine (DOM), 4- hydroxy-amphetamine (4-HO-AMP), 4-HO-N-methyl-AMP, 4- methoxy-amphemmlne (4-MeO-AMP), 4-MeO-N-methyl-AMP, 4- HO-2,6-dimethyl-amphetamine, 4-MeO-2,6-dimethyl-amphetamine and the N-methyl derivatives of these last two compounds. Analgesia was measured using a tail-flick apparatus manufactured by the Columbus Instruments Corp. Dose response curves were obtained using groups of five mice for each dose. The doses ranged from 0.75 to 24 gmol/kg. The animals were tested at 10 min intervals, beginning 30 min after intraperitoneal administration of the compounds in a volume of 0.1 ml/10g. Testing continued until each animal's response time had returned to preinjection control levels. With some of the higher doses, testing was terminated 180 rain post-injection, although some analgesia was still present. All compounds showed some degree of analgesia. In general, the N-methylated compounds were more potent than the nonmethylated equivalent compounds. It is hypothesized that the mode of action of the analgesia is via an interaction at the mu opiate receptor and that these compounds bind to this receptor in a manner similar to that of enkephalin, as suggested by Horn and Rogers (Nature 260, 795, t976). (Supported in part by the Alabama Consumer Fund). Neuropsychiatry Research Program and Department of Psychiatry, University Station, Birmingham, Alabama 35294, U.S.A. 33.05.01 AUDITORY BRAINSTEM EVOKED RESPONSE LATENCIES AND METNYLPHENIDATE PLASMA CONCENTRATIONS J.A. Camp-Bruno and B.G. Winsber 9 We have reported prolonged auditory brainstem evoked response POSTER (ABER) latencies in Attention Deficit Disorder Hyperactivity (ADDH) children and latency normalization with methylphenidate PRESENTATION (MP). Using 0.25, 0.5, and 1.0 mg/kg MP, we then reported that for right ear stimulation, Wave Ill was shorter at 1.0 than 0.5 33.05 mg/kg and Wave VI shorter at 1.0 than 0.5 mg/kg and placebo. We now present data relating ABER latencies and MP plasma levels in 13 ADDH boys tested under placebo, 0.25, 0.5, and 1.0 mg/kg, ABERs to left and right ear clicks were recorded between vertex and ipsilateral mastoid with contralateral mastoid as ground; plasma MP was assayed by gas chromatography, Wave Ill latency change re placebo for left ear stimuli corre- Miscellaneous lated with plasma MP at all three doses, whereas for right ear stimuli significance obtained only with 0.25 mg/kg. However, since not all children showed a linear latency decrease with dose, we reanalyzed Wave III using the dose condition which demonstrate~ maximum latency decrease. This approach yielded a highly significant correlation between right ear maximum latency change in Wave Ill and plasma MP. Based on our prior finding that the major effect of MP was a latency decrease under 1.0 relative to 0.5 rag/ks, difference scores using the 0.5 and 1.0 mg/kg dose data were computed for Waves III and VI and for MP concentrations. Wave V: dose-difference scores for right ear stimuli significantly correlated with plasma MP dose-difference scored: correlation for Wave Ill was significant only for the subgroup showing shorter latencies at i.0 than at 0.5 mg/kg. Like our earlier finding that MP decreased only right ear ABER latencies, no significant correlations emerged between dose- difference scores for left ear latency change and plasma MP. These relations between plasma levels and ABER latency change suggest that MP may exert its therapeutic effect in children by modulating CNS information transmission, perhaps by either a direct effect on monoaminergic activity os afferent generators of ABER components and/or indirectly via pharmacologic altera- tion of efferent feedback from higher CNS structures, Division of Child Psychiatry, Nathan S, Kline Institute for Psychiatric Research, Orangeburg, Ny 10962, USA. 361 33.05.02 33.05.03 PSYCHOPHARMACOLOGICAL TREATMENT OF EATING THE EFFECTS OF DIFFERENT PREPARATIONS OF DISORDERS IN ADOLESCENTS BROMAZEPAM ON LABORATORY ANALOGUES OF CAR DRIVING G.-E. Trott, T. Elliger, H.-J. Friese C.A. Alford t J.Z. Bhatti and I. Hindmarch Acute 6mg doses of bromazepam, given both as a The pharmacological treatment of eating-dis- liquid and in 2 different tablet formulations, orders is not very common, and there have been were compared in a double-blind, placebo and very few investigations as to their efficiancy. verum (lorazepam 2mg) controlled study, i0 Recent biological studies have illucidated on female subjects received all treatments in a the mechanisms of the peripheral and central crossover design ~rith each subject acting as mediators of satiety and appetence. It seems to her own control. Morning drug administration be the logical consequence to try to influence was assessed at i, 2, 4 and 6 hours post dose. these mediators pharmacologically - especiall7 Critical flicker fusion failed to distinguish the neurotransmitters serotonine and norepine- active treatments from placebo. Reaction time, phrine. tracking and word recognition tasks were In the treatment of anorexia nervosa minor significantly impaired by the verum. tranquilizers, antidepressants, lithium , Meto- The time course and degree of impairment clopramid, Naloxone, Clonidine and Cyprohepta- separated different formulations of bromazepam. dine have been used. Relatively good experience The liquid preparation could not be has been made with noradrenerge antidepressants distinguished from placebo on any measures. and Cyproheptadine, but their effet was not Each of the tablet formulations was separated convincing. by different levels of impairment on psycho- In the treatment of bulimia antidepressants, motor performance. Carbamazepine and Fenfluramine have been used. These results emphasise the role of galenics in Positive effects have been seen With Fenflura- the preparation of anxiolytic compounds, where mine and Desipramine. There is also evidence thei; effect on the skilled performance of for ~ good response by Fluvoxamine, but these arabuiant patients is important. effects should still be further evaluated. A multimodal treatment concept should be de- Human Psychopharmacology Research Unit, Dept. signed for bulimic and anorectic patients. A of Psychology, University of Leeds, Leeds pharmacological co-therapy could be of great LS2 9JT, England. importance in this context. Universit~tsklinik und-Poliklinik f~r Kinder- und Jugendpsychiatrie Direktor. Prof. Dr. G. Nissen Fuchsleinstr. 15 D-8700 W~rzburg 33.05.04 33.05.05 THE EFFECTS OF ALCOHOL AND BENZODIAZEPINES ON THE EI~fECTS OF MINAPRIME TAKEN WITH AND WITHOUT BEHAVIOURAL AGGRESSION AND MOOD ALCOHOL ON INFORMATION PROCESSING, PSYCHOKOTCR A.J. Bond and M.H. Lader PERFORMANCE AND CAR HANDLING ABILIT7 A competitive reaction time task designed to measure iT.A.Betts, 2p.Morrison and 3Z.Subhan behavioural aggression has been used to examine the Minaprine hydrochloride is an aminophenylpyridazine effects of alcohol and benzodiazepines. Self-ratings derivative currently under development as an anti- of mood, anxie~y and aggression were completed pre and depressant. It facilitates serotonergic and post treatment and post task. In the first study, dopaminergic transmission (by presynaptie and post- subjects were administered a low dose of alcohol synaptic mechanisms) and facilitates cholinergic (0.25 mg/kg), a moderate dose of alcohol (0.75 mg/kg) transmission by a direct action at the muscarinic or placebo. It was found that alcohol increased receptor site. The results of several placebo bshavioural aggression in a dose-related way without controlled studies evaluating the psycho- increasing ratings of anxiety or aggression. In the pharmacological effects of minaprine both alone and in second study, subjects were administered lorazepam combina'cion with alcohol in healthy volunteers are (i or 2 mg), oxazepam (15 or 30 mg) or placebo. The presented. Objective assessments of pharmacodynamic two benzodiazepines had very similar subjective activity included critical flicker fusion threshold effects but the 2 mg dose of lorazepam increased (CFFT), choice reaction time (CRT), memory scanning, behavioural aggression more than any other treatment. and both simulated and actual car driving. Subjective This may be related to ceiling efficacy. Currently a ratings of mood and degree of sedation were also study of the combined effects of 0.5 g/kg alcohol and conducted. In summary, results from these studies 1 mg alprazolam on behavioural aggression and mood provided no evidence of deleterious effects of is being undertaken. mi/naprine on human cognitive function including actual Institute of Psychiatry, De Crespigny Park, vehicle handling ability. Further, minaprine does not London SE5 8AF. U.K. augment or potentiate the disruptive effects of alcohol on aspects of human performance. These findings are discussed in the context of minaprine's original profile of activity. 1 . 2Unlverslty of Aston, Aston Triangle, Birmingham, U.K. j_Guys Drug Research Unit , London, U .K . Sanofi U.K. Ltd, Wythenshawe, Manchester, U.K. 362 33.05.06 33.05.07 IS EEG MONITORING OF ELECTROCOI,YOLSIVE THERAPY CLINICALLY DIFFERENTIAL EFFECTS OF SINGLE AND REPEATED USEFUL? ELECTROCONVULSIVE SHOCK (ECS) ON FORSKOLIN R. G. McCreadie, K. Phillips and A. D. T. Robinson BINDING IN RAT BRAIN EEG monitoring was carried out in I~9 bilateral and 114 Christoph H. Gleiter*, Jurgen Deckert#, David J. unilateral applications of ECT, given to 51 patients in Nutt*~ Paul J. Maranqos# an everyday NHS setting by junior medical staff. In 2.5% Since ECS has been shown to increase as well as of bilateral and 8% of unilateral applications there was decrease forskolin-stimulated cAMP accumulation disagreement between clinical ~nd EEG assessment as to in cerebral cortex I adenylate cyclase was inves- whether a fit had occurred. When an EEG fit was said to tigated using [3H]Forskolin (FOR) binding in rat have occurred only if it lasted longer than 25s, then cerebral cortex (COR), cerebellum (CER), hippo- disagreement rose to 7% in bilateral and 28% in campus (HIP) and striatum (STR). Rats were given unilateral applications; disagreement was higher with either a single or repeated ECS (80 mA, 0.5 s) unilateral applications as they produced shorter fits via earclips without anaesthesia. They were sa- than bilateral applications. IZ future work shows crificed 30 min or 24 h after a single ECS and seizure duration is clearly associated with clinical 24 h after 10 once-daily ECS. Binding of FOR to efficacy, it is suggested the case for routine EEG crude membrane preparations of the above brain monitoring is greatly strengthened. regions was examined at a concentration of 12 Crichton Royal Hospital, Dumfries, Scotland, DG2 4TG nM. Membranes of each time point were assayed in parallel. Results in fmol/mg protein: 30 min 24 h ECS x 10 CTRL ECS CTRL ECS CTRL ECS COR 81+3 76+3 105+2 124+ 7 105+3 103+ 2 CER 77+4 89+4* 129+5 119+ 4 114+4 132+ 6 HIP 68u 57u 60u 59u 5 56u 44u 2* STR 88u 146u 186u 181u 178u 135u (mean• n =-8/group; *= p- 33.05.08 33.05.09 OOUBLE-BLIND COMPARISON OF LOPJ~ZEPAMVS. HALOPERIDOL FOR THE I~0RTANCE OF BRO~0CRIPTINE/PARLODEL/ THE TRF.ATMEJ~T OF MANIC AGITATION. THERAPY AND DA RECEPTORS IN ALCOHOL ABUSE R.h. Lenox, W. Creelman, G. Amori, S. Weiner. S. P~lfi~ Z. Kovlcs The authors treated chzooic alcoholic pa- Current approaches to the clinical treatmentof manic tients with Psrlodel in m six-month period agitation have generally included the widespread use of of time using the method of double blind neuroleptics to manage the patient while awaiting the examination~ There was a significant differ- therapeutic effects Of lithium. We have previously des- ence in the numbe~ of alcoholic abuses be- cribed an open study examining the efficacy of lorazepam tween those taking Pazlodel end the controls. for the treatment of manic agitation in patients being /exact p-statistics by Fischer - two-side - treated concurrently with lithium (Modell et al 1985, p=o,o126 / Lenox et al 1986). We are reporting the results of our Applying the dose /daily 7~ mg/ there was recently completed double-blind study comparing the no need for the suspension of drug sdministre- efficacy of lorazepamvs. haloperidol in such a patient tion because of side effects in any case. population. Fluctuations in the pro!scrim levels of those in the control group may be ~eleted to more Twenty acutely manic patients fulfilling DSM-III criteria fre@uent and more severe expositions to al- for bipolar disorder, manic type, participated in this cohol, which may elso refe~ %o the in- study on our inpatient service. Upon admission to the volvement of DA metabolism. protocol patients were administered lithium or carbamaze- The change in p~olactin level after the pine,.and orders written for administration of the blinded administration TRH is a basic information medications either p.o., i.m., or i.v. every 2 hours as in the therapeutic effect. needed to achieve a level of behavior sufficient to allow Department of Neuzo!og2 and Psychiatry patient compliancewith milieu and medication. Patients Medicel University SzeEed , Hungary P.OoB.397. were rated daily at the same time by an independent rater H-67oi using the Brief Psychiatric Rating Scale, Mania Rating Scale and Side Effects Scale. Initial data revealed evi- dence ~f three different profiles of response: patients respqnding to the lithium or carbamazepinewith little additional treatment for agitation; patients responding only with addition of the blinded medications; patients requiring discontinuation of protocol due to side effects or uncontrollable agitation. We will report data regard- ing the characteristics Of these response profiles and present a rationale consistent with the use of Iorazepam as a recommendedapproach to the treatment of manic agitation within the hospital setting. Neuroscience Research Unit, Dept. of Psychiatry, Univer- sity of Vermont College of Medicine, Burlington VT, U.S.A. 363 34.01.01 SIBUTRAMIh~E RCL AND OTHER ANTIDEPRESSANT TREATMENTS DECREASE CORTICAL ~.-BUTI NOT 82-ADRENOCEPTORS. W. R. Buekett and D. J. Heal The specific 9.-antagonist! CGP 20712A can be used to POSTER quantify BI- and ~9-adrenoceptor binding (D. J. Dooley, et al, Eur J. Phar~ae. 130, 137, ]986). In this study PRESENTATION CGP 20712A was used to determine rat cortical ~1- and -adrenoeeptors after the administration of 34.01 S~butramine HCI (BTS 54 524) and other antidepressant treatments. Male CD rats (75-175g) were used. Sibutramine HCI (3 mg/kg), ami~riptyline, desipramine (DMI) or zimeldine (all 10 mg/kg) were given orally once daily for ten days. Controls received distilled water. Five eleetroconv~isive shocks (ECS) wer e given to Various anaesthetised rats also over 10 days, with controls receiving halothane alone. 24h after the final Pharmacological Studies treatment, saturation binding experiments were performed using [SH]-dihydroalprenolol (0.]4-2.8 riM). Specific b~nding to ~ - and (81 + 9?)-adrenoceptors was defined by I ~M C~P 207]2A'and 200 ~M isoprenaline respectively. ~ -Adrenoceptor binding was calculated by difference. "~ortieal Bmax values were S1=77 • 7; ~2=40 • 6 fmol/mg protein and Kd values ~i = ].1 • 0.4; ~2 = 0.78 • 0.] riM. After 10 days S.- but not -adrenoceptors were reduced by all treatments: S~butramine BCI (47%), amitriptyline (28%), DMI (45%), zimel~ine (26%) and ECS (31%). After 3 days, sibutramine HCI and DMI reduced ~ -adrenoceptors I by 23% and 40% respectively, but amitriptyline and zimeldine had no effect. A single ECS was also ineffective. The data show that monoamine reuptake inhibitors of varying profile, as well as ECS, all reduce S]-adrenoceptors alone. Furthermore sibutramine HCI, w~ich rapidly reduces ~-adrenoeeptors (W. R. Buekett et al, Br. J. Pharmae 90, 94P, 1987) achieves this solely by decreasing the @ ! subtype. Research Department, The Boots Company PLC, Nottingham NG2 3AA, United Kingdom 34.01.02 34.01.03 EFFECT OF SOKE CALCIU~ CHANNEL ANTAGONISTS AND THE CALCIUX MONOAMINE TURNOVER IN DISCRETE RAT BRAIN NUCLEI CHANNEL AGONIST BAY K 8644 IN PHARMACOLOGICAL MODELS AFTER ADMINISTRATION OF MEDETOMIDINE, A NOVEL RELATED TO DOP/L~INERGIC ACTIVITY a.-ADRENOCEPTOR AGONIST E. Mo~ilnicka. A. Czvrak. K. Golemblowska and J. Nni U~. Pesonen, S. Koskinen, H. H~mninen, R. V[rtanen and M. Koulu The effects of calcium channel antagonists [(the dihydro- Medetomidine is a new imidazole derivative which selectively pyridine antagonists, nifedipine (NIF), nimodipine (NIK)~ activates a2-adrenoceptors. In animals, as weU as in humans, nitrendipine (NIT) and the non-dihydropyridine ones dil- medetomidine has shown sedative, hypotensive and bradyeardic tiazem (DIL) and verapamil (VER)] and the calcium channel effects. agonist BAY K 8644 on the apo~orphine (APO)-, and amphe- Saline or 3, 30 or 100 ug/kg of medetomidine was injected s.c. tamine (AEPH)-induced steremtypy and on the APO- and LY to male Sprague-Dawley rats (n=8 in each group), which were 171555-induced yawning were investigated in rats. In mice decapitated 90 rain later. In a separate experiment, 100 mg/kg of the effect of these substances on the AHPH-induced hyper- NSD 1015, an inhl"bitor of L-aromatic amino acid decarboxylase, motility was checked. The level of HVA was measured in was injected 30 rain before decapitation to rats pretreated with the rat striatum by the HPLC after i.p, administration of 3, 30 or 100 ug/kg of medetomidine or saline 60 rain earlier. The BAY K 8644. brain stem nuclei were punched according to the method of Palko- None of the investigated calcium antagonists influenced vits. HPLC-EC was used for the chemical determinations. the APO- or AKPH-induced stereotypy. BAY K 8544 increased MedetomkIine significantly inhibited the accumulation of DOPA in the APO-induced stereotypy, this effect being counteracted area A1-C1, nucleus tractus solitarii (NTS) and raphe dorsalis by NIF and. DIL. (RD), but not in the locus coeruleus (LC). The basal catechol- NIF (5, I0 mK/kg) significantly increased the APO-induced amine levels remained unchanged after medetomidine. Furthermore, yawnfng in a dose-dependent manner; NIF, NIK and NIT (I0 medetomidine decreased the concentrations of 5HIAA, the ratio mg/kg)~ but not other antagonists si~i~ioa~t~y inoreaced 5HIAAJ5HT and 5HTP accumulation (after NSD 1015) in area the APC- and LY 171555-induced yawning. BAY K 8644 (0.05! A1-C1, NTS, area A5 and LC. In RD the ratio 5HIAA/5HT 0. I, 0.gmKlkg i.p,) reduced dose-depently the APO- and LY dccreased, but 5HTP accumulation remained unchanged. l?1555-induced yawning. The BAY K 8644 (0.5 m~/kg)-induced Th~ results obtained suggest that medetomidine decreases the reduction was antagonized by NIF (I0 m~/kg). BAY K 8644 turnover of NA in various brain stem nuclei, an effect which is (2 mg{kg) significantly increased the HVA level in the raf consistent with the known a2-agonistic properties of the drug. An striatum. effect of medetomidine on inhibitory a2-receptors located pre- None of the calcium antagonists (2.5, 5, i0, mg/k~) affec- synaptically on serotonergic neurons or indirect actions of ted the spontaneous motility in mice, the only exception medetomidine via interactions of noradrenergic and serotonergic being VER which decreased it. Of all the compounds tested neurons could explain the observed decrements in 5HT turnover only NIM and VER (5 mg/kg) significantly reduced the AMPH- after medetomidine. induced hypermotility. BAY K 8644 (0.5, 1 mK/kg) reduced Department of Pharmacology, University of Turku, Finland the spontaneous motility and AMPH-induced hypermotility~ these effects being counteracted by NIF (5, 10 m~/kg). The obtained results support the hypothesis that brain Da dopamine receptors may be functionally linked to calcium channels. Institute of Pharmacology, Polish Academy of Sciences, 12 Sm~tna St., 31-~43 Krak6w, Poland 364 34.01.04 34.01.05 PHOSPHOLIPASE As SYSTEM CONTROLS PURINE REGZ3L~TION OF IDENTIFIED NIGROSTRIATAL AND MESOACCUMBENS p~ 9.&SE AND cAMP LEVELS IN CULTUR~ GLIAL CELLS bOP&MINE NEURONS IN THE RAT F. Cacia@ll, R. Ciccarelli~ P- Di Iorio, L. Tacconelli M. Exner, L.A. Chiodo" and D. Clark "and P. Ballerlni Previous work has suggested that midbrain dopamine (DA) Purines have been identified as Lmportant cotransmltters neurons projecting to functionally distinct forebrain in the CNS, able to inhibit neuronal activity and 81ial re~/cns are regulated in a different fashion. In light cells represent a considerable source of these of the potential importance of these regulatory differ- substances. It is accepted that protein Kinase C (PK-C) ences, we are currently using standard extracellular regulates Ca R+ , K + and CI- fluxes and promotes single unit recording and microiontophoretic techniques transmitter and cotransmitter release. Different membrane to study the regulation of antidromically identified molecular systems have been suggested to exhert opposite nigrostriatal and mesoaccumbens DA neurons in the effects on this Key-enzyme. Among these, a possible role chloral hydrate anaesthetised rat. The present project can be ascribed %o phospholipase AE-prostaglandin focn~ses on the response of these populations of DA (PLAE-PG) system that, at neuronal level, seems to neuron to electrical stimulation (i00 x 0.2 msec pulses, directly control PK-C, without requiring the activation 0.SHz0 0.5-3.0mA) of the caudate nucleus or the nucleus of phosphollpase ~ To ascertain the possible presence of accumbens. Neuronal responses were determined by this mechanism at glial level and its significance, basal analysis of peristimulus time histograms. and electrically-evoKed purine release and cAMP levels Following single pulse stimulation of the caudate were measured in untreated cultured glial cells and nucleus, the majority (83%) of nigrostriatal DA neurons Dexamethasone ([x[o -6 M) or Indomethacln ([xto -4 M) responded with a period of inhibition followed by suitibly treated cells, to obtaln a complete inhibition excitation. In contrast, only 30% of mesoaccumbens DA of PLAE-PG system. This inhibition greatly enhances neurons exhibited this form of response following evoked purzne release and cAMP levels. To evaluate if stimulation of the nucleus accumbens, while 22% PLAE-PG system could be linked to A t receptor activity, displayed only inhibition of firing. The highest the effect of H-etrzylmalelmlde (txlo -5 H), a blOCKer of proportion (39%) responded with a brief period of marked G i protein linked to A t receptors for adenosine, was excitation followed by inhibition, a response never assayed by adding it to treated glial cultures. This drug observed with nigrostriatal DA neurons. These findings does not modify Dexamethasone or Indomethacin effect on suggest that a population of mesoaccumbens DA neurons purine release, while basal and evoked cAMP levels result are regulated by long-loop feedback pathways from the greatly stimulated. This zncrease is strongly forebrain in a different fashion to nigrostriatal DA counteracted when As receptors are blocked. Our results neurons. Current studies are focused on delineating the suggest that, in glial cells, PLAs-PG system seems to be neurochemical identity of the systems involved in linked to A t receptors and inhibits purine release and mediating these neuronal responses to forebrain cAMP accumulation, probably exherting an inhibition on stimulation. PK-C activity. Neuropsychopharmacology Lab., Dept. Psychology, Dept. of Pharmacology Medical School. University of University of Reading, U.K., and "Lab. Neurophysiology, Chieti. Via del Vestini, St - 66Ot3 CHIETI. Italy. Center for Cell Biology, Sinai Research Institute, Detroit, U.S.A. 34.01.06 34.01.07 STRAIR-SPECIFIC SENSITIZATION OF BRAIN STIMULATION REWARD LEVELS OF NERVE GROWTH FACTOR ARE ALTERED DURING By A9-T~-rt{AHYDROCABNABINOL IN LABORAI~RYRATS EXPERIMENTAL DIABETES MELLITUS: A POSSIBLE ROLE E.L. Gardner. W. Paredes. D. Smith, T. See~er. A. Donner, FOR NGF IN THE PATHOGENESlS OF DIABETIC NEURO- C, Milling, D. Cohen, and D. Morrison PATHY? Previous studies have shown that most drugs of abuse sen- R. Hellweg and H.D. Hartung sitize brain stimulation reward, presumably deriving Diabetes mellitus (DM) is the leading cause of their abuse potential from this neuropharmacological neuropathy in nontropical countries. In experi- action (R.A. Wise & M.A. Bozarth, Prog. Neuro-Psychophar- mental animal models of DM an impairment of macol. 5, 467, 1981). However, the action of the cannabi- retrograde axoplasmic transport of several mole- noid drug class on these brain mechanisms has remained cules including nerve growth factor (NGF) has unclear. We therefore studied the action of A9-tetrahy - been observed. This could be of relevance for drocarmabinol (Ag-THC), the psychoactive constituent of the pathogenesis of diabetic neuropathy (DNP) marijuana, on brain stimulation reward obtained from the since in DNP the NGF-sensitive neurons (i.e. medial forebrain bundle in four strains of laboratory sympathetic and neural crest-derived sensory rats. A titrating threshold paradigm of brain stimula- neurons) are affected in particular. Using an tion reward was used (J.M. Nazzaro & E.L. Gardner, Brain improved rapid and highty sensitive two-site Res. 18___99, 279, 1980). Ag-THC (1.5 mg/kg i.p.) produced enzyme immunoassay for NGF, we have investigated robust and consistent decreased thresholds for brain re- whether NGF levels are altered in rats with ward in Lewis rats, but no effect at a wide range of streptozotocin-induced DM which are known to doses (0.37, 0.75, 1.5, 2.0, 4.0 mg/kg) in Long-Evans, develop the equivalent to DNP. We have found Sprague-Dawley, or Fisher rats. We recently reported increase~ NGF levels (up to 300% of control) not that Ag-THC has potent dopamine agonist-like effects in befo.re 2 to 3 weeks after induction of DM in brain reward loci (J.M. Ng Cheong Ton et al., Brain Res. target organs of the autonomic nervous system in press% 1988), as measured by in vivo brain electro- (such as iris or vas deferens). NGF levels are chemistry and intracranial microdialysis - HPLC methods. increased probably due to a developing DNP and Given the involvement of dopaminergic mechanisms in brain lacking removal of NGF by innervating neurons. reward (R.A. Wise & M.A. Bozarth, Brain Res. Bull. 12, Moreover, the observed a]terations of NGF levels 203, 1984), these prior findings, together with the pres- were reflected in the NGF-sensitive perikarya ent data, strongly suggest that A9-THC acts on similar suchi as superior cervical ganglion where NGF brain mechanisms as other drugs of abuse. The ~resent levels were significantly decreased. Since NGF clear strain differences in vulnerability to A=-THC's exerts its neurotrophic activity in the peri- sensitization of brain reward implicate genetic variabil- karya of NGF-sensitive neurons, our results are ity in drug abuse vulnerability to cannabinoids, anala- consistent with the hypothesis that NGF plays a gous to that previously suggested for ethanol. role in the pathogenesis of DNP as far as NGF- Laboratory of Behavioral Pharmacology, Department of sensitive perikarya are affected. This hypothe- Psychiatry, Albert Einstein College of Medicine, 1300 sis possibly opens new strategies for a therapy Morris Park Avenue, New York, NY 10461, U.S.A. of autonomic DNP. Max-Planck-lnstitute for Psychiatry, Kraepelin- strasse 2-10, 8000 Munich 40, F.R.G. 365 34.01.08 34.01.09 EFFECT OF SINGLE AND MULTIPLE DOSE TREATMENT WITH ANTI- NEUROREGULATION OF MiTRICIDAL SUPPRESSION BY CENTRAL MONC- DEPRESSANTS ON APOMORPHINE-INDUCED YAWNING IN THE RAT: ~MINES IN THIAMINE DEFICIENT RATS EVIDENCE FOR NORADRENERGIC MODULATION OF PRESYNAPTIC K. ONODERA D2-RECEPTORS. Previously, Onodera et al., (1981) reported the character- istics of muricide induced by thiamine deficiency in rats. A. Delini-Stula, Ch. Hunn In this study, I investigated the effects of monoaminergic Several lines of evidence suggest that antidepressants agents on this muricide to clarify the neuroregulation of may modify the function of presynaptic D2-receptors, al- muricidal suppression by brain monoamines. On the 30th day though the mechanism of this interaction is not clear. of experimental feeding, the incidence of muricide was 70% Yawning behaviour induced by low doses of apomorphine is ~ne intraperitoneal injection of L-5-hydroxytryptophan, L- considered to be a functional expression of presynaptic dihydroxyphenylalnine (L-dopa), L-dihydroxyphenylserine, and L-histidine suppressed this muricide. The ED50 values D2-receptor stimulation, but the effect of antidepres- are 50, 86, 115 and I55 mg/kg, respectively. Muricidal sants on this behaviour has not been systematically suppression by L-dopa was potentiated by carbidopa, but studied. reduced by pretreatment with ~-mon0fluoromethyldopa or Male albino rats weighing 180-220 gr were treated with FLA-63. The suppression by L-histidine was reduced by pre- single (10 and 20 mg/kg ip) or multiple (10 mg/kg 2xD for treatment with &-fluoromethylhistidine (FMH). In addition, 7 days) doses of imipramine, maprotiline, citalopram and intracerebroventricular injection of serotonin (5-HT) or (+) and (-) enantiomers of oxaprotiline (OXA). (+) OXA is histamine "(HA) suppressed this muricide. Abe et al., re- a highly selective NA-uptake inhibitor. (-) OXA is devoid ported that the microinjection of 5-HT or noradrenaline of any action on the monoamine uptake. APO (0.05 mg/kg sc) (NA) into the medial part of amygdala can inhibit this was given 30 min. after drugs. Yawning was recorded in muricide, but dopamine can not. These data indicate that 10 min. fintervals for I h. Only 20 mg/kg (+) OXA signifi- the inh2bitory meeanisms could be a reflect of activation cantly (p<0.01) inhibited yawning after single doses; of central monoaminergic system, especially 5-HT, NA and CIT increased it (44%). After subchronic administration, HA. Hence, the effects of various depletors of monoamines IMI apd MAP showed 98% and 52% inhibition respectively, on thiamine deficient non-killer-rats were investigated. and t~e effect of (+) OXA was enhanced (99% inhibition). ~-Me~hyl-p-tyrosine, ~-monofluoromethyl-p-tyrosine, FLA- Other drugs were inactive. The results of this study indi- G3, FMH and brocresine could not enhance the muricide. cate that most probably the NA-uptake inhibiting com- Parachlorophenylalnine, a 5-HT synthesis inhibitor can ponent of action of antidepressants is responsible for enhance the muricide. Moreover, this muricide was more the modulation of the presynaptic D2-recepter function. potently suppressed by antidepressants, which inhibit 5-HT reuptake (clomipramine etc.) rather than NA reuptake (de- Research Department, CIBA-GEIGY Ltd., CH-4002 Basle sipramine, maproti!ine, Y-8894). In conclusion, the data obtained here clearly indicate that, among the monoaminer- gic system, only the serotonergic system is involved in the inhibition of ~uricide induced by thiamine deficiency. Department of Pharmacology, Tohoku University School of Dentistry, Seiryo-machi 4-1, Sendal 980, Japan. 34.01.10 34.01.11 ACTION MYOCLONUS TREATMENT ~]TH HIGH DOSE PIIL%- LOCUS COERULEUS IN DEPRESSION- MODEL RATS CETAM K. Inoue, S. Murase, T. Komori, M. Otani, S. Kawaguchi, M. Koishizawa, ~. Akpmar, M. Yardlm. O. Vural, O. Tannda~. T. Alver, D. G/indfiz. M. Harada, L Kitayama, N. Hatotani, and J. Nomura Locus eoeruleus (LC) neurons were investigated in depression-model rats 4 Female patientS a#ng 14,17,21 and 60 ),ears and 2 male patients which continuously showed inactive state after long-term forced running a#ng 21 and 20 3-ears with action myoclonus {AcM) were included in stress. The following two groups of rats were also studied : recovery rats the study. In 5 out of 6 patients generalized tonic clonic seizures which spontaneously recovered after the stress and short-term stressed rats (GTCS) and bilateral massive epileptic myoclonus (PMEP) appeared which were exposed to the stress for 2-4 days. Amounts of norepinephrine at LC area slightly increased in short term stressed rats ,and significantly m- between the ages 10 to 14 years and cerebellar symptonls and AcM creased in depreesion-model rats. Tyrosine hydroxylase activity in LC neu- were added later. The 60 years old patient had her first GTCS and rons increased in short-term stressed rats ,but decreased in depression-model BMEM at the age of 43. These, later subsided but cerebellar sympotms rats. Spontaneousfiring rate and foot-shockevoked responseof LC neurons and AcM developed. In 6 cases, daily activities were challenged by slightlydecreased in short-term stressedrats ,and significantlydecreased in AcM which changed in de~ee from nmderate to severe and made the the model rats. These changes except chemical data of norepinephrine levels in depression-model rats were not found in recovery rats. Imipramine re- patients dependant on others. It was assymetric, being more severe at stored central norepinephrine level in the model rats along with the the res- one side, showed changes in severity and exagerated the cerebenar toration of spontaneous running activity. These results suggest that activity symptoms..Cases were diagnosed as dyssiner#a cerebellaris myo- of LC neurons was decreased in the depressive illness. clonica (DcM). Oaily 6 mg clonazepam (CzP) and 800 mg sodium valproate (SvP) controlled the seizures but not AcM in 5 out of 6 pafients..Compare to placebo piracetam (PrC) 10.4 gr daily in one case alone and in 2 cases in addition to above dru~ ameliorated tim AcM 80-90 percent. In one of the remaining 3 cases in addition to 6 mg CzP,,800 mg SvP and 10.4 gr Prc-daily 300 nag phenobarbital and in 2 cases besides these 4 dru~ I000 nag acetazolaulide had to be added. Then, 70-80 percent amelioration was achived. In 6 cases of DcM clinical an neurophysiological (EEG, SEP) acute effects of PrC, mepetidine, codein sulfate, naloxone, theophylline, metoclopramide and chronic effects of PrC will be discussed. Giilhane Mil. Med. Academy and Medical Faculty. Etlik-ANKARA TURKEY 366 34.01.12 34.01.13 LACK OF TOLERANCE TO IBUPROFEN/CODEINE: A PLACEBO SCHIZOPHRENIA AND MAJOR DEPRESSIVE DISORDER: CONTROLLED CLINICAL PHARMACOLOGY STUDY DIFFERENCES IN SENSORIMOTOR PERFORMANCE. H. Friedman,G. RoTer,H. Oster,C. Seckman and C. Stubbs W. Classen and G. Laux This multiple dose, double-blind placebo controlled, Basic deficits of cognitive and motor performance are randomized, normal volunteer study compared formulations common to schizophrenic and depressed patients. However, of ibuprofen/codeine and aspirin/codeine for systemic differences considering specific aspects of performance tolerance. Sixty male subjects were randomized to one can be demonstrated, i.e. dysfunction of right nondomi- of four treatment groups: I) ibuprofen/codeine 200/30 nant hemisphere related tasks is more frequent in de- mg; 2)ibuprofen/codeine 400/60 mg; 3) aspirin/codeine pressed patients, whereas schizophrenics suffer from 650/60 mg; 4) placebo. Medications were administered in left hemisphere deficits and/or altered interhemispheric a double dummy manner every four hours for seven days. processing. Vital signs, standard hematologic, biochemical and A total of 56 inpatients (29 schizophrenics according urinary parameters, side effects, especially of the DSM III criteria, mean age 31,2 yrs; 29 patients with gastrointestinal tract and central nervous system, as major depressive disorders, mean age 48,9 yrs) were well as mood and mental alertness, were monitored. treated with haloperidol, remoxipride, maprotiline or After 7 days of treatment, significantly lower pulse and moclobemide respectively and assigned to psychomotor respiratory rates were seen in the active treatment performance exam before and after a 4 weeks lasting groups compared to placebo. The magnitude of the treatment period, using visual and acoustic sensorimotor differences was greater for the respiratory (2-3 reaction time tasks and a battery of motor performance breaths/minute, 11-18%, p=.O02) than the cardiac effects tasks (Mot. Leistungs-Serie). Psychopathological symp- (3-12 beats/minute, 4-14%, p=.03). The uricosuric toms were recorded by HRSD and BPRS. effect of aspirin was the only consistent medication In total schizophrenics' level of performance as com- group-related trend seen in the laboratory tests. The pared to depressives was lower, being significant with placebo group had less gastrointestinal side effects and respect to tapping (right and left hand) and pegboard higher stool counts than the active treatment groups. task (left hand). Schizophrenic as well as depressed Hematemesis was seen in two subjects on aspirin/codeine. patients showed impaired left hand performance, some There was statistical evidence for adverse effects of of which (number of mistakes in line tracing) improved aspirin/codeine on mood and mental alertness in in schizophrenics under treatment. Differences in comparison to ibuprofen/codeine and placebo. Thus, theoretical aspects of etiopathogenetic explanations ibuprofen/codeine has a more favorable adverse effect of these dysfunctions will be discussed. profile than aspirin/codeine. Tolerance to the Neurologische und Psychiatrische Universit~tskliniken respiratory and cardiac depressant effects of codeine WOrzburg, FSchsleinstra6e 15, D-8700 WOrzburg was not evident in any active treatment group after seven days of frequent therapy. More work needs to be done to elucidate the factors regulating the development of tolerance to the respiratory and cardiovascular depressant effects of opiates in general, and for codeine in particular. The Upjohn Company, Kalamazoo, Michigan 49001,USA 34.01.14 34.01.15 AN!YAL MODEL FOR STUDY OF CENTRAL CHOLINERGIC SYST~E, TARGET ~YNDROT,~ OF PSYCHOPHARMA-COLOGIC'~L IN- N.i.Hariri.~.PS~n.fF.Z.Kuta~.~S.Demir~6ren.tG~eker. ~ TERVENTION IN PATIE~TTS WITH ACUTE AL~D ~RONIC B.~dem., A.Aktimttr COURSES OF ~C',~ A~D VESTIBUIJ~ DISORDERS. Aging is characterized by many structural and biochemical J. Ba~teck~ ~ O. Skovro~sk#, Z. Bolelouck~ alterations in hrain.A decline in cognitive functions in Depression, anxiety, au~onS~ous disturBanCes and other psychopathological syndromes accom- aged humans and animals has also been reported.Although pany cochlear and vestibular disorders as so- the mechanisms involved in this functional decline is un- matopsyahic r~ction ( secondary psychopatho- clear,dysfunction ef the cholinergic system is considered logy) or take a part in their multifactorlal an • contributing factor.Since many features of aetiology and pathogenesis thus representing aging and those of radiation unjury are externally alike, psychosomatic compon~t of these disorders. i~z!zing radiation may be a convenient model of both mo- Treatma~t with psychctropic drugs has oftau been succesful in some of these diseases~ The- delling accelarated aging and establishing the causes of refore since 1981 we tried to assess psychopa- aglng.The ~resent study was undertaken to develops an ani- thology in cochlear and vestibular disorders ~l model for dementia, for aging or at least for chemico- and searched for psychopathological syndromes pharmacological testing.Fsur groups of mice were used: and symptoms suitable for psychopharmacological 1)Control 2)Hydergine-treated (3 mg~g eraliy once a day interv~ tiono for four weeks 3)Irradiated (head exposure V50 fads) 4)Ir- The aim of the present study was to quantify psychopathology by means of the SCL - 90 ( De- r~!iated and hydergine ~reated.After decapitation the rogatls and coll., 1973 ) and to search for brains were removed and dissected on ice.AchE~ChAT au&MRB target syndromes of psychopharmacological in- (~ascarinic receptor binding H~-QNB) were determined in tervention in acute and chronic courses of the- fr~t~arietal c@rtem, cerebellum hippocampus and corpus se diseases. A sample of 130 inpatients ( 72 s~riatum.Our results sh~" that radiation effects the cho- mere with mean age of 43,9 years and 58 women linergic system significan~ly~especially in the deep nucle~ with mean age of 47,9 years ) was investigated. Samples of 45 engine drivers and 192 nurses and that the resulting changms are similar t@ th@se ob- served as controls for assessma~t of arbitrary served in aging and dementia.Hydergine stimulated Ach syn- borderline values of the psychopathology mea- thesis in normal brain~but did not effect the ChAT levels sured by lO dimensions ( corresponding with in irradiated brain.The radiation induced decrease of AchE psychopathological syndromes ) of the S~L- 90. levels in hippocampus and carpus striatum could be re- According to our h2pothesls significantly more s~red by hydergine.Radia~i~n decreased MHB in corpus psychopathology was found in acute courses. So- matic complaints, depression, anr~ety and sleep s~ri~um while hydergine had n@ effect.Radiatim~+hydergine and eating distortions represented main target si~ificantly decreased ~L~_~ in all regions.The results syndromes. Some psychotropic drugs in low doses den~e that Ach syntesis csuld not be rest@red by hydergine are recommended for the psychopharmaoc!ogical fsll~ing radiation inj~J. interv~ tion. E~ Univ.Med.Sch.Dept @f Physiolo~Born.v~-IZMIR/qlIRKEY Dept. of Psychistry, Postgraduate Medical and Pharmaceutical inst., ~stavn~" 91, 181 02 Praha8. 367 34.01.16 34.01.17 NO EVIDENCE FOR CATECHOL-O-METHYLTRANSFERASE INHIBITION OPIATE RECEPTORS: BINDING OF ANTITUSSIVES AFTER METOPRINE TREATMENT IN RATS M.M. Airaksinen and A. Lecklin Leena Tuomisto and Ewen MacDonald The use of opioid analgetics including codeine as anti- Metoprine is an inhibitor of histamine-N-methyltransfer- tussives has been encumbered by their abuse potential. In ase, the main enzyme catabolizing histamine in the CNS. I Finland codeine has been replaced in over the counter is often utilized to elevate brain histamine levels when preparations by dextrometorphan (DMP), thought to be with- studying the functions of CNS histamine. Our own earlier out euphorizing effect though occasional abuse was re- study with metoprine (I) showed an inhibition of maximal ported until sorbitol was added to the DMP syrups. Both electroshock convulsions with concomitant elevation of the antitussive and addictive effects of opioids may be whole brain histamine concentrations. Sound-induced con- mediated by opioid receptors (Chau & Harris, Natl. Inst. vulsions in susceptible rats were also reduced (2). Drug Abuse Res. Monogr. Ser. 49, 77, 1984) but a speci- The possibility that metoprine could inhibit another meth- ficity to certain opiate receptor subtypes might permit ylating enzyme, catechol-O-methyl-transferase (COMT) was the design of antitussives with no addiction potential. examined by administering the drug i.p. at two dose We have compared the binding to opioid receptors of co- levels, 5 and 20 mg/kg to rats which were then sacrificed deine, DMP and a rather potent novel antitussive vado- at O, I, 4, 24 and 100 after treatment. The ratio of the caine, a derivative of lidocaine, by allowing them to com- two dopamine (DA) metabolites was used as an indirect in- pete with tritiated ligands in rat brain homogenate sub- dex of COMT activity. Dihydroxyphenylacetic acid (DOPAC) fraction. The ligands for ~(mu), 6(delta), K(kappa)and o is the initial metabolite of DA formed after its deamina- (sigma) receptors were dihydromorphine (DHM), D-Ala-D-Leu- tion by menoamine oxidase (MAO). It is then further cata- enkephalin (DADLE), dynorphin and SKF 10047, respectively. bolized by COMT to the final metabolic product, homvanil- If the antitussive effects of codeine and DMP are due to lic acid (HVA). The deaminated metabolite of serotonin, the parent molecules, their only common affinity suggests 5-hydroxyindoleacetic acid (5-HIAA) was also measured in that the C-sites may take part in this effect. However, the brain of the treated rats. The compounds were deter- all the affinities are low if compared to those of mor- mined by HPLC coupled to a coulometric detector with a phine and the major effects of codeine are probably due to slightly modified separation procedure from Mefford (3). its metabolism to morphine. The rather low affinity of DMP There was no evidence for metoprine-induced inhibition of to C-, K-: and o-sites may or may not explain its oc- COMT. However, the higher dose of metoprine inhibited the casional abuse. Vadocaine was significantly bound only to formation of DOPAC at earlier time points. Since there was the o-receptor, which is probably not involved in the no corresponding decrease in 5-HIAA levels, this is inter- antitussive effect which might be peripheral and related preted as being due to inhibition of DA release rather to its local anesthetic effect (M~nnist~ et al. Arzneim. than inhibition of MAO. The effect of metoprine on DA Forsch./Drug Res. in press 1988). turnover and its possible relationship with the inhi- Table. ICsD:s (~M) of antitussives competing with ligands bition of histamine metabolism is under investigation. Antitussive DHM DADLE dynorphin SKF-I0047 I. Tuomisto L Tacke U: Neuropharmacology 1986:25:955-958 Codeine 3.5• 15~I 231• 232• 2. Tuomisto Let al.: Agents Actions 1987:20:252-254 Dextromethorphan 356• 30=3 35• 18• 3. Mefford IN: J. Neurosci. Methods 1981:3:207-224 Vadocaine 77• . 393• 209• 28• Department of Pharmacology and Toxicology, University of Department of Pharmacology & Toxico|ogy, University Of Kuopio, POB 6, SF-70211 Kuopio, Finland Kuopio, P.O.B. 6, SF-70211 Kuopio, Finland 34.01.18 34.01.19 EFFECT OF PHENYLETHANOLAMINE-N-METHYLTRANSFERASE INHIBITOR OPIOID PARTIAL AGONISTIC PROPERTIES OF A RECENTLY ABUSED ON LOCOMOTOR ACTIVITY IN RATS ANALGESIC M. Nakagawara, T. Kariya, T. Asada, M. Atobe, M. Kubota A.M. Persico, L. Janiri, E. Tempesta and N. Motohashi Lephetamine is a new drug of abuse, displaying central Recently adrenaline and adrenaline-Torming enzyme, Phenyl- analgesic activity and a spectrum of clinical effects ethanolamine-N-methyl-transferase (PNMT) are found in of the opioid partial agonistic type.On the ground of hypothalamus. This study was undertaken to investigate recent reports on its unexpected abuse, the Authors per- whether hypothalamic adrenergic function is involved in formed a microiontophoretic study in order to evaluate locomotor activity in rats. Male Wistar Strain rats and the effects of the drug on the spontaneous and evoked male Fischer 344 rats, approximately 70 days old, were firing of rat single neurones. Interactions with puta- used. Fischer 344 were reported to have a= adrenoceptor tive transmitters and with morphine were also investi- subsensitivity and higher PNMT activity in hypothalamus. gated. Rats were housed individually under a 12-hr. dark/light The study was carried out at the somatosensory cortical cycle (lights on at 6:00 a.m.). The horizontal locomotor activity in rats were measured in photocell-employed level. Opposite patterns of response were elicited by activity recording devices (0N-3420). Rats were treated lephetamine. Excitatory effects on the spontaneous firing with the PNMT inhibitor, SK&F 64139 50mg/kg, intra- rate were frequently recorded; other units were slightly peritoneally at i0:00 a.m. In Wistar strain rats the inhibited or showed no response. The latter pattern of locomotor activity counts were significantly increased effects always corrisponded to an evident inhibition of after the PNMT inhibitor injection, when compared with glutamate-evoked excit@tory responses. Preliminary data the saline injected group. The locomotor activity counts indicate that this anti-glutamate activity, which is ty- in Fischer 344 rats were also increased after injection. pical of opiates, is reversed by systemic admi,istrdtion These increased counts of locomotor activity in Fischer of naloxone (0.15 mg/Kg IP). Non- specific interactions 344 rats were significantly higher and continued longer were observed with substances such as norepineohrine, than those in Wistar rats. These results sugsest that serotonin, GABA and acetylcholine. decreased central adrenaline levels might induce the Our results give initial evidence that leohetamine may increment of locomotor activity in rats. exert even at the sinole neurone level an ooiate-like activity of a partial aoonistic type. Acknowledgements:We deeply thank Prof. Norbert Matussek Drug Dependence Unit, Dept. of Psychiatry - Catholic (Psychiatric Hospital, University of Munich) for all his Univ. S. Heart, Largo A. Gemelli 8, 00168 Rome, Italy. helpful suggestions. We thank Smith Klein & French Laboratories (Philadelphia, USA) for the presentation of the SK&F 64139 and Mrs. Chisato Watanabe (Yamanashi Medical College) and Mr. Kiyomi Ohara (Ohara Co. Ltd.) for their invaluable assistance. Dept. of Neuropsychiatry, Yamanashi Medical College iii0 Shimogato, Tamaho-chc, Nakakoma-gun, Yex,anashi-ken 409-38 Japan 368 34.01.20 34.01.21 THE ROLE OF THE NUCLEUS ACCUMBENS IN MEDIATING HALOPERI- DIFFERENT ~CHANIS!.~ UNDERLIE THE DEVELOPMENT D0L INDUCED FORELIMB MUSCULAR RIGIDITY IN RATS AND EXPRESSION OF HEROIN-INDUCED PLACE B.A. Ellenbroek, J. van den Hoven & A.R. Cools PREFERENCE IN THE RAT Haloperidol is known to produce muscular rigidity in a Timothy h Hand, Luis Stinus and Michel Le Moal number of different muscles including forelimbs and hind- neroin, a drug self-administered for nonmedical limbs (DeRyck & Teitelbaum Exp. Neurol., 79, (1983), 54). reasons, is known to produce a preference for Whereas the stiato-nigro-collicular system is known to be stimuli reliably paired with its administration. involved in the expression of hindlimb rigidity (Ellenbroek This conditioned place preference (CPP) is known et al, Neurosci.Lett. 54, (1985), 189),relatively little to persist for long periods of time after drug is known about haloperidol induced forelimb muscular ri- conditioning sessions, llowever, little is known gidity. We have investigated whether the nucleus accumbeDs a~out how heroin-induced CPP develops, and there might play a role in this respect. Rats were chronically i~as been no investigation of what underlies the implanted with two cannulae aimed at either the nucleus accumbens or the neostriatum and with two stainless steel ~ost-conditioning expression of this CPP. teflon insulated wire electrodes in either the forelimb Using a novel 3-compartment place conditioning triceps (TRIC) or the hindlimb gastrccnemius soleus (GS) apparatus, we confirmed that heroin produces a muscle. strong and long-lasting CPP over a wide range of coses up to 1 mg/kg. Pretreatment on all 6 days Injections of haloperidol into the neostriatum were found of conditioning with naloxone (50ug/kg) or pimo- to induce rigidity in the GS but not the TRIC muscle. This zide (50 and 200ug/kg) prevented the development GS rigidity could be antagonised by apomorphine. On the of CPP induced by 250ug/kg heroin. Pretreatment other hand, injections of haloperidol into the nucleus ac- with clonidine (50ug/kg) resulted in an attenu- cumbens were found to induce rigidity within the TRIC but ated but significant CPP. We then determined not within the GS muscle. This TRIC rigidity, however, was wnether these same treatments could disrupt an found to be insensitive to apomorphine, but could be anta- already established CPP. Animals underwent the gonised by intra accumbens injections of phenylephrine. These data suggest that the noradrenergic system within conditioning procedure with 250ug/kg heroin, and were given naloxone (50 or 1000ug/kg), clonidine the nucleus accumbens plays a role in regulating forelimb (50ug/kg) or pimozide (50 or 200ug/kg) prior to muscle tone whereas the dopaminergic system within the h~e test session only. Surprisingly, only pimo- neostriatum plays a r01e in regulating hindlimb muscle zide at the highest dose disrupted the estab- tone. lished CPP; naloxone failed to do so, even at Psych0neuropharmacol. Res. Unit, P.O. Box 9101, 6500 HB 1000ug/kg. Together, these results suggest that Nijmegen, the Nether]aDds. while opiate and catecholamine systems contri- bute to the development of heroin CPPs, the post conditioning expression of these effects is not opiate-mediated, but rather is partially dopa- ~ine-mediated. Thus, the mechanisms underlying the development and expression of heroin reward are pharmacologically dissociable. I.N.S.E.R.M. U-259, F-33077 Bordeaux Cedex 34.01.22 34.01.23 EFFECTS OF VARIOUS TREATMENTS INTERACTING ENHANCED DOPAMINE RELEASE MAY BE FUNDAMENTAL WITH THE DOPAMINERGIC TRANSMISSION ON NEUROPHARMACOLOGICAL BASIS OF CROSS REVERSE AMINEPTINE-INDUCED HYPERACTIVITY IN MICE. TOLERANCE BET~FKEN COCAIN AND METHA~HETAMINE S,Otsuki,T.Hamamura,K,Akimoto.Y.Kazahava A. CHAGRAOUI, M. VASSE and P. PROTAIS and M,Sato It is well known that animals pretreated with Amineptlne, administered at increasing doses (5-40 mg/kg, i.p.) in mice, methamphetamine(MAP) exhibit behavioral augmenta- induces a dose-dependent hyperactivity (measured either in d~sical acfimeter tion in response to a challenge of cocain. or in DIGISCAN actimeter) which persists about 8 hours at 20 mg/kg. The Conversely,a challenge of MAP produces intense hyperactivityinduced by 20 mg/kg amineptine is dose-dependently antagonized abnormal behaviors in animals preEreated with by metoclopramide (1.25-120 m~w'kg,i.p.), SCH 23390 (75-8000 ag/kg, s.c.) and amisulpride (1.56-100 rag&g, i.p.). Nevertheless, whereas amineptine-induced coeain. In vivo dialysis technique was used to hyperactivity is completely antagonized at a relatively low dose of the study neuropharmacological basis of this phenome- discriminant banzamide derivative amisulpride (50 mg/kg, i.p.), it is completely non in the rat striatum. Exp.l;Both rats pretrea- antagonized only at a high dose of the selective D-2 antagonist metoelopramlde ted with coeain(2Omg/kg i~ 14days) and control (80 mg/kg, i.p.) or of the selective D-1 antagonist SCH 23390 (4000 ug/kg, s.c.). (pretreated with saline 14 days) recerved a chal- Amineptine-induced hyperactivity is significantly reduced (i) by low doses of lenge of MAP(4mg/kg i.p:)o After the injection, apomorphine (25-300 ug/kg~ s.c.) stimulating dopamine autoreceptors, (ii) by a release of dopamine(DA) was greater in cocain pretreatment with reserpine (4 mg.fkg,s.c., 24h prior testing) which depletes the pretreated group (Figol). Exp.2;Both rats pretre- vesicular stores of monoamines and (iii) by gammabutyrolactone (100 mg/kg, ated with MAP(4mg/kg iop. 14days) and saline i.p., 30 rain after amineptine) which inhibits the firing rate of dopaminergin neurons. Similar data are also obtained with the selective dopamine uptake pretreated control were administered cocain(20mg/ inhibitor GBR 12783 (10 mg/kg, i.p.) but not with dexamphetamine (5 mg/kg, ~g i.p.). After injection,release of DA was i.p.) whose effects persist in reserpine-pretreated mine and in gamma- greater in MAP pretreated group (Fig.2) These butyrulactone-treated mice. Fmully, the study of the interaction of increasing data suggest that enhanced DA release plays an doses of amineptlne with dexamphetamine (5 mg/kg, [p.) indicate that a low important role in cross reverse tolerance. dose of amineptine (5 mg/kg) potentiates dexamphetamine hyperactivity whereas a high dose of ~mlneptine (40 mg/kg) reduces dexamphetamJne- @COCAIN(14days ) ~r~)- F OCONTROL z~ induced hyperactivity. These data indicate that the stimulation of dop~mine 2000' MAP (14days) receptors induced by zmineptlne depends at least in great part on the ~0CONTROL dopamine released from the vesicular stores by the faring rate of dopaminerglc neurons. The similarity of the results obtained with amineptine and with the o selective dopamine uptake inhibitor GBR 12783 suggests a common mechanism of action which differs from that of dexamphetamine. i000 Laboratoire de Physiologic (U.A. CNRS 1170), U..E.R. de M4decine-Pharrnacie de ROUEN, B.P. 97, 76800 Saint Etienne da Rouvray, France. MAP "-4 COCAIN 0 0' 0 60 120 180 rain o eo mo leo | Department of NeuroDsyehiatry_Okavama University Medical School, ShiKa~a-cno, oKayama 700 Japan 369 34.01.24 34.01.25 LOCUS COERULEUS EXCITATION'BY NICOTINE IS IN VIVO MEASURENENT OF EFFICACY OF THE TWO PARTIAL AGONISTS Ro 16-6028 AND Ro 17-1812. MEDIATED VIA PRE%t&RY SENSORY AFFERENTS M.-C. Potier, L. Prado de Carvalho, P. Venault, G6ran En~ber~ and Mih#v H~ljos G. Chapouthier and d. Rossier. Previous electrophysiologioal studies have shown that nicotine The imidazobenzodiazepines Ro 16-6028 and Ro 17-1812 bind with high affinity to central benzodiazepine receptors, causes excitation of noradrenergic neurons in the locus coeruleus and have been described as partial agonists: they are (LC). In the present study, single unit recording techniques were anticonvulsant, anxiolytic, without being sedative (Haefely, 1984). Behavioral effects and in vivo binding of employed to pharmacolo#cally analyze this effect of nicotine. Ro 16-6028 and Ro 17-1812 were studied in mice, and Low doses of nicotine (40-160 l.tg/kg, i.v.) were found to receptor occupancies were correlated to behavioral effects In vivo binding studies: Ro 16-6028 and Ro 17-1812 were dose-dependently increase the LC firing rate (20-100 per cent). injected s.c. 27 min before the injection of (3H)Ro15-1788 The effect was instantaneous, shortlasting and no tachyphylaxis (50 pCi/kg i.v.), and 30 min before sacrifice. There was a dose-dependent inhibition of (3H)Ro 15-1788 binding to was observed. The effect was antagonized by pretreatment with cerebellar, cortical and hippocampal membranes by the quaternary ganglionic blockers hexamethonium (12 mg/kg, Ro 16-6028 and Ro 17-1812. Doses of Ro 18-6028 and Ro 17-1812 inhibiting 50% of the specific binding of i.p.) or chlorisondamine (0.3 mg/kg, i.v.). The typical effect of (3H)Ro 15-1788 (ID~n'S) were found to be 0.1-0.2 mg/kg and nicotine on LC discharge was, in all essential, mimicked by the 0.2-0.4 mg/kg respectively. Behavioral effects: correlation to receptor occupancies: quaternary nlco~ic agonist wtramethylammonium (TMA). Also, A dose of 0.2 mg/kg s.c. of Ro 16-8028 or Ro 17-1812, neonatal treatment with capsaicin, a procedure that is associated corresponding to 30-60% of receptor occupancy, was suffi- -cient to prevent tonic-clonic convulsions induced by with a selective degeneration of primary sensory C-fibre pentylenetetrazol (80 mg/kg s.c.). A higher dose (0.3 mg/ afferents, clearly antagonized the effect of nicotine on LC kg s.c.) of either ligand, corresponding to higher receptor occupancy (40-70%) were anxiolytic in a conflict neurons. test. However, even at 100% receptor occupancy, Ro 16-6028 We propose that the action of nicotine on central noradrenergic and Ro 17-1812 (5mg/kg s.c.) did not produce any deficit in a rotarod test. Previous studies of in vivo binding neurons in the LC is primarily executed peripherally via activation have demonstrated that anticonvulsant and anxiolytic of primary sensory C-fibre afferents. effects of full agonists (diazepam and flunitrazepam) appeared at less than 10%, and ataxic effects at higher Department of Pharmacology, University of Gothenburg P.O. level (30%) of receptor occupancy. Box 33031, 400 33 Gothenburg, Sweden Thus, higher levels of receptor occupancy seem necessary for induction of the same pharmacological effect by a partial agonist than by a full agonist. Haefely Clinical Pharmacol. 7(1) p.670. (1984) Laboratoire de Physiologic Nerveuse, C.N.R.S. 91190 Gif-sur-Yvette, France. 34.01.26 34.01.27 EFFECT OF MINAPRINE ON SYNAPTIC TRANSMISSION IF EFFECT OF MINAPRINE ON ISCH~MIA-INDUCED CHANGES THE RAT NEOCORTEX IN VIVO OF MONOAMINE CONTENTS IN DISCRETE BRAIN REGIONS S. Okuyama and H. Aihara OF MONGOLIAN GERBILS The effects of minaprine and/or excitatory amino H. Araki, Y. Tsuyuki, Y. Karasawa and H. Aihara acid antagonists on transcallosal responses Minaprine [3-2-morpholinoethylamino)-4-methyl- (TCR) were examined in urethane anesthetized 6-phenyl pyridazine dihydrochrolide] protects rats. The TCR was recorded from the sunface of against ischemia-induced destraction and dis- the anterior neocortex following electrical appearance of CAI neurons in the hippocampus in stimulation of the contralateral corpus mongolian gerbils (J. Pharmacol. Exp. Ther. 242, callosum. The TCR consisted of a biphasic 686, 1987). Neurotransmitters may be involved positive - negative waveform (S. Okuyama and in the destruction of these neurons. Next we H. Aihara, Neuropharmacology 27, 67 1988). clamped the common carotid arteries of gerbils Intravenously administered minaprine increased for 5 min and the levels of monoamines and their the amplitude of the positive- and negative- metabolites were measured using HPLC. waves, in a dose dependent manner. Levels of noradrenaline, dopamine and serotonin Intracortical microinjection of (• (5-HT) in the hippocampus, cortex and striatum phosphonovalerate (APV) and gamma-D-glutamyl- remained unchanged during the ischemia, however, glycine (DGG) reduced the amplitude of the following re-circulation these levels decreased negative-wave, with no effects on the amplitude from 5 min-2 hrs. Besides, homovanillic acid, of the positive-wave. L-glutamate diethylester 5-hydroxy~ndol acetic acid and dihydroxyphenyl (GDEE) had no effect on the TCR. The minaprine- acetic acid (DOPAC) also did not change during induced increase in the amplitude of the ischemia, but these levels increased from 5 min- negative-wave was completely antagonized by 2 hrs after re-circulation. 3-Methoxytyramine simultaneous intracortical microinjections of (3-MT) increased during ischemia and up to 30 APV and DGG which, per se, did not affect the min after re-circulation in the striatum. When TCR. In contrast, APV and DGG had no effect on minaprine in a dose of 50 mg/kg was given for 3 increase in the amplitude of the positive-wave days before the occlusion, decreases in 5-HT in to minaprine. The enhancing effect of minaprine the hippocampus and increases in DOPAC in the on the TCR remained unaltered in case of an striatum were significantly diminished 5-30 min intracortical microinjection of GDEE. These after recirculation. Further increases of 3-MT findings indicate that the negative-wave of the were recognized during ischemia. TCR may be related to excitatory amino acid The protection of destruction and disappearance receptors. The possibility that the of the CAI neurons as induced by minaprine may pharmacological action of minaprine on the be related to the serotonergic neuronal function synaptic transmission in the neocortex may be in the hippocampus. linked to the excitatory amino acid receptors warrants further attention. Research Center, Taisho Pharmaceutical Co. Ltd., Research Center, Taisho Pharmaceutical Co., Yoshino-cho, Ohmiya, Saitama 330, Japan. Ltd., Yeshino-cho, Ohmiya, Saitama 330, Japan 370 34.01.28 34.01.29 PHARMACOLOGICAL PROPERTIES OF THE ENANTIOMERS OF THE ~2- INVOLVEMENT OF CENTRAL DOPAMINERGIC NEURON AGONIST HEDETOMIDINE SYSTEMS IN BETA-PHENYLETHYLAMINE (PEA)-INDUCED R. Virtanen~ T. Viitamaa and L. Nyman BEHAVIORAL SENSITIZATION OF THE RAT Medetomidine, (~)-4- l-(2,3,dimethylphenyl)ethyl -1H-imi- T. Kuroki r T. Tsutsumi r M. Hirano r T. Matsumotof dazole, (MED), is a newly developed potent, selective and H. Uchimura, A. Shiraishi and T. Nakahara specific ~2-adrenoceptor agonist which has shown sedative , Beta-phenylethylamine (PEA) is an endogeneous analgesic and anxiolytic effects in animal models (Lammin- trace amine, which resembles amphetamine both in tausta et el., ACNP Meeting 1986, p. 205; MacDonald et al. structure and pharmacobehavioral effect. We Fed. Proc. 46, 699, 1987). The racemic compound has re- studied effects of chronic intermittent cently been resolved to its d- and 1-enantiomers (HPV-1440 treatment of PEA on stereotyped behavior and and MPV-1441, respectively) and the present paper descri- central dopaminergic neuron systems of rats. In bes some pharmacological properties of these two forms. male Wistar rats receiving 25 or 50 mg/kg of PEA In receptor binding experiments (BH-elonidine and 3H-pra- intraperitoneally once daily for 28 days, zosin displacement) both MED and MPV-1440 showed high af- progressive enhancement of stereotyped sniffing finity on ~2-binding sites (ICSO-values 3.3 and 1.2 nM, and head movement was observed. Rechallenge of respectively) while MPV-1441 was about ~0 times less ac- different doses (12.5, 25 or 50 mg/kg, i.p.) of tive. ~2/~i selectivity ratios of 46000, 5000 and &O00 PEA to behavioral sensitized rats withdrawn for for MPV-1440, MED and MPV-1441, respectively, were ob- 7 days reinstated dose-related characteristic tained in these experiments. In field stimulated mouse features of enhanced stereotypy. This behavioral was deferens preparation MED and MPV-1440 showed potent sensitization persisted up to 61 days after e~-agonistic effects while MPV-1441 was 5-4 orders of mag- withdrawal. Thus, we confirmed the formation of nitude less active. In studies with rats and mice MED and long-lasting behavioral sensitization induced by MPV-1440 had potent, dose-dependent sedative and analge- PEA similar to so-called 'reverse torelance' to sic effects which were antagonized by ~2-blockers. MPV- amphetamine. 1441 was essentially inactive. Furthermore, in narrow An in vivo release of striatal dopamine (DA) in dose range, both MED (5-10 ug/kg s.c.) and HPV-1440 (0.5- PEA-induced behaviorally sensitized rats was 1 ug/kg), but not MPV-1441, increased punished responding examined by using intracerebral dialysis. Re- in a multiple VI-FR conflict procedure in rats. challenge of PEA (25 mg/kg, i.p.) remarkably These results show that the ~2-agonistic activity of MED enhanced striatal DA release in the rat resides almost totally in the d-enantiomer. received repeated PEA (50 mg/kg, i.p.) treatment Farmos Group Ltd, Research Center, P.O. Box a25, SF-20101 after 7 days withdrawal, in parallel with the Turku, Finland intensity of the stereotyped behavior. These results suggest that repeated administration of PEA presynaptically alters the nigro-striatal dopaminergic neuron system, possibly, in the same manner of amphetamine sensitization. Center for Emotional & Behavioral Disorders, Hizen National Mental Hospital, Kanzaki, Saga 842-01, Japan. 34.01.30 34.01.31 THE ENHANCED DOP.~[LNE(DA) RELEASE AND PRODUCTION BY INFLUENCE OF RITANSERIN AND RO-15.]788 ON FLUNITRAZEPAM INDUCED CHANGES IN MORPHINE WITHDRAWAL BEHAVIOR. CARBA}~ZEPINE(CBZ) ON RAT STRIATUM. J.Gibert-Rahola, J.Valverde, R.Maldonado, I.Leonse~ui. R.H1shlda,S.Kanek~TM.Matsuna~,and K.Takebe* M.C.Saavedra, J.Esteban r and J.A.Mico. Effects of CBZ on dopaminergic system have not been fully Several BZD, among these f]unitrazepam (FZP), can modify clarified yet. This study was designed to elucidate the different signs of morphine withdrawal in animals. The effects of CBZ on metabolism and release of DA in rat pharmacological basis of this effect re,wains unknown.Mor- phine abstinence syndrome is a complex behavioral pattern striatum(adult male Wistar) by means of measuring DA and mediated by a fine balance of neurotrans~itter systems. its metabolites,in vivo volta~m~etry technique and DA uptake Thus, the shaking behavior is related to the serotoniner- method. (1)CBZ(50mg/kg,dissolved in D~O) or placebo(con- gic system,particularly 5-H~ and an inverse relationship between GABAergic activity ahd jumping has been reported. trol) was administered intraperitoneally,and the striatum It is known that GABA mediates many pharmacological ac- was removed following the decapitation at 0,1 and 2hr after tions of BZD. However, it seems that other nearotrans- injection. Catecholamines were extracted with n-butanol mitters may also be involved, perhaps indirectly, in same of the behavioral effects of BZD, for example, several and measured by HPLC with ECD. DA and DA+DOPAC+HVA findings suggest an involvement of serotonin. increased significantly lhr after CBZ administration as Previous work from oar laboratory has established that compared with the predose- and control-|hr values,respec- FZP reduces the number of jamps in morphine dependent mi- ce but inversely exacerbate shaking behavior. The present tively. study examines the mechanisms implicated in these effects The values for DOPAC+HVA/DA,DOPAC/DA and HVA/DA remained Opiate dependence was induced in OF1 mice by administra- unaltered during 2hr after injection, respectively tion of morphine s.c twice daily (9 a.m and 6 p.m), the doses were progressively increased from 25 to 150 mg/kg (2) Differential pulse oxidation current(DPOC) in rat over a period of 5 days and 2 hr. after the last morphine striatum was measured by in vivo voltammetry technique. administration,the withdrawal syndrome was induced by i.p DPOC increased with the peak observed within 30 min injection of naloxone (Smg/kg). The nsmber of jemps and we% dog shakes (WDS)were counted after na!oxone injection postinjection in the CBZ-treated(20mg/kg i.p.)rats,whereas for a i0 min. period. Mann-Whitney U test was used to DPOC remained unchanged in the control rats. (3) In vitro analyze the results. with slice of rat striatum,CBZ(10-3,10-4and I0-5M) did not FNZ (I mg/kg) decreased jemp escape attemps (U=I0 p~=.0]) and markedly increased WDS (U=5.5 p<.01). Ritanserin inhibit DA reuptake. As CBZ does not block DA receptor, (0.5 and I mg/kg) a specific 5-HT2antagonist, inhibited our results indicate that CBZ primarily enhances both the effect of FNZ on jumping (0.5 mg/kg U=15.5 p~=.05; release and production of DA in presynaptic site of 1 mg/kg U=I0 p-=.01) but only inhibited WDS at 1 mg/kg (U=24 p-=.01}. dopaminergic neuron. Ro-15.1788 a specific BZD-antagonist inhibited jumping *The Third Dept.of Internal Medicine, and WDS at 40 mg/kg (jumping: U=I4 p~=.05; WDS: U=I8 **Dept.of Neuropsychiatry, p~=.05), 20 mg/kg was completely ineffective. These results suggest that concurrent stimulation of the *eeDept.of Neurology,Hirosaki University School of Medicin% 5-HT~ receptor and the BZD-receptor may be responsible 5Zaifu-cho,Hirosaki,036 Japan. for ~he observed effect of FZP on morphine withdrawal be- havior in mice. Department of Neuroscience. Faculty of Medicine. Plaza de Falla, 11003, Cadiz (SPAIN). 371 34.01.32 34.01.33 MEDETOMIDINE AND ATIPAMEZOLE BIND SELECTIVELY TO ALPHA-2- EFFECT OF ACUTE MORPHINE ON THE REGIONAL DOPAMINE METABO- ADRENOCEPTORS LISM IN THE MOUSE BRAIN V. Saano, E. MacDonald and R. Virtanen J. Airi% L. Sepp~l~ M. Viitanen and L. Ahtee Medetomidine (MED) is an agonist, and atipamezole (ATI), Morphine (MO) is known to affect the cerebral impulse an antagonist for cK-2-adrenoceptors. In this study the af- flow and to increase the concentr:~tions of acidic dopa- finities of these compounds for various receptors were in- mine (DA) metabolites DOPAC and H~A. Less is known about vestigated using radioligand-displacement technique in the regional DA metabolism in the mouse brain, especially vitro. The inhibition constant (Ki) of MED for Oc-2-recep- concerning 3MT. In the present experiments MO (3, i0 and tors was 1.08 nM, and Ki of ATI was 1.56 nM. For other re- 30 mg/kg) was administred subcutaneously. 1 h after the ceptors, the affinities were markedly lower: Ki-value of acute dose (or 0.5, 1 and 2 h after 30 mg/kg) the mice MED for O~-1-receptors was 1750 nM, for benzodiazepine re- were decapitated and the brains were dissected into 5 ceptors 261900 nM, for tryptamine receptors 14370 nM, for parts: hypothalamus (HYP), striatum (STR), limbic fore- delta-type opiate receptors 45390 nM, and for 5-HT-2 re- brain (LIMB), rest of ferebrain (RFBR) and lower brain ceptors 14360 nM. The Ki-values of ATI, respectively, were stem (discarded). The concentrations of DA and its acidic 13300, 117500, 130400, 38790, and 27320 nM. Both compounds metabclites DOPAC and HVA, as well as 3MT in STR and enhanced the binding of muscimol to GABA receptors by app- LIMB, were measured using HPLC with electrochemical de- roximately 50% at I @M concentration. tection. In LIMB 30 mg/kg of MO increased the DA concen- To further study the effect of MED and ATI on GABA recep- tration by 34 % and 24 % at 0.5 and 1 h, respectively. tors, their interaction with a GABA receptor antagonist, The limbic 3MT concentration was not affected by MO, but bicuculline (BIC), was investigated. BIC was infused into MO elevated dose-dependently the DOPAC and HVA concentra- mouse tail vein and the convulsion threshold for three tions, the maximum increase in DOPAC being 129 % at 0.5 h successive stages (I= myoclonic jerk; II= clonus of upper and in HVA 95 % at 2 h after 30 mg/kg of MO. In sT]{ the limbs; Ill= generalized tonus) was determined. MED at do- DA concentration was not altered. The 3MT concentration ses ! 30 ~g/kg lowered by 24-32% the threshold for stages fell at 0.5 h by 41% and at 1 h by 21% but not at 2 h I and II tp 34.01:34 34.01.35 MAGNETIC RESONANCE SPECTROSCOPY (MRS) - EVIDENCE FOR 5-HTIa-DEPENDENT IPS!L~i~LT CIRCLING IN A NEW METHOD FOR IN VIVO INVESTIGATIONS 6-OKDA-LESI ONED P~.TS OF NEUROLEPTICS IN THE MAM~[AL BRAIN. D.M.Coward and S.Urwyler K. Mann, M. Bartels, K. Albert and H. Rembold Previous studies have shown that the DA D-2 agonis% Clinical effects of neurolepsics are not predic~ CV 205-502 can cause paradoxical IPSILA~L circling in table on the basis of plasma concentrations. CSF 6-0HDA-lesioned rats under certain conditions (D.M.Coward and plasma levels show marked interindividual & R.Markstein, In "Studies in Neuroscience", ed. W.Winlow, differences even under standard dose therapy. Manchester Univ. FTess, In Press). i.fe now present data NRS provides a new method fcr determining con- linking this effect to an interaction ~th 5-HTla rec- centrations of fluorinated pharmacological eptors. agents in the brain of live n~nnals. In our study rats were either fed daily doses of Lesions and receptor binding studies were carried out by fluphenazine dihydrochloride (5-50 mg/kg) by ga- conventional means. Rats exposed to 2.5 mg/kg i.p. d- vage for several weeks or they received one amphetamine in post-lesion week 6 and an inactive dose single dose of fluphenazine intravenously. of the D-1 agonist CY 208-243 (0.1 mg/zg i.p.) in weeks Fluorine-19 spectra of fluphenazine were recor- 7-9 showed ca. 700 ipsilateral turns/~-h following their ded at 188.3 MHz on a 4.7 Tesla spectrometer first exposure to CV 205-502 in week lO. Repeated "CV" (BRUKER MSL 200). Two different coils were used treatment caused diminution of ipsilateral activity and (coil a: 60 mm imaging head with a saddle type the emergence of conventional contralateral circling. integral coil, and coil b: 6 mm probe head with Identical results were obtained when saline treatment was surface coil - 10 x 18 mm). Using coil a, substituted for amphetamine or CY 208-243 exposure. The F1 spectra of the intact rat head were observed high affinity of CV 205-502 for both D-2 and 5-HTla rec- at 63 ppm with a width of 400 Hz (number of eptors prompted us to examine the 5-HTla-agonist 8-0H- scans 48000, measuring period i0 h). Fi spectra DPAT in this test paradigm. Weekly exposure to 0.6 mg/kg indicated brain concentrations of 5-10 x &0-5 M. i.p. 8-OH-DPAT in post-lesion weeks 7-9 resulted in ipsi- The application of surface coil b led to marked- lateral circling after the second and third treatments ly narrower signal shapes (250 Hz). F1 spectra were detectable after 8 minutes following a (ca. 200 turns/90 min., 2p~O. O01). Subsequent CV 205-502 single intravenous application of fluphenazine - induced ipsilateral circling in these animals was no (number of scans: 480, concentration: different from that seen in saline pretreated controls, 0.4 x 10-5 M. possibly indicating that sensitisaticn to this paradoxical The 100 fold reduction in the recording time action of CV 205-502 is maximal under placebo treatment is very promising for application of Fluorine-J9 conditions. The findings suggest CV 205-502 - induced MR Spectroscopy in man. ipsilateral circling reflectsa complex interplay between University of TGbingen, Departments of stress, 5-HTla-receptor activation and endogenous dopamine Psychiatry and Organic Chemiszry, systems. Osianderstra~e 22, D-7400 TGbingen. Sandoz Research institute Berne Ltd., P.O.Box 2173, CR- 3001 Berne, Switzerland. 372 34.01.36 34.01.37 NEUROPHARMACOLOGICAL EFFECTS OF L-threo-3,4- IS THE PROTECTION AGAINST PILOCARPINE INDUCED SEIZURES AF- DIHYDROXYPHENYY.qERINE (L-DOPS) ON NEUROLOGICAL TER TRANSIENT OLIGAEMIC HYPOXIA CAUSED BY INCREASED GABA- DISEASES. LEVELS IN DIFFERENT VULNERABLE BRAIN STRUCTURES ? M. Yamamoto and H. Ujike C. Heim, M. Sieklucka-Dziuba, Z.A. Bortolotto, W. L6scher, L-DOPS is a synthetic precursor of noradrenalin E.A. Cavalhelro, K.-H. Sontag (NA). This agent i~proved freezing phenomenon BiLateral clamping ot carotid arteries (BCCA) in pentobar- in parkinoson's disease and orthostatic bitaI anaesthetized normotensive Han Wist rats for 24 or hypotension in familial amyloid polyneuropathy. 36 min leads to decreased seizure susceptibility 14 days (Narabayashi et al. Pro Jpn Acad 57B,351,1981) after application of pilocarpine (increase of potency ra- In this study,we first administered L-DOPS alone, tio 51% after 24 min of BCCA, 35% after 36 min of BCCA). and then in combir~tion with carbidopa to patients No tissue damages could be observed. GABA-levels were in- with parkinsonism(n=6) and olivo-ponto-cerebellar creased significantly in substantia nigra (17 or 24%), atrophy(n=3). NA and 3-methoxy-4-hydoxyphenylglycol hippocampus (19 or 22%), amygdala and piriform cortex (15 (MHPG) in cerebrospinal fluid(CSF) and p~asma were or 18%), frontal cortex (22 or 21%), parietal cortex (8 measured. or 12%), thalamus (16%), coil. sup. (12%); GABA-T activi- pretreat L-DOPS L-DOPS ty was decreased significantly after 36 min of BCCA in +carbidopa hippocampus (10%), frontal cortex (11%), thalamus (8%), NA in CSF 61, 29 324e147 55• striatum (19%), cerebellum (13%), hypothalamus (11%); GAD activity remained unchanged. (n=8,pg/ml) NA in plasma 128• 45 573~491 131• 54 It may be suggested that the increased C~BA levels in the most vulnerable structures prevent the generalisation of (n=9,pg/ml) seizure activity, controlled by EEG. But the results de- MHPG in CSF 7.4• 9.1• 6.3• (n=9,ng/ml) monstrated that not in all vulnerable structures the in- MHPG in plasma 5.0e0.9 4.8• 4.3~i.i creased GABA content is accompanied by decreased GABA-T (n=9,ng/ml) (mean~SD) activity. Furthermore nearly the same GABA content 14 days NA in CSF and plasma were significantly increas- after 36 min of BCCA did not protect animals to the same ed by L-DOPS therapy alone compared to both pre- extent as animals with 24 min of BCCA. Therefore not only treatment and L-DOPS+carbidopa therapy. M/~PG in the increased GABA content in the most vulnerable brain CSF showed significant increase by L-DOPS therapy structures alone should be the limitating factor for sei- alone. These findings suggest that carbidopa zure activity. inhibits the conversion of L-DOPS to NA in the Max-Planck-lnstitute for experimental Medicine, Hermann- periphery and facilitates its transport into the Rein-Str. 3, D 3400 GOttingen, F.R.G. CNS. Clinical effects will be also discussed. Deparment of Neurology,Kagawa Central Hospital, Bancho,Takamatsu 760,JAPAN 34.01.38 34.01.39 RILUZOLE (PK 26124) INDUCES DISCRIMINATIVE STIMULI INRATS. NMDA RECEPTORS MAY MEDIATE TONIC INHIBITORY Rataud J., Bardone M.C., Stutzman J.M., Mazadier M., CONTROL OF DOPAMINERGIC TRANSMISSION IN RAT ~Blanchard J.C., Laduron P. MEDIAL FRONTAL CORTEX Riluzole was found to possess an original profile as anti- T.Nishikawa, N.Hata and K.Takahashi. convulsant drug and seems to interfere with glutamate neu- The effects of bilateral infusion of excitatory rotransmission. Indeed it protected animals against con- amino acidergic drugs into the medial frontal vulsions induced by nicotine in mice (ED 50=5.8 mg/kg po) cortex on cortical dopamine (DA) metabolism and those caused by supra maximal electroshock in mice have been examined in conscious rats. Local in- and rats (ED 50=4.8 mg/kg ip and 1.5 mg/mg po respective- jection of N-methyl-D-aspartate (NMDA) receptor ly). Furthermore, it inhibited post-discharges and beha- antagonists, 2-amino,5-phosphonovalerate (APV) vioral manifestations induced by amygdala stimulation in and 2-amino-Y-phosphonoheptanoate (APH), in- rats (kindling phenomena ; ED 50=I.25 mg/kg ip). creased the amount of 3,4-dihydroxyphenylacetic In contrast to benzodiazepines, which are known to inhibit acid (DOPAC) and the DOPAC/DA ratio in the the seizures induced by pentylene tetrazole (PTZ) or pi- medial frontal cortex. Furthermore, APV, APH crotoxin, riluzole (20 mg/kg po) did not antagonizeclonic and 3-((~)-2-carboxypiperazin-4-yl)-propyl-l- seizures induced by these agents. Nevertheless, it protec- phosphonate (another NMDA receptor antagonist) ted animals against tonic seizures like carbamazepine.But locally applied to the medial frontal cortex, unlike benzodiazepines, it did not antagonize PTZ stimuli facilitated cortical DA utilization after inhi- in rats (LAL test). This product is not a true sedative bition of DA synthesis induced by intraperito- agent although it was able to induce at low doses(2mg/kg neal administration of ~-methyl-p-tyrosine (a ip) slow wave and REM sleep in rats. tyrosine hydroxylase inhibitor). In contrast, Owing to its original profile and preliminary positive Jntra-meaial frontal cortex infusion of gluta- clinical results observed in schizophrenic patients, we mate diethylester (a quisqualate receptor an- decided to test the possible discriminative properties tagonist), r-glutamyl-aminomethyl sulphonate (a of riluzole. Male rats were trained to discriminate the quisqualate/kainate receptor antagonist) and interoceptive effecz of riluzole (4 mg/kg po) from saline NMDA failed to affect the cortical DOPAC/DA in a standard two levels operant conditioning procedure. ratio and DA utilization. These findings are Only 50 percent of the rats learned to discriminate this consistent with the view that NMDA receptors compound from saline. The stimulation was not dependent of the route of administration and the ED 50 value after may be involved in tonic inhibitory regulation inzraperitoneal injection was 1.5 mg/kg. In contrast MK801 of dopaminergic transmission in the medial did not generalize to the riluzole discriminative cue. frontal cortex. All these results suggest that riluzole possessesdiscri- Division of Mental Disorder Research, National minative properties and although the precise mechanism Institute of Neurosc~ence, NCNP, 4-1-1, Ogawa- of its antiglutamate action remains to be elucidated, Higashi, Kodaira, Tokyo 187, Japan. this compound markedly differs from MK 801 which is a well known non competitive NMDA antagonist. RHONE-POULENC SANTE, Centre de Recherches de Gennevil]lers, 35, quai du Moulin de Cage, 92231 Gennevilliers (France) 373 34.01.40 34.01.41 NEUROENDOCRINE EFFECTS OF INTRAHIPPOCAMPAL KAINIC ~H-PN 200-110 BINDING SITES ASSOCIATED WITH ACID LESIONS: AN EXPERIMENTAL MODEL FOR STUDYING SLOW CALCIUM CHANNELS IN CULTURED NEURONES EPILEPSY AND PREGNANCY. J.N. Octave and J.M. Maloteaux D. Amaro, IoT.N. Verreschi and M.P.P. Berzaghi Several tritiated ligands of the dihydropyridine Intrahippocampal kainic acid lesions offer an chemical group have bee_n used to characterize experimental model of epilepsy which is the slow calcium channels in rat brain. The characterized by the late appearance of specific binding of =H-PN 200-110 was studied spontaneous recurrent seizures (SRSS). using homogenates from rat cultured neurones. Experimental studies demonstrated that pregnancy The Scatchard analysis allowed to calculate a and nursing decrease the frequency of SRSs in Bmax value of 22.7 fmoles/mg protein and a Kd rats after KA administration in dorsal value of 0.206 • 0.055 nM which was in the same hippocampus. Data obtained from several studies range than the Kd value of 0.571 nM obtained in have firmely stablished the neuroendocrine rat brain homogenates. Competition experiments effects of neuroexcitatory amino acids. These of ~H-PN 200-110 specific binding were performed findings prompted us to study sistematically a using several calcium entry blockers and the possible endocrine influence on the development calcium activator BAY K-8644. The ICmo values of our experimental model of limbic epilepsy. demonstrate that the different drugs which have Intrahippocampal KA injections in female rats been used interact with a common binding site. markedly affected the estrous cycle. Progesterone The 4~Ca=- uptake into neurones has been studied levels 24 h following KA (Acute Period), were in 5- and 50 mM K" depolarizing medium. The similar to those found in no treated rats. 4~Ca=" uptake increased rapidly in depolarizing However, two weeks later (Silent Period), it was codition, reaching 235 % of the basal uptake clearly observed a significant decrease in after I minute incubation. The calcium antago- progesterone levels among KA treated female. nists nitrendipine, verapamil, diltiazem, These data suggest that our experimental model flunarizine and pimozide did not decrease either of epilepsy in pregnancy is of particular the basal or the 50 mM K" induced 4~Ca =§ uptake interest in understanding the relationship in cultured neurones. BAY K-B644 significantly between seizures activity and neuroendocrine enhanced the 4mCa =§ uptake in depolarizing status. conditions and this effect was completely inhibited by 1 uM nitrendipine or by I0 ~M Supported by FAPESP, FINEP and CNPq from Brazil. flunarizine. In cultured neurones, calcium antagonists only LaboratSrio de Neurologia Experimental da Escola inhibit the effect of BAY K-8644, whereas in Paulista de Medicina peripheral tumoral cells from neuronal origin, Rua Botucatu, 862 - Caixa Postal 20265 these calcium antagonists are also able to block BROIO00 - SAO PAULO (SP) - BRAZIL the K ~ induced calcium uptake. Universit~ Catholique de Louvain, laboratoire de Neurochimie, UCL 1352, B-1200 Brussels, Belgium. 34.01.42 34.01.43 UNALTERED HIPPOCAMPAL ~-CONOTOXIN GVIA AND DIHYDROPYRI- INFLUENCE OF SOCIAL ISOLATION OF TIME-DEPENDENT DINE BINDING SITES AFTER REPEATED ELECTROCONVULSI\~ SHOCK CHANGES IN PENTOBAPH3ITAL RESPONSE OF MICE IN RATS H. Watanabe and N. Ogawa D.J. Dooley Introduction Hypnotic effect of sodium Although the efficacy of eleetroconvulsive treatment pentobarbital (PB) varies within a day and is (ECT) in human depression is indisputable, the relevant influenced by socio-psychological condition. physiologic changes effected by this therapeutic approach We examined the role of pharmacokinetic facet remain controversial and elusive. Since ECT undoubtedly in these phenomena. affects some of the processes underlying calei~-depen- Methods After PB injection (50 mg/kg, i.p.) at dent neurotransmitter release, there is the possibility 0300, 0900, 1500 and 2100, the sleeping time that ECT-induced alterations in hippocampal voltage-sen- (onset and duration) and the drug levels at the sitive calcium channels (VSCCs) may contribute to the awakening in brain were observed. Mice were antidepressant effect. The existence of such alterations housed in group of 5 or singly for 2M prior to was addressed by repeatedly administering electmoconvul- the experiment with food and water ad lib. sive shock (ECS) (ear-clip electrodes; BO mA, 0.5 s, Automatically-controlled artifical illumination 50 Hz sinusoidal; 1 x i0 days) to rats [Sprague- provided alternating 12 h periods for light Dawley, ~, 120-130 g], sacrificing these animals 24 h (0700-1900) and darkness (1900-0700). after the last ECS, and preparing crude hippocampal Results The time-dependent variations in the membrane suspensions for use in radiolig~ binding durations of sleeping and in the drug levels assays for N-~y~e VSCCs (0.I-I0 pM or 4 pM I-~-con- at the awakening in both groups of mice were otoxin qVIA ( I-~-C~)), L-type VSCCs (lO-lOOC pM or well fitted cosine-curve (p<0.01). In both i00 pM ~H~isradipine (H-ISR)), ~nd beta, adrenoceptors groups of mice, the durations were shorter and (0.25 nM ~H-dihydroalprenolol). Saturation experiments the drug levels at the awakening were higher yielded ~lar K and B values for the sham and ~CS in the dark phase (both p<0.01, ANOVA). The groups ( I-~-~: ~0.4mpa~, ~ 600 fmol/mg protein) (~H- duration in isolated mice was significantly ISR: ~60 pM, ~i000 fmol/mg protein). Betal-adrenoceptor reduced as compared to that of the aggregated binding (positive control) was significantly decreased mice (p 374 34.01.44 34.01.45 A PHASE ADVANCE OF THE LOCOMOTOR RHYTHM IN METHAMPHETAMINE THE MCID IM_~GE ANALYSIS SYSTEM OF FLUORESCENT PRETREATED RATS TISSUE ON BRAIN AMINES H.Takagi~ S.Yamada~ H.Eojima~ Y.Noda~ S.Rarajiri~ S.Nishi I T. Shibuya and K. Sate and K.Inanaga2 Using the MCID system ( Imaging Research Inc. Effects of chronic pretreatment with methamphetamine(MAP) Canada ) to examine fluorescent tissue specimens and its withdrawal on wheel running and open field of brain a/r.ines, we studied the coloration and activities in rats were investigated. MAP (1.6 mg/day) was the quantification of fluorescent intensity. infused continuously by osmotic minipump for 28 days. The animals used in this experiment were male During MAP infusion, locomotor activity in an open field Wistar rats. After excising the brain tissue, apparatus for 3 min was significantly enhanced. fluorescent tissue specimens were prepared In contrast, the withdrawal of MAP caused a significant according to the formaldehyde method. Fluo~es- reduction in locomotor activity for more than 2 weeks. cent standards were prepared with concentrations Ten days before or 4 days after the drug withdrawal, the of 0.5, 5 and 10 pg/ul noradrenaline or dopamine animals were housed individually in a running wheel cage in a 1% albumin solution. A conversion table of and the number of cage revolutions were continuously optical density and fluorescent intensity was recorded until the 28th day after the drug withdrawal. compiled. To analyze fluorescent images, photo- During the MAP infusing period, rats markedly increased graphic slides were placed upon an illuminator the number of cage revolutions and such a hyperactivity for conversion to a shading gradation video continued for more than 28 days after the drug withdrawal. image by a CCD camera. The shading level recog- However in the rats which were housed from the 4th day nition was further facilitated by a pseudo-color after the drug withdrawal, there was no significant depiction (256 colors). By applying this method, difference in the number of revolutions between the it is ~=~^ to measure minute quantitative control and MAP-treated groups during the dark period changes in the brain catecholamine levels, such (19:00 to 7:00). On the other hand, during the light as those caused by increased intracranial pres- period (7:00 to 19:00) MAP-treated rats showed a greater sure produced by the drug, Midodrine. This number of revolutions than the control rats. This method offers an image analysis of amines in the increased activity continued up to 2 weeks following drug brain or in the adrenal medulla and it can withdrawal. Moreover, the highest activity of the MAP determine variations of amine fluorescence in group appeared 2 hours earlier than that of the saline the blood. Based on the above results, this group. These data indicate that the withdrawal of chronic method can analyze localization and movement of MAP treatment advances the onset of active phase which brain amines on the cellular level. Moreover, normally coincides with the beginning of the dark phase. an accurate quantitative protocol significantly increase the utility of the fluorescent assay Institute of Brain Diseases I, Department of Neuro- for catecholamines. psychiatry 2, Animal Center 3, Kurume University School Department of Pharmacology, Tokyo Medical of Medicine, Xurume, Fukuoka 830, Japan College, 6-i-I, Shinjuku, Shinjuku-ku, Tokyo 160 JAPAN 34.01.46 34.01.47 PLASMA DHPG DOES NOT REFLECT REDUCTION OF NORADRENALINE PLASMA HVA AND GROWTH HORMONE RESPONSE TO RELEASE AFTER ALPHA2-ADRENOCEPTOR AGONIST ADMINISTRATION METHYLPHENIDATE INFUSION IN MAN A. Kallio, M. Koulu, R. Ponkilainen, H. Scheinin,M.Schei- R.P. Sharma, 3.I. 3avaid, R. Kartan, M. Easton, G. Pandey nin MPV-1440, the pharmacologically active d-isomer of mede- Methylphenidate is a non-amphetamine psycho-stlmulant tomidine, is a highly selective alpha2-adrenoceptor~ ago- with predominantly dopaminergic properties, and is a nist. It effectively reduces the concentration of nor- potent activator of schizophrenic symptoms. Recent adrenaline (NA) in plasma presumably by activating inhib- work indicates that plasma HVA may be a valid index of itory alpha2-receptors on sympathetic nerve endings and central dopamine release. We set out to measure the in the CNS. In this study, increasing i.v. doses of MPV- behavioral response to methyJphenidate in conjunction 1440 were given to five healthy male subjects in order with measures of postsynaptic receptor stimulation to investigate the effect of reduced sympathetic nervous (growth hormone response), and presynaptic dopamine activity on the plasma levels of DHPG, an important me- release (plasma MVA response). 13 research inpatients tabolite of NA. MPV-1440 powerfully and dose-dependently (RDC diagnoses included $ schizophrenics, 2 decreased the concentration of NA in plasma. After the schizoaffectives, 5 major depressions and 2 bipolars) highest dose, the decrease was 92 %, on the average. underwent a washout period of 17 day (SD=4 days). A Plasma NA levels remained below 25 % of baseline between placebo randomized, i.v. methylphenidate injection (0.5 15 and 90 minutes after drug administration. However, mg/kg) was administered after the washout period. 7 there was only a slight (up to 25 %) reduction in plasma blood samples (15 mls) were obtained from patients on DHPG (p<0.001), and this reduction was not clearly dose- both placebo as well as active days (-#0,- dependent. 15,+30,+60,+90,+120 minute% +24 hours.). Pulse rate and The modest decrease in plasma DHPG despite almost total blood pressure recordings were obtained before and after inhibition of NA release (as indicated by disappearance infusion on either day. Clinical symptoms were rated by of NA from plasma) may be a result of continued intra- the BPRS (lg item) and GAS. A preliminary analysis neuronal NA metabolism by monoamine oxidase. Thus, the indicates a robust behavioral and growth hormone concentration of DHPG in plasma may actually reflect response to methytphenidate, and a tentative association intraneuronal noradrenaline metabolism and turnover between increases in suspiciousness and plasma HVA. rather than release of the transmitter. This conclusion is supported by the rapid decrease of plasma DHPG levels after administration of the MAO-A inhibitor moclobemide (Scheinin et al, this meeting). Department of Pharmacology, University of Turku, Kiinanmyllynkatu 10, SF-20520 Turku, Finland. 375 34.01.48 34.01.49 OXIR~CETAM ANTAGONIZES ~E EFFECT~ O? SCOPOLAMINE ON EFFECTS OF DANTROLENE ON BRAIN NEUROTRANSMITTERS LEARNING AND MEMORY ON THE RADIAL ARM MAZE IN THE RAT J. Takeuchi, Y. Kiuchi, T. Kobayashi, H. Shimizu O. Pozzi, M. Magnani and S. Banfi H. Ogata and M. Toru Since it has recently been reported that the nootropic The neuroieptic malignant syndrome is succes- drug oxiracetam (OXI] can prevent scopolamine (SCOP) sfully treazed with dopamine agonists, such as amnesia in a passive avoidance paradlgm by interacting bromocriptine, amantadine, levodopa / carbidopa. wlth central chollnergic mechanisms, the present Dantrolene, which relaxes muscle tone by inter- experiments were deslgned to investigate whether OXI fering wizh the release of calcium ions from the exerted a slmilar effect against the disruptive action sarcoplasmic reticulum, has been used effective- of SCOP on cholce accuracy in the radial maze. Male ly for management of this syndrome. It is well Wlstar rats (n=15), 2 months of age, 250 g body weight, known that the patients treated with dantrolene were malntalned at about 80% of their free-feeding body show central side-effects, such as sleepiness, weight and trained in a 8-arm radial maze using the dizziness, fatigue, insomnia, headache, speech Olton procedure untll they performed the task without disturbance, depression, mental confusion, errors. Thereafter, the rats were assigned, on separate epileptic seizure, enphoria, nervousness, etc. days, to each of the following treatments: (a) SCOP 0.2 The effects of dantrolene on brain neurotrans- mg/kg s.c., (b) OXI 30 mg/kg i.p. plus SCOP 0.2 mg/kg mitters were studied by using rats. The rats s.c., (c) methylscopolamine (MethscoP) 0.2 mg/kg s.c., were killed by decapitaltion and the brains were (d) OXI 30 mg/kg i.p., (e} SCOP 0.2 mg/kg s.c. plus divided into prefrontal cortex, striatum, physostigmine (PHYS) 0.3 mg/kg s.c. Performance during anterior hypothalamus and posterior hypothala- eachsession was assessed in terms of efflciency of mus. No significant change was found in GABA, respondlng and running tlme. SCOP induced a slgnificant gulunamic acid ana noradrenaiine concennrau• decrease in the efflclency of respondlng while in 4 brain areas 60 min. after i.p. injection MethSCOP, which does not cross the blood brain of dantrolen(5, i0, 25mg/kg). Dose-dependent barrier, was devoid of any effect. OXI and PHYS increase in 3,4-dihydroxyphenylacetic acid completely antagonized the disruptive effect of SCOP on concentration in anterior hypothalamus was the efficiency of response. On the other hand SCOP noted. produced a pronounced increase in running tlme which was not evident after the administration of MethSCOP Department of Psychiatry, Shinshu University and was antagonized by PHYS but not by OXI. Since both School of Medicine, 3-.I-1 Asahi, Matsumoto, these effects seem to be mediated through central Japan 390 cholinergic systems, as MethSCOP is unable to induce any of them while P~YS suppresses both, it can be suggested that OXI selectlvely enhances those cholin- ergic mechanisms whlch are involved in learning and memory. ISF - Laboratories for Bxomedlcal Research Via Leonardo da Vincl I - 20090 Trezzano s/N. (Milano) Italy 34.01.50 34.01.51 CERbq_s AN~D HALOPERIDOL DECRE~SED INSULIN LEVELS AND CHRONIC LITHIUM TREATMENT ENHANCES THE 5-HTIA-MEDIATED LXCRK%SED DOPAC/DA IN LIMBIC FOREBRALN SEROTONIN SYNDROME PRODUCED BY 8-OH-DPAT VIA CATHECHOL- J.Manzanares, P. Gomez-Polledo, C. Grande~ J. Saiz-Ruiz, J. Benedi AMINERGIC SYSTEM, NOT VIA POST-SYNAPTIC 5-HTIA RECEPTORS and F. Zara$oza Y. Uchitomi, S. Yamawaki, I. Hide, N. Yokota, Experiments were performed on female Wistar rats with a body H. Havakawa and K. Sarai. weight of 250-270 g.animals were divided in six groups with n=20 Previously, Goodwin et al(Psychopharmacol. 90, 488, each. Group I: Control (Saline 0.9%). Group II (Haloperidol 0.05 1986) reported that subacute lithium treatment enhanced mg,TLg/day) given intraperitoneally for 10 consecutive days. Group the serotonin(5-HT) behavioural syndrome produced by 8- IIk (Ceruletide 0.03 mg.'I 376 34.01.52 34.01.53 EFFECT OF CHRONIC ANTIDEPRESSANT TREATMENT ON PROTEIN MET-ENKEPHALIN, GIVEN ONLY EARLY STAGE OF STRESS, PHOSPHORYLATION IN DISCRETE BRAIN AREAS. ATTENUATES STRESS-INDUCED INCREASES IN NORADRENALINE D. Tinelli, J. Perez, S. Ciancio, I. Zucchi and G. TURNOVER IN RAT BRAIN REGIONS M. Tanaka, Y. Ida, A. Tsuda and M. Yoshida Racagni. By measuring levels of noradrenaline ~NAT-and its major Considerable evidence indicate that several neurotrans- metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol mitters produce many of their biological responses by sulfate (MHPG-S04), we investigated effects of Met-enke- regulating the intracellular concentration of cyclic AMP phalin (Met-ENK) administered at the three different (cAMP), cyclic GM~ (cGMP) or calcium (Ca++), thus stages of stress on increases in NA turnover caused by modifying the activity of protein kinase enzymes respon- stress in rat brain regions. Het-ENK either at 50 ~g or at 150 ug, or saline, was injected i.c.v. 0 min, 5 min, sible for the phosphorylation of substrate proteins. A or 10 min after exposure to 1-hour immobilization stress chronic antidepressant administration is associated with in male Wistar rats. Levels of NA and MHPG-S04 in the a number of adaptive changes in the central monoaminergio six brain regions were measured fluorometrically. Immobi- system. Aim of the present study was to analyze the lization stress caused significant increases in MHPG-S04 pattern of protein phosphorylation in the frontal cortex levels in the hypothalamus, amygdala, hippocampus, thala- and hippocampus of rat after a treatment with desipramine mus, midbrain and locus coeruleus (LC) region, which suggests that stress increases NA turnover in these brain (DMI), a tricyclic antidepressant. Only in the soluble regions. Met-ENK 50 pg injected immediately before fraction of cerebral cortex we observed a higher stress exposure significantly attenauted stress-induced incorporation of 32p in a protein band of apparent increases in MHPG-S04 levels in the amygdala, thalamus molecular weight of 280 KDa in basal and stimulated and LC region but the peptide injected neither 5 min nor conditions. The high molecular weight and the cAMP 10 min after stress exposure. Similarly, Met-ENK 150 ug injected at 0 min significantly attenuated these increases dependent protein kinase phosphorylation could surest in all brain regions examined, however, the peptide that this .protein may represent a microtubuleassociated injected neither 5 min nor 10 min. Number of defecation protein. Since an acute administration of DMI doesn't and weight loss caused by stress were also significantly seem to induce 8ny modification the change in the attenauted by Met-ENK injected only at 0 min. These phosphorylation of this protein could be related to the results suggest that the attenuating effect of Met-ENK biochemical modifications induced by a chronic treatment on stress-induced increases in NA turnover is greatly affected by the time of the peptide administration and with trioyclie antidepressants. that Met-ENK may inhibit increases in NA turnover in the Center of Neuropharmacoloy=y, University of Milan, Via brain regions caused by stress by affecting the initial Balzaretti 9, 20133 Milan, Italy. phase of stress. It is further suggested that these attenuating effect of the peptide may be related to the relief of fear and/or anxiety of the animals exposed to stress. Department of Pharmacology, Kurume Univeristy School of Medicine, Kurume 830, Japan. 34.02.01 CDRTISOL, ACI~ AND BETA-ENDORPHIN DURING COLD PRESSOR TEST IN PARKINSC~ DISEASE Rabey JM, Scherf M (i), Oberman Z and Graff E (2). (1)-Dept of Neurology and (2)-Dept of Pathol Chem, POSTER Tel-Aviv Med Center and Sackler School of Med, Tel-Aviv PRESENTATION University, Tel-Aviv, Israel. Stress stimulates several adaptive hormonal responses. 34.02 Prominent among them are the secretion of catecholamines from the adrenal medulla, corticosteroides from the adrenal cortex and adren~cor rico tropin (ACIH) and beta-endorphin from the pituitary. In Parkinson disease some of the neurotrans-~it ters (dopamine and norepinephr ine ), which modulate the response at hypothalamic hypophyseal level may be altered. In order Neuropharmacology of to evaluate the impact of hSe disease to the system we administrated the Cold p ressor test (hand immersion for 2 Hormones minutes in ice Water) to seventeen parkinsonian patients (twelve "old" aged 60-80 and five "young" 40-50) and twelve controls (six "old" and "young" age matched). Blood pressure, heart rate and blood samples for cortisol, ACIH and beta-endorphin determination (by radioimmunoassay) were taken at -15,0,2,4,8 and 15 minutes during the test. During the paradigma the increase of beta-endorphin s ~nol,/! (p<0.0005) and cortisol Z =2.6 ug/dl (p<0.005) was significantly lower among the p~-rkinsoni~n old patients compared with the matched controls ( ~ =16.2 pmol~ /i and 9.1 ug/dl respectively). The ACTH response in old patients was similar among both groups (A =17.0 pg/ml and n =40 pg/ml) (p<0.0003). Young parkinsonians patients also showed a lower response of all the parameters during the test. Peripheral responses as measured by heart rate and blood pressure were different among groups. In conclusion, the altered response observed, indicates that the mechanism regulating the central release of scx~e hormones in " the hypo thalami c-hypophysea i pathway during stress is deranged in Parkinson's disease affecting the peripheral response. 377 34.02.02 34.02.03 DOPAMINERGZC CONTROL ON PLASMATIC ~-MSH DETERMINATION OF RAT ADRENAL CATECHOLAMINES BY SECRETION IN MAN. LIQUID CHROMATOGRAPHY/ELECTROCHEMICAL DETECTION I.Rainero, P.Limone, C.Merlini, T.De Gennaro, (LCEC) CONFIRMS A LACK OF POSTMORTEM CHANGE IN LEVELS OF COMPOUNDS D.Piazza, G.M.Molinatti and L.Pineesi. Y. Maruyama~ Y. Ikarashi and S. Tadokoro Several studies in rats have shown that G(-MSH We present a simple, rapid and specific method is synthetized in the neurointermediate lobe for the determination of adrenal catecholamines {NIL) os the pituitary by post-translational in rat through LCEC by direct sample injection, processing of pro-opiomelanocortin. The release with no al~mina extraction. The time required to os the pep=ide from rat NIL into plasma is under obtain a full chromatogram(20 min) was signifi- cantly shorter than that needed when alumina ex- direct inhibitory dopaminergic (DA) control. traction procedure was employed(90-120 min). The existence os DA control os @(-MSH release in Direct assay of sample was accomplished by set- man has never been investigated. We therefore ting a low oxidation potential, of 0.4 V. measured the effects os acute administration os Although the sensitivity of norepinephrine, epi- metoclopramide, DA antagonist, on plasma o~-MSH nephrine and dopamine at +0.4 V was decreased by 57, 53 and 89 %, respectively, from the response concentrations. 5 male healthy subjects (mean at the optimal potential of +0.6 V, individual age Z SD = 30.0~3.2 yrs) were selected for the amounts in the adrenal tissue were sufficient study. Each subject received metoclopramide (10 for detection. The levels of norepinephrine(96 mg.iv) and placebo. Blood samples were drawn at Ng), epinephrine(465 ~g) and dopamine(3 pg) ob- 0,15,30,45,60,90 an4 120 min. following the ad- tained by direct sample injection exhibited an exellent agreement with those obtained via alu- ministration os the drug. Plasma ~-MSH-like im- mina extraction procedure. Direct sample injec- munoreactivity (~-MSH-LI) was measured with a tion method was employed to examine postmortem specific RZA kit. The antibody cross-reacted in change in levels of adrenal catecholamines in equal amount with acetyl-~(-MSH and des-acetyl- rat. The adrenal tissue was kept at room tem- -MSH. The assay sensitivity was 4 pg/ml. Basal perature(23~C) following decapitation. No sig- -MSH-LI concentration {mean ~ SD) was 9.8 + nificant postmortem change in the level of each compound was determined during 60 min after 3.8 pg/ml. Metoclopramide induced a biphasic- sacrifice. Levels of enzymes collaborating with o(-MSH increase, characterize~ by a first peak these compounds are also discussed. at 15' (la.Z=4.7 pg/ml p 34.02.04 34.02.05 BLUNTED PROLACTIN RESPONSE TO DOMPERIDONE IN SCHIZO- THE DEXAMETHASONE SUPPRESSION TEST IN PARKIN- PHRENIA SON'S DISEASE - RELATIONSHIP TO SEVERITY OF u and N.Eato DEPRESSION Prolactin(PRL) response to domperidone(DPD) (lOmg,per O. Auert, R. Rupprecht, K. P. Lescht G. Fuchs~ H. Przuntek and W. Kuhn os), that is reported not to enter the blood brain The sature os depression in Parkinson's Disease barrier and directly act on the pituitary grand, was (PD) is not clear at present. The Dexamethasone evaluated in 38 schizophrenic patients and 9 normal Supp:ession Test (DST) has been extensively volunteers. Blood samples were collected at 0,30,60, studied in depressive disorders. However only 120 and 180min after the administration. Plasma PRL few cata are available in parkinsonian patients concentrations were measured by RIA. In controls, with depressive symptoms. We compare the results the peak PRL level was observed at 30 and 120min, of the DST in 35 untreated (de novo) patients female(mean level 420ng/ml) and male(mean level 85ng/ with PD, 20 patients with endogenous depression, 20 patients with non-endogenous depression and ml), respectively. In schizophrenics, the baseline 28 h~althy control subjects. Severity of depres- PRL level was from 64 to 370ng/ml. Ten patients sion was assessed by the Hamilton Rating Scale showed no PRL increase after DPD administration for depression. Cortisol values ~ere obtained at (blunted response) and 4 patients showed delayed 8 a.e. and 4 p.m. after oral administration of response. l mg dexamethasone at ll p.m.. Cortisol nonsup- Thyrotropin releasing hormon(TRH) test was performed pression was defined as a failure to suppress in 8 patients with blunted response and 2 patients both postdexamethasone levels to below 5 ul/dl. with delayed response, and normal PRL response, which Cortisol nonsuppression occurred in 66 % of the endoeenous depressives, in 28 % of the parkin- peak time at ]Smin, was revealed in all patients. soni~n patients, in 25 % of the non-endogenous One unmedicated patient showed blunted response to depressives and in 17 % of the controls. The DPD and normal response to TRH. After treatment of mean Hami&ton score was 25 in endogenous depres- haloperidol, PRL response to DPD was still blunted. sion, 16.5 in PD, 21 in non-endogenous depression These data indicate the possibility that blunted and 5.5 in controls. As parkinsonian patients response to DPD did not due to increase of PRL basal mostly have lower Hamilton scores but higher non- ]eve] by antipsychot~c drugs but due to subsensitivity suppression rates than non-endogenous depressive patients, the abnormal DST results obtained in of dopamine receptor on the pituitary cell. PD do not only reflect severity of depression. Neurologische Universit~tsklinik, Oosef-Schnei- Chichibu Psychiatric Hospital, 1404 Terao, Chichibu, der-Str, ll, D-8700 WOrzburg. Saitama 368, JAPAN. 378 34.02.06 34.02.07 ACUTE EFFECTS OF MONOAMINERGIC DRUGS ON THE LEVELS CORTICOTROPIN RELEASING HORMONE (CRH) STIMULATES OF fl-ENDORPHIN IN RAT HYPOTHALAMIC NUCLEI HYPOTHALAMIC OPIOID RELEASE BOTH IN VIVO AND IN A. Nohtomi, M. Itoh, H. Kawasaki and K. Nohtomi VITRO K.E. Nikolarakis, O.F.X. Almeida, D.J.S. Previous studies have shown that dopamine inhib- Sirinathsinghji* and A. Herz Disturbances of the hypothalamo-pituitary-adre- its the release of B-endorphin-like immnnoreacti- nal axis are associated with several psychotic vity (B-ENDi) from rat hypothalamus in vitro (I. disorders. Hypersecretion of corticosteroids in Vermes et al.,grain Res.,326:41,1985). However. depressive patients has been extensively exam- little is known as to the acute effect of monoa~i- ined and hyperactivity of CRH neurons is well nergic drugs on the levels of B-ENDi in rat hypo- established. On the other hand, endogenous opio- thalamus in vivo. In the present study, the levels ids modulate neuronal transmission and there is of B-ENDi were determined in the hypothalamic nu- evidence indicating their involvement in the pa- thophysiology of affective psychoses. clei of the rats acutely treated with the monoam- The interaction between CRH and opioid neurons inergic drugs. were examined both in vivo and in vitro experi- In the median eminence, snlpiride (20 mg/kg) or ments in rats. Exogenous CRH applied to hypotha- domperidone (2.5 mg/kg) decreased the levels of B lamic slice preparations in vitro induced a 2- -ENDi, and L-DOPA (200 lg/kg) increased the levels fold increase in the release of B-endorphin, dyn- of B-ENDi. In the nucleus arcuatus, isoproterenol orphin and met-enkephalin. Blockade of endoge- (25 ~g/kg) increased the levels of B-ENDi, and nous CRH by the specific CRH receptor antagonist u-helical CRF9_41 both in vivo (push-pull method) propranolol (2.5 mg/kg) reversed the effect. Con- and in vitro was followed by a significant de- current injection of 5-HYP (B0 mg/kg) with fluoxe- crease in B-endorphin and dynorphin release. tine (10 mg/kg) increased the levels of B-ENI)i in These results indicate that exogenous CRH stimul- the nucleus anterior hypoth&lali, nucleus periven- ates opioid release, while hypothalamic opioid tricularis and nucleus paraventricularis. neurons are tonically stimulated by CRH releas- These results suggest that dopamine, noradrenal- ing neurons. These CRH-opioid interactions may in and serotonin Ray regulate B-endorphinergic thus have implications in the pathophysiology of neurons in rat hypothalalus. affective disorders. Max-Planck-Instiut f~r Psychiatrie, Dept. Neuro- Department of Neuropsyehiatry, Faculty of Medicine, pharmacology, Am Klopferspitz 18a,D-8033 Planegg. Kyusyu University, Fukuoka 812. JAPAN. F.R.G. *AFRC Institute of Animal Physiology, Cambridge, England. 34.02.08 34.02.09 TRH STIML~LATION TEST IN PRIMARY DEGENERATIVE DE>ENTIA THE CENTRAL ACTION OF CORTICOTROPIN-RELEASING (PDD) AND CONTROLS FACTOR - A BEHAVIORAL AND BIOCHEMICAL STUDY - M.W. Dysken, A. Falk, M. Kuskowski, and D. Krahn I.V~TSUZAKI, Y.TAKAMATSU and T.MOROJI Previous TRH stimulation studies in PDD patients vs. Corticotropin-releasing factor that consists controls have shown no difference in ~TSH (Peabody et al, of 41 amino acids and releases both ACTH and Biol Psych 21, 553,'86; E1 Sobky et al, Acta Psych Scand 6-endorphin from the anterior pituitary gland. 74, 13,'86), a blunted~TSH in patients (Sunderland et all Recently, CRF and its receptors have been Psych Res 16, 269,'85; Thomas et al, Acta Psych Scand 76, reported to to be widely distributed 158,'87), no difference in~PRL (Thomas et al, v.s.), an throughout mammarian brains. In the present augmented ~PRL in patients (Peabody et al, v.s.; E1 Sobky study, effects of CRF on behaviors and et al, v.s.), and a blunted~PRL in patients (Newhouse et turnover rates of catecholamines in discrete al, Biol Psych 21, 963,'86). We performed TRH stimula- various regions of the forebrain were examined tion tests in 18 DSM-III PDD patients (10M, 8F; age=68• when injected intracerebroventricularly 7) and 12 controls (7M, 5P; age=61• Patient Mini- (i.c.v.) in rats at a dose level of 1.0 or i0 Mental State~ExamiGation scores ranged from 2 to 28 with ug/10~l. CRF of 1.0 ug increased locomotor ll!SD=18• control scores were all equal to 30. Patient activity, while CRF of i0 ug induced HAM-D scores ranged from 2 to I0 (M=6). Protirelin (500 stereotypy characterized by grooming. CRF ug) was injected IV and blood was sampled at 0,15,30,45, injected i.c.v, caused a dose-dependent 60, and 90 min for TSH and PRL. There were no signifi- increase in the turnover rate of dopamine (DA) cant differences between patients and controls in base- in the frontal cortex (FC). DA turnover rates line T4,T3 uptake, or TSH; TRH stimulated TSH at all in the striatum, hippocampus (HIPP) and times; TP~ stimulated PRL at all times; and AUC for TSH amygdala were increased, but not in a dose and PRL. Duration of illness, M24SE, and HAM-D scores did dependent manner. These findings, taken not correlate significantly with stimulation test results together with behavioral changes observed, There was, however, a significant relationship between indicate that the behavioral change gender and stimulated TSH and PRL. The TSH peak (30 min) characterized by grooming may be associated for women (patients=20• controls=9• was significantly with the activity of the mesocortical DA greater (F=8.3, p(0.01) than for men (patients=12• system. The turnover rate of norepinephrine in controls=7• The PRL peak (15 min) for women (patients the FC and H!PP was increased significantly =66• controls=31• was significantly greater (F=7.1, but not dose-dependently, supporting the p~0.02) than for men (patients=53• controls=23• hypothesis that CRF in the brain may be an GRECC Program (IIG), Minneapolis VA Medical Center, endogenous anxiogenic factor. One Veterans Drive, Minneapolis, ~, USA. Department of Psychopharmacology, Psychiatric Research Institute of Tokyo, 2-1-8 Kamikitazawa, Setagaya-ku, 156, Tokyo 379 34.03.01 AN I'~ S'II~Y ON S~I~ MASAYK~KI U}~MATSU~ M.D. AND HI~ KAIYA, M.D. All subjects consenting to this study were physically healthy male adults under 50 years of age. Since the size POSTER of the corpus callosum is thought to be gender-related, only male subjects were used. The group of normal PRESENTATION controls consisted of 17 volunteers(all right-handed, mean_+ SD age of 31.5_+ 5.5 years old) in whom mental 34.03 disorders and a history of brain lesions could be excluded. Forty patients(39right-handed, I undetermined, mean+_SD age of 32.2+_ 6.7 years old) were diagnosed as having schizophrenic disorders based on DSM-III criteria (APA, 1980). An MRI system(Picker, Vista MR) with a 0.5 tesla superconducting magnet and a radio frequency coil, 30 cm Neuroimaging in in diameter, was used in this study, The images were constructed on a 256)< 256 matrix display. Slice thickness Neuroscience and Psychiatry was approximately 10 mm, with a special resolution of I.Tx 1.7 am. The image in a mid-sagittal cut was made using an inversion recovery pulse sequence(inversion time: 500 msec, repetition time: 2000 msec). Each demographic variable was documented for all patients. Each clinical measure on the Brief Psychiatric Rating Scale(Blm~S)(Overall and Gotham, 1962) and negative and positive symptoms(Andreasen and Olsen, 1982) were also obtained for all schizophrenic patients. All data were input into a microcomputer and treated statistically. Results, schizophrenic patients had a higher septum pellucidum : brain ratio(PBR)(t=2.92,p<0.01) and a higher anterior one third of the corpus callosum : brain ratio(ACBR)(t=2.17,p<0.06) than normal controls. There were no significant differences in corpus callosum : brain ratio(CBR), callosum width ratio(CWR), length of the corpus callosum between schizophrenics and normal controls. However, ~ithin the schizophrenic group, there was a correlation between certain morphological measures and distinct clinical features of the disease. Department of Neurology and Psychiatry, Gifu University School of Medicine, 40 Tsu~achi, Gifu, Japan. 34.03.02 34.03.03 A SPECIFIC METABOLIC PATTERN RELATED TO THE HALLUCINATORY COMPUTERIZED TOMOGRAPHY IN AFFECTIVE DISORDERS: ACTIVITY IN SCHIZOPHRENIA IRELATIONSHIPS WITH PSYCHOMOTOR RETARDATION J.D. Buret, A. Lesur, J.L. Martinot, B. Mazoyer, S.SCHLEGEL, W.MAIER, D.NIEBER, K.KRETZSCHMAR S. Pappata, A. Syrota, J.C. Baron, T. Lemp~ri&re In 44 patients with a major depressive episode, The cortical metabolic pattern of 12 schizophrenic according to DSM III, CT investigations were inpatients experiencing either true or pseudo- performed. hallucinations was studied using positron emission tomo- CT measurements: Ventricular brain ratio (VBR) graphy (PET) and 18-fluoro-deoxyglucose. All patients was measured with three different methods, fullfilled the DSM III criteria for schizophrenia and linear distances of the third ventricle, the their clinical symptomatology and the evolutive aspects of frontal horns , the bicaudate diameter, Sylvian their illness were carefully investigated. A specific and interhemispheric fissures were performed. hypothesis concerning the hallucinatory activity was Correlation analyses with different rating elaborated before data analysis. This hypothesis involved scales showed most significant correlations a particular imbalance between the activities of the with those scales which obtained "retardation" posterior associative (PA) and of the non-associative related items, e.g. Bech-Rafaelsen-Depression- sensory cortex (NAS). Variables thought to be the most Scale (BRMS), Brief Psychiatric Rating Scale, representative of this hypothesis were a priori selected Global Assessment Scale, whereas the Hamilton for the statistical analysis: the regional glucose meta- Depression Rating Scale and different anxiety bolic rates (rCMRGIu) in the PA region and in the NAS rating scales did not correlate significantly regions together with the ratio of these two values. 18- with any CT measurement. The item analyses of F-DG PET studies were also performed in a group of 6 age- BRMS items demonstrated most significant matched control subjects. The analysis revealed a signi- associations with lowered mood, verbal, motor, ficant decrease of the CMRGIu in the PA cortex (pc.05, emotional, and intellectual retardation. Such Kruskal and Wallis test) together with a marked increase relationships were not found for the items: of the ratio NAS/PA (pc.004) in the schizophrenic group. anxiety, somatic complaints, sleep disturbances We also found a significant increase of the metabolic and suicidal impulses. index (the ratio of the rCMRGIu to the whole cortex Based on these data we developed the hypothesis metabolic rate) in the NAS visual cortex (p<.0001) in the that only the "retarted" subtype of depression schizophrenic group. These results are in good agreement is associated with mild brain atrophy. In order with recent PET studies showing a reduction of the rCMRGIu to reconsider these results on the basis of in the posterior associative area in schizophrenic pa- measurements of verbal, motor and intellectual tients. Moreverp the apparent imbalance between the PA and retardation, a study of a new sample of NAS cortex activities offers a functional approach of the patients is in progress. First data of this hallucinatory phenomena whatever their sensory modality investigation will be presented. could be. This particular pattern is also in agreement Department of Psychiatry, University of Mainz, both vith the clinical phenomenology of schizophrenia and Untere Zahlbacherstr.8, D-6500 Mainz, F.R.G. with some psychophysiological theories developped about hallucinations. Serv. Bosp. F. Joliot, CEA, 91406 0rsay,France 380 34.03.04 34.03.05 VOLUME, SHAPE, LOCATION AND GRAY/WHITE TISSUE ANALYSIS Corpus Callosum Imaging in Schizophrenia OF BRAIN MAGNETIC RESONANCE IMAGES M. Casacchia, A. IRossi, P. Stratta, V. Di Nichele, 5. Ceccoli, R. H.H. Holcomb, H.L. Loats~ C.A. Tamminsa~ A. Summerfelt Fassariello~, M. Gallucci*. and A. Slusarcick Clinica Psichiairica, *Catiedra di Radiologia Computer assisted stereotaxic measurements of brain Ospedale S.H. Collemaggio. tissue is a prerequisite for assessing the role of University of L'Aquila. abnormal brain morphology in neuropsychiatric illness. 67100 L'Aquila -ITALY Magnetic resonance images (MRI), obtained with a 1.5 Tesla magnet, 3 millimeters thickness, TR=3000, TE=20 Available evidences indicate that schizophrenia may be associated and 80, were acquired of the entire brain in an initial with morphological brain changes. Among others, the possible sample of three normal volunteers and six patients with existence of structural callosal pathology in schizophrenia was firs~ psychiatric illness. These images were digitized and suggested in i972 by lqosenihal and Bigelow who reported finding a subjected to a series of measurements and transforma- significant increase in the "thickness" of the Corpus Callosum (CC) tions on a biomedical image analysis system. First, in post-mortem brains of schizophrenics compared to a psychiatric using the glabella-inion axis, we determined the x,y,z control group (i) .' stereotaxie coordinates of all image pixels. Centroid With the advent of Magnetic Resonance Imaging (MRI) technology the coordinates and volume estimates of selected problems of posi-moriem studies may be overcome because we are subcortical structures (caudate, putamen, amygdala) able to obtain detailed images of the brain in multiple planes with were determined. Lateral and third ventricle volumes an e~celleni delineation of morphology of the CC in vivo. were also measured in association with a serial slice We underlook a MR) controlled s~udy in schizophrenia by means o~ analysis of shape. The latter was accomplished using a an Ansaldo Esatom 5000 scanner operating at 0.5 Tesla magneli~ Fourier expansion of the structure's perimeter. The field (2). shape was described using the amplitudes and phase A midsagillal slice (5 mm thid0 and 8 axial slices (10 mm thid0 were angles of the first eight harmonic terms. Trend obtained. Several midsagittal and axial measurements were analysis and principal component analysis provided performed on 30 palienis and 30 strictly matched controls, estimates of harmonic term influence over rostro-caudal Schizophrenics showed a sial)st)tally significant larger Venlricular and dorso-ventral axes. In each slice gray/white Brain ratio and lower Corpus Callosum to brain ratio. Structural tissue contributions were assessed using optical callosal differences may be useful for further exploration of transmission thresholding. By using the cingulate functional organization in the normal human brain and of possible cortex or superior frontal pole as an internal control, alteration in normal cerebral organization thai a~-e associated wiiJl we were able to determine the precent of brain tissue the paiophysiology of schizophrenia. that provided magnetic resonance signals characteristic of gray matter, white matter, or cerebrospinal fluid. I> lqosenihal R., Bigelow L.B. (i972): Quantitative brain This set of morphometric analyses will substantially measurements in chronic schizophrenia. Br. J. Psychiatry 12,259. improve the quantitative assessment of brain tissue 2) ~cssi A., Stralia P., Casacchia N. et al (1988): Brain morpholog~ shape, volume, topology, and gray/white in schizophrenia by Magnetic Resonance Imaging (MR)). Acta characteristics. University of Maryland Psychiatric Psych)air. Scandinavica (in press). Research Center; Johns Hopkins Medical Institutes; and Loats Associates, Inc.; Baltimore, MD 21228, USA. 34.03.06 34.03.07 ~mpairment of saccadic eye movements in MRI AND CT IN CHRONIC ALCOHOLISM - EFFECTS OP schizophrenics. ABSTINENCE CN !NTRACRANIAL CSF VOLUME AND BRAIN DENSiUY. A. Mackert, C. Woyth G. Mundle: K. Mann~ D. Petersen~ H.W. Schied~ G. Schroth an~ H. He)mann Schzzophrenlcs have well known dificiencies in Alcoholic brain shrinkage has been considered to be due to dehydration of the brain whereas its smooth pursult eye tracking. The present inve- reversibi!i~y following abstinence has been at- stigation focusses on saccadic eye movements tributed to rehydration. We tested this hypothe- responsible for rapidly directing the fovea sis using ccm~uted tomography (n=45) and magne- to a target in visual space. tic resonance imaging (n=10) in chronic alcoho- 47 acute schizophrenics without neuroleptics lics before and after a six weeks detoxification fulfilling RDC criteria participated in the program. study. The BPRS, SANS and Prognostic Scale Intracranial volumetry revealed a highly signif~ served as instruments for psychopathology. The cant reduction of CSF volume (p> 0.001) after control group included 28 age and sex matched abstinence. Uhe partial volume effect could be healthy volunteers. A luminous target was dis- better resolved by MR!. T2-relaxation times for placed unpredictably from 7,5 to maximal 2o ~ in withe matter were estimated by linear regression both directions. Saccadic eye movements were from 16 echoes of a CPGM sequence. Significant recorded by electrooculography in the horizonta increases which one would expect from higher plane. free water content (i.e. rehydration) could not Schizophrenics produced significantly more dys- be verified. metric saccades undershooting the target mainly CT density measurements were performed in 45 for small amplitudes (7,5 and Io~ Signiflcant patients. Brain density increased significantly correlations were found in patients with early in the dorsc-nedial part of the thalamus, manifestation and disadvantageous course of whereas cakate nucleus, inner capsula, and fron- illness. There were no signs of lateral asym- tal white and grey matter did not differ signi- metries in the group of schizophrenics. ficantly. Correlation between density increase The most likely explanation for the higher rate in thalamus and volume change of the ventricles of hypometric saccades in schizophrenics is a was -0.77. dysfunction of the command centers located in These results are in contradiction with the the cereDral cortex. "rehydration hypothesis". Other influences, such as a regeneration of the neuropil, might be more Department of Psychiatry important th~n previously thought. (Head: Prof. Dr. H. Helmchen), Free University Departments of Psychiatry and Neuroradiology, of Berlin, University cf ?~bingen, F.R.G. Eschenallee 3, D-looo Berlin 19 OsianderstreZe 22, D-7400 THbingen. 381 34.03.08 34.03.09 CT SCANS AND NEUROLEPTIC RESPONSE IN COMPUTED TOMOGRAPHY SCAN ~iD MEDICATION SCHIZOPHRENIA: A MULTIDIMENSIONAL APPROACH RESPONSE IN BIPOLAR AFFECTIVE DISORDER W. F. Gattaz, W. Rest, K. Kohlmeyer, K. Bauer, C. v. S. Pu• M. Berpsewicz, E. Bidzi~ska,,, K. Hfibner and T. Gasser A. Kalinowski, T. Kryst, P. Koztowski, Structural brain abnormalities in schizophrenia have M. Zatuska, E. Bos B. Habrat, been reported by several computertomographJc (CT) studies. However the prevalence and the localization Using computed tomography ventricular and of the abnormalities vary widely among studies. sulcal measurement were completed in 40 depres- These differences might stem from samples sed patients with bipolar affective disorders heterogeneity, from the choice of the CT parameter to /with long-term course of illness/. Amongst be investigated or from the use of different criteria 67 % patients cortical atrophy, enlargement of for defining abnormalities. To overcome these lateral ventricle and/or ventricle asymmetries difficulties we investigated 12 CT parameters in 80 were found. Findings suggest that above brain schizophrenic patients (mainly acute schizophrenia} changes are more frequent in patients with and in 30 sex- and age-matched controls and severe course if illness. evaluated the data simultaneously through Detailed analysis of psychotropic drugs effi- Multidimensional Scaling (MDS). MDS provides a cacy during last 3 years /antidepressants. graphic representation in which subtle deviations in lithium carbonate, neuroleptics/ showed no the different CT parameters can be detected, significant differencies in cortical atrophy independently of predetermined criteria for the and ventricular enlargement amongst responders definition of abnormalities. In our sample MDS and nonresponders. All patients with ventri- identified 18 patients with deviant measures from the cular asymetry belong to subgroup of nonres- controls in one or more CT parameters. Five of these ponders. 13 patients were first onset schizophrenics. Patients Institute of Psychiatry and Neurology, with deviant CT parameters showed significantly A1. Sobieskiego 1/9, 02-957 Warsaw, Poland poorer response to a standardized haloperidol therapy over 3 weeks as compared with patients without deviant CT parameters. Our results suggest that the multidimensional approach used here might be useful to identify more precisely patients with and without structural brain abnormalities for the further study of the features that could characterize these subgroups. Central Institute of Mental Health Mannheim P. O. Box 5970, 6800 Mannheim 1, F. R. G. 34.03.10 34.03.11 GREATER LEFT CEREBRAL HEMISPHERIC METABOLISM NEURO-IMAGING OF PAIN RELATED POTENTIALS IN TH IN BULIMIC PATIENTS AS ASSESSED BY POSITRON FREQUENCY DOMAIN EMISSION TOMOGRAPHY J. C. WU, B. Blinder, M. S. Buchsbaum, B. Bromm and E. Scharein M. Derrfler, J. Haqman, W. Y. Tai, Institute of PhTsio]o~, Hamburg University, FaG E. Hazlett and N. Sicotte We now report for the first time a study of ~ncreasingly, cerebral potentials evoked by pain- the functional neuroanatomy of bu!imic ful stimuli are investigated as an assessment to behavior as assessed by positron emission experimentally induced pain. Significant correla- tomography (PET) study of regional cerebral tions between late components of somatosensory glucose metabolism. Eight DSM-III diagnosed evoked cerebral potentials (SEPs) and painfulness bulimic subjects (mean age 28.6!6.5 yrs, all of the applied stimulus have been documented. The women, six right-handed and two left-handed) present paper describes the transformation of SEPs and eight normal controls (mean age 28.9 • 7.7 (500 ms) into the frequency domain with the para- years, all women, all right-handed) had a PET metric spectral estimator based on the maximum en- scan according to methods previously described tropy method (MEM, l) as a new approach to monitor (Buchsbaum et al, 1984). The PET scan the time course in efficacy of centrally acting procedure involved the administration of 4 to drugs. Imipramine was chosen as an example of a 5 millicuries of 18-fluoro-deoxyglucose. tricyclic antidepressant, and meperidine (pethidi- There was a significant three-way interaction he) as a synthetic opioid with strong analgesic (hemisphere by quadrant by group, F=2.82, properties. The influence of the treatments on SEP D.F.=3,42, p=.05) which confirmed a finding of spectra were monitored over 4 hours in a sample of hypofrontality. The bulimic left-sided 24 healthy subjects. Results: Most of all the PSDs subcortical structures were higher than the of the SEPs impress by an immense power peak in normal left sides structures, whereas the the 2-4 Hz range (delta). A second peak rises be- bulimic right-sided structures were less than tween 4-8 Hz (theta), and a 3rd accumulation of the normal right-sided structures. Clinical activity can be observed in the alpha band (8-12 correlations with structural metabolism: Hz). Pain ratings as well as delta power of the Significant negative clinical correlations SEP spectra were diminished by a single dose of were found for striatal and thalamic imipramine to an extent similar to that by the structures relative metabolism with the EAT. narcotic meperidine. Differences in time course of Significant positive correlations were found efficacy could be attributed to the different for the limbic structures. pharmacokinetics of the two drugs. The SEP spectra Department of Psychiatry, University of obtained by MEH are shown to be a good tool in California, Irvine, Med Sci I, Room D404, differentiating the cerebral hie-availability of Irvine, California 92717 the drugs applied. (1) Scharein E. et al. (1984), in: Pain Measure- ment in Man, B. Bromm (ed.) pp. 189-202, Else- vier, Amsterdam. 382 34.03.12 34.03.13 PET-SCANNING WITH C 11 LABELED METHYL SPiPERON AND TOPOGRAPHICAL EEG FLAPPING AND NEUROPSYCHO- PROLACTIN PROVOCATION TESTS IN THERAPY RESISTANT LOGICAL PARAMETERS IN PARKIN~N'S DISEASE ~.ND PSYCHOTIC PATIENTS DEMENTIA OF ALZHEIMER TYPE H.J.Coppensl.2 r C.J.Slooff 4, A.M.S.PaansSr W.Vaalbur~ 3, L. Fr~lich, R. Ihl, W. Kuhn, K. Maurer J.W.Louwerens 4 and J.Korf I Topographical EEG mapping shows differences of It is generally assumed that neuroleptics require a electrical brain activity in patients with blockade of cerebral dopamine-D2-receptors for their dementia of the Alzheimer Type compared to antipsychotic action. We studied whether this is a healthy controls. Some patients suffering from necessary condition in therapy resistant schizophrenics. M. Parkinson also develop a dementive syndrom. Therefore D2-receptor binding with C 11 labeled methyl The aim of the study was to uncover differences spiperon in vivo was performed with PET-scanning, the in the topographical EEG pattern of both disea- psychological condition was assessed by the present state ses. These differences might be of relevance examination (PSE) and the extrapyramidal side effects for an adequate pharmacological treatment. were evaluated by the Chouinard scale. I0 persons (2 men, 8 women) with idiopathic Six patients (between 22 and 40 yrs old) who were all Parkinson's disease volunteered to participate diagnosed as schizophrenics, according to the DSM III in our study. The characteristics of this criteria (APA'80), having positive psychotic features, sample were as follows: mean age = 64.2 years; were treated with a megadosis of neuroleptics during at duration of illness = 5.4 years. All patients least six weeks. Despite the high dosis the psychosis were receiving levodopa/benserazid and some did not change significantly. We found that all patients combination of bromocriptine, deprenyl. had a maximal D2-receptor blockade. budipine and amantadine. Parkinsonian symptoms In a second test patients were "provocated" with 500 mg were assessed by the Columbia Rating Scale and L-DOPA (plus 50 mg Carbidopa) and with i0 mg haloperidol the Zung Scale. I0 patients with probable DAT subsequently, to study changes in the prolactin blood (2 men, 8 women)(mean age = 64.8 years; concentrations. L-DOPA lowered significantly prolactin duration of illness = 4.8 years) free of concentrations, but b aloperidol was without effect. The psychotropic drug treatment were investigated results with PET and the haloperidol provocation tests for comparison. To evaluate the degree of indicate that the megadose treatment leads to a complete dementia brief cognitive rating scale (BCRS) D2-receptor blockade. was applied. For further characterization of The persistent effect of the DOPA provocation may the memory impairment "Syndrom-Kurz-Test" was indicate that under this condition not all (D2)- used. Differences were found between patients agonistic activity is suppressed. If so, therapy- with M. Parkinson and patients with DAT. resistance may be related to remaining D2-activation by Dementive syndrome~ in M. Parkinson differed in endogenous dopaminergic neurons. brain electrical activity from patients with M. (This investigation was in part supported by SQUIBB Ned) Parkinson without dementia as well as from Departments of Biological Psychiatry I , Clinical patients with DAT. Psychiatry 2 and Nuclear Medicine ~ of the Groningen Dept. of Psychiatry, University of Wdrzburg, University, and Psychiatric Hospital Licht en Kracht, FQchsleinstr. 15, D-8700 WQrzburg Assen 4, the Netherlands. 34.03.14 34.03.15 T~E INF~ OF PS~ISFHAT~ ON THE TOPOGRAPHY OF EVENT-RELATED POTENTIALS BEFORE TO~C DIST~ON OF ~ AND ~ 300. AND AFTER ANTIOEPRESSIVE THERAPY Th. Dierks, K.Maurer G.Carl, R.Dierks, K.Maurer, G.Laux Six healthy subjects volunteered in a study to investigate the Endogenously depressive (DSM III, IC0-9) influence of phosphatidylaerine on the electrical activity of the patients (3 females, 2 males; aged 37-60) were treated for 28 days with the MAO- brain as measured by electrical brain mapping. 6~ inhibitor moclobemid (300 mg/day). The average phcsphatidylserine were administered intravenously. The HRSD-score was 31 prior to treatment. On day 28 the mean HRSD-score was 14. On the day topogra~h/c distributian of ~G was measured prior to before treatment and on day 28 the administration, 30, 60, 90 and 120 rain afterward. The audibly topographical distribution of the event- related acustically evoked potentials were evoked P300 was elicited ~efore, 60 and 120 min after the recorded. N 100 and P 300 latencies and application of the substance. ~ results showed a ~mlnution of amplitudes were compared with the differences on the psychometric scales before and after delta and slow theta activity (0-5.5 Hz), whereas the fast theta treatment. Improvements in the HRSD-scores and slow al~ha (6.0-9.5 Hz) activity underwent an increase. during treatment correlated significantly as far as statistics are concerned (p 383 34.03.16 34.03.17 EFFECTS OF FIVE MONO,~MINE-INFLUENCING DRUGS ON THE FRONT.~L MIDLINE THETA ACTIVITYAND PLATELET MAO IN HUMAN APPEARANCE OF FRONTAL MIDLINE THETA ACTIVITY (Fme). SUBJECTS. H.MLrKASA, M.HASHIMOTO, J.NAKAMURA, S.YAMADA AND K.INANAGA J.NAKAMURA, H.MUKASA, M.HASHIMOTO, M.OTSLrKAAND K.INANAGA The distinct theta rhythm which appears from the frontal The distinct e rhythm which appears in the frontal midline midline during the performance of mental tasks has been area during the performance of mental tasks is called Fme. designated as frontal midline theta (Fm0). Fm8 shows indi- The appearance of Fme shows individual differences and vidual differences and seems to be related to certain seems to be re&ated to certain personality traits or the personality traits or anxiety level of the subjects. In anxiety level of the subjects. In the present study, I) several studies, it has been indicated that low platelet placebo, 2) L-DOPA (200 and 600 mg), 3) dopamine (DA) monoamine exidase (MAD) activity is also associated with releaser; a TRH analog (DN~1417:80 mg), 4) noradrenaline certain personality traits. In the present study, we have (NA) precursor; L-threo-DOPS (600 mg), 5) DA receptor investigated the correlation between the appearance of blocker; sulpiride (150 mg) and 6) MAD inhibitor; safra- Fm~ and platelet MAO activity. The subjects were 22 male zine (15 mg) were administered to healthy male students students. The serial addition task was continued for 5 for 5 days respectively. The subjects were all extrovert min and an EEG" #ecording was made during this period. The and did not show neurotic tendencies as measured by same procedure was repeated every other week up to a total Maudsley Personality Inventory (MPI) and Karolinska Scales of 3 times. MPI, MAS.and STAI were used in order to assess of Personality (KSP). EEG recording, determination of the the personality traits and anxiety level of the subjects. changes in the background activity of EEG, and The platelet MAO activity was assessed by the method of Spielberger's State-Trait Anxiety Inventory-1 (STAI-I) Jackman et al. Results were as follows: there was negative were carried out before, during and after the each drug correlation between the appearance of Fm~ and the platelet administration. The appearance of Fme showed significant MAD activity. The person with marked extroversion showed increase after the administration of L-DOPA (600 mg) an~ high amounts of Fm@ and low MAO activity. But no correla- DN-1417 (80 mg). But the appearance of Fm~ had not been tion was found between the anxiety level and platelet MAD changed by placebo, L-DOPA (200 mg), L-threo-DOPS (600 mg)~ activity. These results indicated that FmS, an electrophy- sulpiride (150 mg)and safrazine (15 mg). As to the anxi- siological marker, may be useful in the investigation of ety level, the scores of STAI-I showed no significant monoamine functions in the central nervous system by way change during the experiments. From these results, we of platelet MAD activity, a biological marker. In other consider that the change of the appearance of Fm@ due to words, the biological backgrounds of individual differ- drug administration ocurrs not via NA but through the ences in Fm8 appearance may be ascribed to the contribu- mediation of DA, and not necessarily associates with the tion of the central monoamine system. Furthermore, the change of the anxiety level. correlation of such markers as platelet MAO activity and Fme with personality traits as measured by various psycho- Department of Neuropsychiatry, Kurume University, School logical tests may prove to be of great importance in the of Medicine, 67 Asahi-machi, Kurume 830, JAPAN. exploration of the biological bases of personality. Department of NeuropsyChiatry, Kurume University, School of Medicine, 67 Asahi-machi, Kurume 830, JAPAN. 34.04.01 Hyperbilirubinemia in Schizophrenic Psychosis P. Schiller, N. MUller, M. Ackenheil It was observed, that patients suffering from schizophrenia (ICD 295.0 - 6) frequently show a slight increase of bili- POSTER rubin. In a retrospective study, the bilirubin blood con- centration of every patient, who was admitted to the psy- PRESENTATION chiatric hospital in 1985, was recorded. Excluded were patients with a liver disease and patients suffering from 34.04 alcoholism or drug abuse. A hyperbilirubinemia - comparable to the incidence of the Gilbert's syndrome is expected to occur in approximately 5-I0% of the general population. All patients having a bilirubin concentration of l,l mg% or more were listed. We found ll4 out of 858 patients with a hyperbilirubinemia (see Table below). In schizophrenics, there were~signifi- Neuroimmunomodulation cant more patients with a hyperbilirubinemia (CH~- = 20,7; p~O,OOl) compared to all other patients. Compared to the patients suffering from affective psychosis or a neurosis/ personality disorder, schizophrenics showed an extraordina- ry high ra~e of hyperbilirubinemia cases (CHI2 = 15,5; p< O,OOl; CHI~ = 18,5; pLO,OOl). In most cases, the hyperbi- lirubinemia was evident on admission to hospital and disap- peared gradually during treatment. Two aspects should be discussed. l) Is there an increased coincidence of Gilbert disease and schizophrenia, which would point to a genetic linkage or 2) an increased vulnerability of erythrocytes in schizo- phrenics? reg. pat. h.-bilirubinemia part 9atients 858 114 13,3~ schizophrenie 187 47 25,1% affective psychoses 393 39 9,9% neuroses 2D5 18 8,8% others 72 I0 13,9% ~ab]e: general view over registered patients, diagnoses and hyperbilirubinemia Psychiatric Hospital of the University of Munich 384 34.04.02 34.04.03 UTAH MOLECULAR gENETIC STUDY OF }ta_XIC-DEPRESSION 2-D-ELECTROPHORE SIS OF PROTEINS IN LYMPHOCYTES W Byerley, J-M Lalouel, M Leppert, P O'Connell, FROM PATIENTS WIT~[ PSYCHIATRIC DISORDERS. J Holick, D Stauffer, K.Bullen, F Reimherr, P Wender B Grosser, R White D.B.Wildenauer, W.Hoech~len, D.Waldinger, M.Ackenheil Recent studies indicate that agene on the short arm of ...... the llth chromosome and an allele on long arm of the X- Alterations in the composition of lymphocyte proteins chromosome determine the expression of manic-denression Were studied in patients with schizophrenic disorders in some but not all families (Egeland et al Nature 783, and compared to heakhy controls. Proteins were labeled 325, 1987, Baron et al Nature 289, 326 1987 and by treatment of lymphocytes with 88S-methionine and Mendlewicz et al Lancet 1230, i, 1987). As part of the separated by two dimensional polyacrylamide geletectro- Utah Molecular genetic Study of ~nic-Depression and phoresis according to O'Farretl. The polypeptides were Schizophrenia, we identified several multigenerational detected by autoradiography. The electrephoresis pa~tern pedigrees afflicted with manic-depression. Each family of 29 patients with schizophrenic disorders and of 24 has multiple persons affected by either Bipolar I or II healthy controls were analyzed for variations.. 14 areas, disoraer or recurrent major depression. Diagnoses were as localized by reference proteins, were found with made according to modified Research Diagnostic Criteria. variations, i.e. spots were missing, new spots appeared In a preliminary investigation, we tested for linkage or the position was changed. One of the variations between one large Utah manic-depressive family and 6 appeared to be predominant in schizophrenics: an polymornhic DNA markers (H-ras, piNS-310, pADJ762, additional polypeptide was detected in the pattern of JWI51, FTHLF, and pTT42) localized to the short arm of 12 (n=22) schizophrenics with the subtype 295.1 chromosome #ii and 6 DNA probes (Stl4 DXI3, D52A. (hebephrenic), 295.8 (paranoid) and 295.6 (chronic), p19-2, pYh~3, and pDXY$1) on the long arm of the but only in one of the controls and not in 6 patients X-chromosome. Close linkage, however, was ex&luded for with schizoaffective disorder (295.7). The respective H-ras (lod score -0.76 at 8=0.10) as well as for Stl4 molecular weight and isoelectric point of the protein (lod score -0.7] at 8=0.10). Work in progress will use is 40KD and 5.8. Correlation with biological variables the human linkage map to identify loci that confer as well as significance for schizophrenic disorders needs susceptibility to manic-depression in the Utah families. to be investigated. Dept of Psychiatry and Howard Hughes Medical Institute, Psychiatric Hospital of the University of Munich, D-8000 Univ of Utah Med Ctr., Salt Lake City, Utah 84132 USA Mfinchen 2, NuabaunstraSe 7, FRG (Head: Prof.Dr.H.Hippius) 34.04.04 34.04.05 STRESS-INDUCED MODIFICATIONS OF SOME IMMUNOLOGICAL PARA- HYPC ~RZACTIVITY TO ]]~&~ERFERON INDUCTiCN IN METERS IN THE RAT. PERIPHERAL HLOCD MONON~CLEAR LEHCCCYTES OF PSYCP~ATR IC PATIENTS. P. Foresta, C. Albertoni, A. Caprioli, M.T. Ramacci and *L. Angelucci A - -eYY- { -*_ k_- The purpose of this study was to evaluate in the rat the We have observed that peripheral blood mono-: effect of repeated stress on the responsiveness of spleen nuclear leucocytes /P~/ of patients with cells to mitogen stimulation; the activity of splenic schizophrenia ~nd affective disorders have a phagocytes; and the cytotoxicity of peritoneal macro- reduced capacity to produce interferons upon induction with Newcastle diseases virus/~V/, phages. These paramete_rs were examined in correlation ohytohemagglutinin/PHA/,phcrbol myristate with their respective hemocytometr ic analyses. Male acetate/P~[A/ or !ipopolysaccharide/LPS/.Whole Sprague-Dawley rats, aged 8 months, were used. They were blood technique was used and interferon subdivided into 3 groups: one control group (n=8) and two antiviral-activity was measured by a microbic- stressed groups (n--4 per group), with stress consisting assay using E~tC virus as challenge. T.~e response in the immersion of the animals into 4~ water for 3 rain of P~.% to h~V or LPS was more suppressed than the response to PHA+P~.We have investigated for 6 consecutive days. Then, they were subjected to whether the hyporeactivity was corrected with examination at 30 rain and at 24 hr after completion of mode of treatment.ln 20 pts subjected to ECT- the stress cycle to ascertain stress-induced immunolo- therapy we did not found any effect of ECT- gical modifications, if any. In 30-rain samples, an therapy on the induced interferon levels. increase in phagocytosis (C. albicans) accompanied by The effects of psychotropic drugs and possible total WBC increment, and a decrease in mitogen-induced transmission of hyporeactivity by serum is proliferation (PHA and LPS) were found, whereas no change under investigation. was observed in the animals sacrificed 24 hr later. The Psychiatric Clinic of the Medical University cytotoxic capacity of peritoneal macrophages showed no 25,St.Kraszewskiego,50-229 W~OCLAW,pCLAND statistically significant modification at any time. Biological Research Labs, Sigma Tan S.p.A., 00040 Pomezia, Rome, Italy and *Pharmacology II, School of Medicine, "La Sapienza" University of Rome, Italy. 385 34.04.06 34.04.07 LACK OF CORRELATION BETWEEN REDUCED NK ACTIVITY AND INCREA LY~:/~HOCYTE SUB-POPULATIONS IN MAJOR AFFECTIVE DISORDERS SED ACTH AND CORTISOL VALUES IN MAJOR DEPRESSION D: Nerozzi, A. Santoni, G. Bersani, A. Magnani, G. Frajese P.P. Pani, L. rondo, C. Burrai, L. Scamonatti, G.F. Floris, Recent reports have pointed out the reduced functional ca- P.E. Manconi pacity of the immunocompetent system in depression (S. Schleifer, Arch. Gen. Psych.41,484,1984). We evaluated the Although the interrelationship between Immune System and cytotoxic activity of Natural Killer cells (NKCA) since CNS is still far from being clear, there are several cli- this immunological parameter is involved in surveillance nical and pre-clinical observations showing the existence against neoplastic disease (R.B.Herberman, Ad. Canc.Res.27, of a relationship between psychopathological states and 305,1978) and since depression may elevate the risk of immune functions. Among psychiatric disorders depressive death from cancer (R.B.Shekelle, Psychos.Mad.43,117,1981). states are the most oftenaccompanied by abnormalities in The aim of the study was also to verify the relevance of the number and function of lymphocytes. In particular the ACTH and cortisol on NKCA in depression. Twenty-two pa- followinghave been noticed: A decreased proliferative tients free from medical disorders, diagnosed as major de- response to mitogens after bereavment (i); a negative cor- pressive with melancholia, were selected in a drug-free relation between cellular NK activity and Depression score state and compared to 22 sex- and age-matched healthy con- at the MMPI (2); a total decrease of T and B lymphocytes trols. NKCA studies were performed as previously published anda decrease proliferative response to mitogens in pa- (A.Santoni, J.Immun.iS4;2799,1985). ACTH and cortisol va- tients with Majo Depressive Disorders (3). However some of lues were measured by RIA methods. Statistical analysis these results have been disputed. The present study deals was performed using the Student's T teat (two tailed). The with abnormalities in lymphocyte sub-populations in pa- NK activity was reduced in the depressed group while ACTH tients with Major Depressive Disorder vs. a control group. and cortisol values were enhanced compared to controls Subjects have been evaluated using the MMPI and a clinical (see TAB). All tests of correlation and linear regression interview. All of them were totally drug-free. Lymphocyte performed between hormonal and immunological parameters we sub-populations were studied by monoclonal antibodies using re negative. Since alterations in various neurotransmit- a flow cytofluoremeter. ter systems in depression are well documented, a direct ac l) Scheifer S.J., Keller S.E., Camerino M., et el. tion of neurotransmitters on the immune system can not bo Suppression of Lymphocyte stimulation following bereav- excluded. ment. JAMA ,250, 374-377, 1983. l~e~ti~ol i^CTH : ...... l 2) Heisel J.S., Locke S.E., Kraus L.J., Williams R.M...... ~.~J.l l.F'-1 ~{...... '~'" I .--__ so:,...... I 2s:,* •I...... ~=,* I NK Cell Activity and MMPI Scores of a Cohort of College Students. Am. J, Psychiat. 143, 1382-1386, 1986. 3) Scheifer S.J., Keller S.E., Meyerson A.T., Rastin M.J. o.oo~ a.ool i a.o~ . o.e~ o.o2 t~ ~-~. I Lymphocyte Function in Major Depressive Disorders. Arch. Gen. psychiat. 41, 484-486, 1984. Clinics Psichiatrica, Via Liguria 13, 09127 Cagliari,ITALY / 34.04.08 34.04.09 ABNORMAL NEUTROPHIL FUNCTION IN DEPRESSION : A POSSIBLE IS THERE AN INFLUENCE OF NEUROLEPTICS ON CELLULAR STATE-DEPENDENT MARKER? IMMUNE RESPONSE? Bernadette O'Neill and B.E. Leonard. NEUMANNi N.-U., LANZINGER, 0., SANCHEZ-DELGADO, E.. Several studies have linked depression to an increased Increased cellular immune response was found in 81 incidence of cancer (Shekelle et al., Psychosom; Med., patients receiving neuroleptic treatment. In order to 45, 117, 1981), allergies (Nest et al., 3. Affect. Dis., quantify changes in the immune function we measured the 3, 2~I, 1981) and autoimmune disorders (Rogers et al., delayed cutaneous hypersensitivity reactions with ~sychosom. Med., 41, 147, 1979). Kronfol etal., (Life standardised "Multitest-Merieux". Hypersensitivity skin Sci., 55, 241, 1983) have sheen that there is a reduced reactions were significantly stronger and the average response of lymphocytes to mitogen stimulation in number of positive reactions to antigens were higher depressed patients. Our preliminary studies have sho~n than in normal controls. The increased cellular immune that neutrophil activity may also be decreased in a state- response found in these patients could be explained, et dependent manner in patients with endogenous depression least in part, by the inhibitory effects of neuroleptic (O'Neill and Leonard, IRCS Med. Sci., 14, 803, 1986). In drugs on histamine release from mast cells (calmodulin the present study we have investigated a larger patient antagonism), since histamine activates suppressor-T-cells population undergoing treatment with mianserin, through H~-receptors This blockade of suppressor fluoxetine or ECT. The results of this study show that activity,. . L with. resulting stimulation of cell-mediated neutrophil activity was reduced in drug free depressed immunity, could be of clinical relevance in immune patients'but returned to control values in response to deficiencies, malignancies and infectious desease. effective therapy. This only occurred ~hen the patients Bezirkskrankenhaus GDnzburg, Abteilung Psychiatrie II own serum was used to opsonize the zymosan usedto der Universit~t Ulm, Ludwig~Heilmeyer-Stra6e 2, initiate phagocytosis, suggesting that a Factor may be D~8870 GOnzburg present in the serum which is responsible for the suppression of phagocytosis. Experimental evidence suggests that increased serum prostenoids might be responsible. The specificity of the neutrophil test for depression was investigated by assessing neutrophil responses of panic disorder, schizophrenic, alcoholic and anxiety patients. It was found that panic disorder patients exhibited a similar decrease in neutrophil activity to depressed patients ~hich was reversed only in response to effective antidepressant treatment and was independent of anxiety symptoms. Serum cross-over studies confirmed the findings in depressed patients that the reduction in neutrophil activity was due to a serum defect rather than a cell defect. The other psychiatric groups sho~ed no differences compared to controls. Pharmacology Department, University College, Galway, Republic of Ireland. 386 34.05.01 PLASMATIC SOMATOSTIN, A STATE-MARKER OF PSYCHOPATHOLOGY IN SCHIZOPHRENIA? J. Saiz-Ruiz, J. Manzanares, J.L. Carrasco, A. Hernanz, M. Mart ln & C. Grande. POSTER Since the recognition of Somatostatin (SMT) in 1982, several roles including neuromodulation and behavioral PRESENTATION actions have been p00posed for this peptide. Research related to schizophrenic patients has been per- 34.05 formed on brain and CSF samples.The results were contro- versial and the only paper which atteapted to correlate psychopathology and CSF-SMT demonstrated a negative rela- tionship (Gattaz et al.,Psychiatry Res 17/1,1,1986). Blood levels of SMT have not been investigated in schi- zophrenic populations. We have studied 50 patients that fulfil DSM-III criteria Neuropeptides - for Schizophrenic Disorder (Age,mean:27.8;s.d. :6.9 yrs. ; 38 male,12 female). Morning blood samples were taken Basic and Clinical Aspects from fasting subjects. Determinations of SMT and Insulin were performed by RIA methods. The evaluation of psycho- pathology was made by the Spanish version of Andreasen Scales (S.A.P.S. & S.A.N.S.). SMT plasma=tic levels in our group of patients were sig- nificantly increased ~ed to a control group matched in age and sex (Student's Test,P 0.001). The results show also a positive correlation (P 0.05, Spearman Ccef. ; Factorial Analysis) between plasmatic levels of SMT and positive schizophrenics symptomatology indexes, specially Hallucinations and Delusions. On the contrary, there was no correlation with plasmatic gluco- se, insulin~ hepatic enzymes activity, sex, body weight, type or length of neuroleptic treatment and other consi- dered variables %~ne results should be further discussed considering the lack of knowledge about the physiology of peripheric SMT and possible interaction with central SMT.Other factors, such as ackninistration of psychotropic drugs and stress perhaps could explain the findings. Hospital Rar~n y ~Cajal (SQ de Psiquiatrla). iC~ Colmenar, Ks. 9,1. E-28034. Madrid (Spain). 34.05.02 34.05.03 NOREPINEPHRINE (NE) PLASMA CONCENTRATION AFTE~ J.TOPINKA, B. BINKOV~ PLACEBO, DESMETHYLIMIPRAMINE (DMI) AND RECEPTOR BLOCKERS PLUS DMI IN HEALTHY SUBJECTS. INFLUENCE OF ANTIOXIDANTS ON FREE RADICALS R. Lehle, G. Laakmann, K. Zygan, A. Weiss, DAMAGE OF LYMPHOCYTES. M. Wittmann, M. Ackenhei], N. Matussek The tricyclic antidepressant DMI mainly inhibits Oxidative damage in biological systems can oc- NE and less serotonin reuptake. It stim~!ates cur ~ue to the presence of high level of super- growth hormone (GH). Since receptor blockers in 0xid~-, hydroxyl- free Tadicals and hydrogen fluence GH stimulation differently, NE plasma perdxide, which oxidize susceptible target mo- concentrations after placebo, DMI and DMI plus lecules in living cells. They iniciate the pro- receptor blockers were compared. cess of membrane lipid peroxidation ,~ and they In 7 different groups of 5 healthy male subjects react als0 with DNA causing modification of each the NE plasma concentration was assayed. At molecular structure of genetic material. Natu- t=0 min one group'received placebo (NaC1) i.V., ral and artificial antioxidants can play a pro- the other groups DMI 50 mg i.v. Five DMI groups tect~ve role against free radical action in were premedicated with either methysergide 12 mg cells. p.o. (5-HT receptor blocker) or propranolol 15 In our experiments "in vitro" withhuman pheri- mg i.v. (B-blocker) or phentolamine 60 mg i.v. pheral lymphocytes from healthy volunteers was (~-i/~-2 blocker) or yohimbin 10 mg i.v. (~-2 measured unschedulded DNA synthesis (UDS) in blocker) or prazosin 1 mg p.o. (~-I blocker). the relation to degree Of lipid peroxidation The areas under the seven NE mean curves (AUC) (LPO) induced by Catalytic system FeII/ascorba- between~t=-30 and t=-0 min and between t=0 and te. The degree of induced LPO was measured spe- t=120 min were compared. ctrophotometrically by thiobarbituric acid ass- Neither placebo nor DMI influenced N E concentra- ay. UDS was determined by scintillometric mea- tion. Phentolamine and yohimbin increased NE surement cf incarporated H3-thymidina into DNAo concentration significantly, which was further Protective action of fatsoluble vitamin E (alp- increased by DMI. Prazosin, propranolol or me- hs-tocopherol) and some nootropics drugs on thysergide plus DMI did not influence NE concen- both LPO and UDS was studied~ tration. Thus it was:ishown that particularly ~-2 Psychiatric Research Institute, Ustavnl 91, blockade causes an increase in peripheral NE 181 o3 Prague 8, Czechoslovakia concentration which' increases further after NE reuptake inhibition by DMI. In spite of peripheral HE increase DMI-induced GH stimulation was inhibited by phentolamine and yohimbin. This indicates that GH stimulation is mediated by postsynaptic ~-2 receptors which re- main ~nhibited after their blocking despite the NE increase. Psychiatrische Klinik der Uniyersit~t MGnchen, Direktori Prof. Dr. H. Hippius, NuBbaumstr. 7 387 34.05.04 34.05.05 EXCITATORY EFFECTS OF CYCLIC CCK ANALOGS $ELECTIVE FOR EFFECT OF AGE ON BINDING SITES FOR CALCITONIN GENE-RE- CENTRAL (B-TYPE) RECEPTORS IN RAT BRAIN SLICES LATED PEPTIDE (CGRP) IN THE RAT CENTRAL NERVOUS SYSTEM G.A. B6hme, J.M. Stutzmann, J.C. Blanchard, B. Charpeniier A. Pecile, F. Guidobono, C. Netti, V. Sibilia and I. (*), B.P. Roques (*) and P.M. Laduron . Villa Cyclization of the N-terminal part of CCKB led to BC 197 [Soc-D.A~p-Tyr(SO3H)-Nle-D.L~s-Trp-Nle-Asp-Phe-NH 2] and BC Specific binding sites for CGRP have been documented 254 [Boc-D. Gfu-Tyr(SO3H)-Nle-D.L}s-Trp-Nle-Asp-Phe-NHp], two in the CNS and their distribution in a variety of synthetic analogs showing both high affinity (Ki = 5 1 and brain and spinal cord areas is suggestive of a role of 0.49 nM, respectively) and high selectivity (Ki pancreas / the peptide in CNS control mechanisms. Considering Ki brain = 179 and 1979, respectively) for central (B-type) that possible age-related changes of CGRP binding CQ< receptors in guinea pig. Because of their very lo~ activity in peripheral tests (pancreatic amylase release and might help in understanding the physiological signi- ileum contraction), we decided to evaluate the potencies of ficance of the peptide in CNS function(s) we compared BC 197 and BC 254 for enhancing the spontaneous activity of the binding site distributions of CGRP in the CNS of neurons in rat hippocampal slices, an electrophysiological aged rats (24 months old) with those of young rats (3 response known to involve central CCK-B receptors. months old) in brain and spinal cord preparations Extracellular recordings of spontaneous action potential using an in vitro autoradiographic technique. Coronal discharge frequency were obtained in CA1 area of rat hippocampal slices maintained completely submerged in sections, 16 ~m, from unfixed and frozen rat CNS were oxygenated artificial cerebrospinal fluid. Neurons sho~ing mount~ on gelatine-coated slides, incubated with reproducible excitations without tachyphylaxis Iollowing 3xlO --M l125-Tyr rat CGRP in 50 mM Tris-HCl contain- repeated bath-applications of CCKB Were tested with ing 5 mM MgCLp; 2 mM EGTA, 0.05% bacitracin and I% BC 254 and/or BC 197. Applications of both peptides resulted BSA. incubation was at room temperature for 2 h. N~n in reversible and concentration-dependent excitation. When the maximal firing rate increase of individual neurons specific binding was assessed in the presence of IO--M was expressed as percent of the response of the same neurons rat CGRP. The results showed that in old animals while to 0.5 vM sulfated CCK8 (taken as IO~A), bath-applications CGRP binding sites disappear in the colliculus su- of 0.5, 2 and 8 ~M BC 254 produced 81• (n=4), 62~7% (n=5) perior and are markedly reduced in the dorsal horns of and 92• (n=4) excitation, respectively. Similarly, after the spinal cord, they strikingly increase in the cere- 2, 5 and 10 ~M BC 197 the mean excitatory responses were 23• (n=4), 49• (n=6) and 71• (n=5), respectively. bellum. The increased binding sites in the cerebellum Potency comparisons with the excitation achieved by the with age is suggestive of an important role of CGRP in native peptide show that BC 254 was 16 times less potent the activities controlled by this brain area and of an than Cs 8. BC 197 appeared slightly less potent than BC 254. adaptive process possibly due to a decline of the These results are consistent with an excitatory activity oI peptide synthesis with age. BC 197 and BC 254 on functional processes in the rat brain. Dept. of Pharmacology, Chemotherapy and Medical Toxico- Rhfne-Poulenc Sant6, Centre de Recherches de [/]try, 94400 Vit~v-Sur Seine, FRANCEand (~) D~partement de chimZe orga- logy, University of Milan, 32 Via Vanvitelli, 20129 Mi- nJque, INSERM U 266 CNRS UA 498, Facult6 de PharmacJe, lan, Italy 755YPGParJs, FRANCE. 34.05.06 34.05.07 CAERULEIN SUPPRESSES ENDOGENOUS DOP~\IINE RELEASE EFFECTS OF THE NEUROPEPTIDE ACTH 4-10 ON NRITING PRES- ViA VAGAL AFFERENT SYSTEM,STUDIED BY IN VIVO SURE AND SPEED IN HEALTY SUBJECTS INTRACEREBRAL DIALYSIS * K.C.Steinwachs & H.L. Fehn T,Hamamura,K.Akimoto,Y.kazahaya,M.Sato, Nemerods investigations has documented the effects of and S.Ozsuki ACTH and ACTH fragments on animals and human behavior. Caerulrein(CLN),a cholecystokinin-related These effects have been discussed in relation to diffe- peptide,has been reported to posess neuroleptic rent psychological constructs such as anxiety, motiva- like activity. In vivo intracerebral dialysis tion, attention, memory and facilitation of signal de- technique was used to study the effect of CLN tection. ACTH 4-1D-analogs increased muscle AP amplitude (2,20,2O0ug/kg) on release of endogenous and decrease fatigue in intact and hypophysectomized dopamine(DA) from rat striatum. After administ- rats. It appeard promising to investigate peptide ration of CLN(200ug/kg),DA decreased between effects on psychomotor behavior and koordination in 0.5 and 5h. Maximal reduction of DA(by 29%) human. As a sensitive method for the registration of was observed at 2-2.5h. CLN(20~g/kg) also subtle motor variation the recording of writing pres- decresed DA by 21% at 1.5-2h. CLN(2~g/kg) did sure curves were used. In a rondomized cross-over not change DA level. Subdiaphragmatic vagotomy double-blind study with 10 healthy male subjects in reversed this inhibitory effect of CLN. each group the effects of 200 ug ACTH 4-10 (sniff) on These data suggest that peripherally administer- writing pressure curve parameters such as v~iting time, ed CLN suppresses ~ndo~no~s CA r~lease via final maximum pressur and pressur amplitude were in- vagal afferent system. vestigated. Paraoeters were recorded from a pressure sensitive pad during standardized testword v~iting - momon - before administration 1,2 and 3 hours after administration. i00 - i00, Compared to the placebo ACTH 4-10 increased the sponta- neous action speed of automated ~iting (ANOVAP p (0,1) and increased the final v~iting pressure (ANOVA P s 0,01) o t ~ The v~iting pressure patterns were operationally inter- laJ. ** P 0 O" Labor for Neuroendokrinologie, University of Ulm FRG, 0 1 2" 3 5 *Bezirkskrankenhaus Erlangen, Am Europakanal 71, 8520 C hrs ) ( hrs ) Erlangen FRG. Department of Neuropsychiatry,Okayama University Medical School,Sikata-eho,Okayama 700,Japan 388 34.05.08 34.05.09 RESPONSE OF GH TO GRH AND TRH "IN VITRO" IN GH- TEMPORAL ASSOCIATION BETWEEN THE SECRETION OF SECRETING ADENOMAS: EVIDENCE FOR TWO DIFFERENT LUTEINIZING HORMONE AND DSIP IN PLASMA FROM NORMAL TUMOUR CELL TYPES. HUMAN MJ~LES B.Oiivan.~O.A.Cabranes.~I.Torres.~P.Mata.~O.~Uria. R. Knabe, A. Ernst, M. Hugentobler, P. Dick, p. schulz M.Fern~ndez. TA.Duran.~E.Bordiu.,A.L.Charro. Delta sleep-inducing peptide (DSIP) shares the same topographical distribution as luteinizing hormone The different patterns of "in viva" respon- releasing hormone (LH RH) in rabbit and human brain se to diagnostic tests observed in GH-secreting (Y. Charnay, personal communication). It was recently tumours together with the variability in clinicai shownthat DSIP could release luteinizing hormone (LH) response of acromegalic patients treated with di from rat hypothalamus. Moreover , in rats the secretion verse pharmacological agents, both suggest hereto of DSIP shows a temporal association with that of geneity in the pathogenesis of this disease. corticosterone. These and other results suggest that The current study ~as undertaken to asses -- DSIP might have a role in the function of biological and characterize GH response to synthetic GRH and clocks. TRH in an " in vitro " superfusi6n system in 7 GH We therefore studied whether the secretion pulses of LH secreting pituitary adenomas obtained following and DSIP were synchronous in human plasma. Four young transsphenoidai or transfrontaI surgery. 3 of th~ male volunteers participated. Plasma was sampled every se tumours also produced PRL, as demostrated by - 30 minutes during 24 hours of either complete bed rest inmmunohistochemicsI techniques. or normal daily activity. Both hormones were measured The administration of 200 ng/mi of GRH yiel- with immunoassays. ded a significant increase in the GH content of Depending on the subject, there were 0 to 6 major the superfusi6n liquid in all four (lO0~) of the_ pulses of DSIP and 4 to 8 majorpulses of LH secretion pure GH-produeing sdenomas (PA) and in 1 of 3 -- during 24 hours. Overall, LB showed a higher pulsatile (33,3~), of the mixed GH-PRL-producing tumours (MA amplitude than DSIP in all subjects. Less than one I00 ng/ml of TRH resulted in s significant eleva- third of LH pulses were accompagnied by a DSIP pulse. tion of the GH concentration in the superfusi6n - However, half of the DSIP pulses were synchronous to a liquid in 2 out of 3 (66,6%) of the PA, and in LH pulse. We therefore obtained some evidence of a 1/3 (33,3~) of the MA. temporal association in the secretion of these two peptides in human plasma. We conclude that in the tumours studied, PA Service de la recherche biologique et de cells were more responsive to GRH than MA cells. psychopharmacologie clinique, 8 ch. Petit-Bel-Air, Furthermore, PA cells tended to have a stronger CH - 1225 Ch~ne-Bourg, Switzerland and Medizinisches response to TRH than MA cells. Our results s~port Centrum Mariastein, CH - 4115 Mariastein, Switzerland the possibility that PA cells and MA cells charac terize 2 separate types of acrsmegaly, with diffK rent mechanisms of GH-secretion. Hospital Universitario de San Carlos. 28040-MADRID SPAIN 34.05.10 34.05.11 BIOLOGICAL Ah~ PSYCHOLOGICAL EFFECTS OF RESTRICTED CHOLECYSTOKININ-LIKE-I~MUNOREACTIVITIES IN ENVIRONMENTAL STIMULATIONS THERAPY (REST) IN NORMAL SCHIZOPHRENIC POST-MORTEM BRAINS HUMANS H__~. Shibuya*f F__~.Fukamauchi* r R__t. Takahashi*r Ch.H. Kaspar, P. Schulz, J. Widmer, M. Hugentobler, H__~. Mitsushio** r K__~.Noda** r M__t.Takashima** r P. Dick, R. Tissot M. Toru** REST consists in placing an individual during 60 minutes Cholecystokinin-like-immunoreactivities in a special environment with a very low level of (CCK-L-I) in the post-mortem brains from 13 external stimulation. The individual floats in an schizophrenics and 10 controls were assay- insulated chamber containing highly salted water at ed. Schizophrenics were classified by DSM- 35 C. This has been reported to produce deep relaxation III as disorganized (7), undifferentiated with a sensation of wellbeing and some metabolic changes. (4), paranoid (I) and catatonic (I). The We measured the subjective response to REST and the brain tissues were homogenized in 3 vols of concentration in plasma of thyroid stimulating hormone 0.32 M sucrose and boiled for 20 min. CCK (TSH), lutefnizing hormone (LH), prolactin (PRL), was extracted with distilled water and cortisol and homovanilic acid (HVA). Urinary matabolites followed with 0.5 N acetic acid. CCK-L-I in of monoamines were also studied. Subjective responses water extract consisted of 74% of CCK-8 and were evaluated with analogue visual scales. Biochemical 21% of CCK-33, however, 67% and 20% of CCK- studies were done using immunoassays or BPLC. The L-I in acetic acid extract were identified variables were studied in five normal males once before, as CCK-33 and CCK-8 , respectively; CCK-L-I during and after 60 minutes of REST and once during a of schizophrenic group showed in general control situation consisting of relaxing on a bed. Before the tendency of high in water extract and participating to the study, the subjects got used to the low in acid extract. In schizophrenic practice of REST on three Occasions scheduled during two brains, CCK-L-I in acid extracts were sig- weeks. Both the REST and control sessions led to a nificantly low in the subiculum, the cor- decrease in the values Of all biochemical variables, with ticomedial nuclei of the amygdala and the the exception of LH. Compared to the control session, posterior portion of the pyriform cortex. during REST, a deeper relaxation with some euphoria was Besides, decreased CCK-L-I in acid extracts observed in all subjects. This was accompagnied by a were observed in the lateral occipito- trend towards a greater decrease in TSH and cortisol temporal cortex and the premotor area of concentrations in plasma and a greater decrease in the frontal cortex from the off- and on- vanil-mandelic acid in urine. Different relaxation drug schizophrenics. Our results suggest techniques are known to induce biological changes the alteration of CCK synthesis in these opposite to those observed during stress. Our study parts of schizophrenic brain. confirms other authors' results. *Dept. of Neuropsychiatry, Tokyo Medical Service de la recherche biologique et de and Dental Univ. I-5-45, Yushima, Bunkyo- psychopharmacologie clinique, 8 ch. Petit-Bel-Air, ku, Tokyo 113, **Dept. of Psychobiology, CH - 1225 Ch~ne-Bourg, Switzerland National Center for Mental and Nervous Disorders, Kodaira-shi, Tokyo 187, JAPAN 389 34.05.12 34.05.13 NEUROTENSIN RECEPTOR SHARES THE COMMON MECHANLSMS FOR BIDIRECTIONAL TRANSFER PHEN0~W~ON BETWEEN CHEMICAL KINDL- THE STIMULATION OF CYCUC GMP FORMATION AND OF INOSITOL ING WITH METHIONINE ENKEPHALIN ~ND CARBACHOL KINDLING OR PHOSPHATEs RELEASE WITH LOW-AFFINITY MUSCARINqC RECEPTOR ELECTRICAL KINDLING. (M1) IN NEUROBLASTOMA CLONE NIE-115 H. Takeshita, T. Tanaka, T. Sakanoto, J. Takasu, R. Kiyoke S. Kanha, Shigenobu Kanba, Elliott Richelson and Shuichi Shibata Kawahara and H. Hazama Murine neuroblastoma clone NIE-I15 cells possess various receptors including Bidirectional transfer phenomenon between chemical kindl- two-subclasses of muscarinic receptors and neurotensin receptor. ing with methionine enkephalin (~) and carhachol or e- Ix these cells, neurotensin-mediated biochemical responses are'very similar to low- lectrical kindling was investigated to elucidate the aff'mity (putative M 1)muscarinic receptor-mediated responses: both neurotensin neurochemical involvement ofME on kindling phenomenon. and carbachel, muscarinic agonist, stimulate the formation of intracellular cyclic Male Wistar rats were stereotaxically implanted with GMP and the inositol phosphates. We have reported that an active tumor pro- guide cannulae for ME or carbachol injection and bipollar motor, 4/9-phorbol 12-myristate 13-acetate (PMA), selectively inh~its low-affinity electrodes into the right amygdala. muscarinic receptor-mediated inositol phosphates release and cyclic GMP formation ME (i0 L~) or carbachol (2.5 nmo!e or 20 nmole) dissolved in NIE-115. Some inhibitors of metabolic pathway for arachidonic acid also inhibit in 1 ~LI of sterile saline was repeatedly injected into the carbachol-st~nulated cyclic GMP formation in these cells. In this study, we exanuned right amygdala every 48 hours through the guide cannulae. effect of PM#. and inhibitors of metabolic pathway for arachidonic acid on neuro- Electrical stimulation of after discharge threshold was tensin receptor-mediated second messenger activation. supplied to the right amygdala once a day. Bidirectional When neuroblastoma ceils were stimulated by 10nM neurotensin after preincubation transfer phenomefion was investigated between chemical with PMA for 45 rain, stimulation of cyclic [aH] GMP formation was irdl~ited in kindling with ME and carbachol or electrical kindling. the dose-dependent manner. The release of [3Hi inositol phosphates by neurotensin As results, transfer was found in the ME kindled rats was also inhibited by PMA in the identical manner to that for cyclic G~tP formation. from ~ kindling te electrical kind!ing as well as to ICso for PMA for the inhibition of cyclic [SH] GMP formation and the release of earbacho! kindling. In contrast the transfer phenomenon [3Hi inosital phosphates stimulated by neurotensin was 35+-6nM and 35-+8rLM, res- was not found from electrical kindling or carbachol pectively. These lCse values are in reasonable agreement with those for muscarimc kindling to ME kindling. receptors stimulated by carbachol. IJpoxygenase inhibitors and phopfi'o!ipase A2 These results suggest that the ~-enkepalinergic system inhJbitors inhibited neurotenshi-stimulated cyclic [SH] GMP formation with similar may play an impgrtant role in the kindling phenomenon, ICso values to those for carbachol. The effect of extracellu!ar Ca2§ and temperature but is not involved in the essential nervous system for were also examined. the completion of the rat amygdaloid kindling. All these pharmacological aspects of nedrotensin receptor-mediated second messen- Department of Neuropsychiatry, Tott0ri University School ger systems are similar to tose for inw-affinity muscarinic receptor. We concluded of Medicine, 56 Nishimachi, Yonage 683, Japan that neurotensin receptor shares" the common mechanism for the stimulation of cyclic GMP forrhation and of inositat phosphates release with low.affinity muscaxinic receptor. Dept. of Neuropsychiatry, Tokyo Women's Medical College, 8-1. Kawada-cho, Shtnjuku-ku, Tokyo 162, JAPAN 34.05.14 34.05.15 EXCITATORY ACTIONS OF X~-qqOPSIN, NEUROTENSIN AND RELATED EFFECTS OF BOMBESIN AND RELATED PEPTIDES ON PEPTIDES ON DOPAMINERGIC NEURONES IN VITRO SCRATCHING BEHAVIOR IN RATS M.F. Pozza, E. Kueng, S. Bischoff and H.R. Olpe Akira Masui and Nobumasa Kato The actions of the octapeptide xenopsin (a natural ana- qBombesin(BBS), a tetradecapeptide originally iso- logue of neurotensin), neurotensin (a tridecapeptide) and lated from amphibian skin, has potent biological structurally related peptides were tested on the activity effects such as hypothermia, gastrointestinal of single dopaminergic neurones of the substantia nigra hormone secretion and anorexia. Recently, the slice preparation. Extracellular recordings were made ~n excessive grooming after intracerebroventricular the pars compacta region of the rat substantia nigra. ~ne (icy) administration of BBS is often described. spontaneous firing rate of identified dopaminergic cells BBS-induced grooming is characterized as the hind (Grace and Bunney, 1983} was displayed aS the composite limb scratching compared with the bodily grooming number of spikes within 30 s periods (Pinn0ck, 1985). by other peptides(substance P, CRF). However, Xenopsin (0.I 0-M) strongly excited dopaminergic neurons the comparison among BBS-related peptides, which by 58 % (n = 6). Ala increased firing rate was also found share the common carboxy terminus, on the scratch with neurotensin (NT), NT (8-13) and D-Trp (II)-NT (all ing behavior has poorly been mentioned. In the 0.i 0-M), whereas NT (1-8) had no effect even at i0 ktM. present study, 10 BBS-related peptides(BBS, neuro- Dopamine (i00 gM) reduced the firing rate by 55 % (n=10}. medin B, gastrin releasing peptide(GRP) [I-27], Xenopsin showed similar efficacy as D-Trp (II)-NT but NT GRP[14-27], GRP[18-27], Ac-GRP[20-27], Leu-phyll- and NT (8-13) were slightly less efficacious. Injection ~litorin, Phe-phyllolitorin, and des-Trp analogs of depolarizing current through the recording electrode of phyllolitorins). (intracellular experiments)~ elicited repetitive firing of male Wistar rats, weighing 250-300g, were used. the dopaminergic neurones. The frequency was decreased by 'Cannulation was performed stereotaxically in the dopamine (I00 ~M) and increased by xenopsin and NT third ventricle under light anesthesia. The (0.i ~LM). animal was icy in~ected with each peptide at These data confirm the original findings of Pinnock that 'least 5 days after the surgery in dose grading NT and NT (8-13)exert excitatory effects on nigral dopa- 'from 0.i ug, 1.0 ug to i0 ug / i0 ul / min. The minergic cells. In addition they provide evidence that animal was placed in a plastic cage and scratch- xenopsin can mimic functional properties of (NT). Surpri- ing behavior was determined cumulatively in sec / singly D-Trp (ll)-h~ which possesses low affinity for NT min for 30-180 min. The results were as follows; receptors (Quirion eta!., 1982) also strongly excites I)BBS, neuromedin B, GRP[I-27], [14-27], [18-27] dopaminergic neurones. The strong effect of D-Trp(II)-NT were all potent in eliciting the behavior, but could be related to the presence of a D-Trp in the key the effect of BBS was the most prolonged. 2)The position ii which may protect this NT analogue from degra- effects of phyllolitorins were significantly less dation. than BBS and des-Trp analogs were totally in- Grace, A.A. and Bunney, B.S. (19~3) Neuroscience 10/2, active. The study suggests that thebiological 301-315 activity of BBS-related peptides resides in its Pinnock, R.D. (1985) Brain Res. 338, 151-154 C-terminal heptapeptides, and that Trp-residue Quirion etal. (1982) Peptides 3, 757-763 apears to be essential. Biology Research Laboratories, Pharmaceutical Division, Dept. of Psychiatry, Shiga Univ. of Med. Sci. Ciba-Geigy Ltd., CH-4002 BASLE, Switzerland Otsu 520-21, JAPAN 390 34.05.16 34.05.17 MODULATION OF DOPAMINE RECEPTORS BY YHTROTROPIN-RELEASING PRESYNAPTIC OPIOID RECEPTORS IN THE SAPHENOUS HORMONE IN THE ~4T BRAIN ARTERY OF THE RABBIT K. S. Funatsu and K. Inauaga Aniko Kovacs, T. Friedmann, Z. Furst Wide distribution of thyrotropin-releasing hormone (TRH) Opioid peptide receptors Were detected first by in the mammalian brain is known. Is is also known that TRH Knoll (1). The s~pathetic axons of the different potentiates the central dopaminergic system. There are arteries of the rabbit possess both delta and evidences that TRH stimulates the release of dopamine (DA) kappa receptors (2,3). Our experiments on isolat- from the nerve-ending in the rat nucleus accumbens. How- ed, perfused, electrically stimulated saphenous ever it has not yet been known whether TRH modulates DA arteries of the rabbit show: receptors. We therefore investigmted whether there is a -Mu receptor agonists (DAGO, morphine) are in- receptor-receptor interaction between TRH and DA using the effective; radioligand binding technique. -Delta receptor agonist (DADLE) has strong ago- Rat striatum and the limbic forebrain that includes the nist potency (ID50:7.93 nM); nucleus aecumbens and the septum were used. These regions -Kappa receptor agonists (ethylketocyclazocine are known to contain abundant DAergic nerve-endings and DA /ECK/,U-50488H, N-cyclopropyl-methyl-norazido- receptors. Membrane preparations of these regions were dihydro-isomporphine/CAM/, bremazocine) are preincubated with 100nM TRH. After the ~emoval of TRH the effective having the following rank order of ~embrane preparation was incubated for H-apomorphine or agonist activity: ECK>U-50488H>C~{>bremazocine; ~H-spiperone binding. TRH caused a significant decrease of -This tissue shows very rapid habituation to the H-apomo~phine binding sites (by 30%) in both regions effect of kappa agonists. whereas ~H-spiperone binding was not af#ected. Our'data indicate the presence of delta and kappa The binding of DA agonists and antagonists to T~H r~cep- receptors in the saphenous artery. As C~M showed tors was also tested. DA and apomorphine displaced H-TRH agonist activity this preparation seems to have binding partially, suggesting the presence of TRH receptor opioid "A" type (4). The presence of "A" receptor subpopulation that has a high affinity to DA agonists. DA type makes this artery different from the central receptor antagonists (neuroleptics) had virtually no af- ear artery characterized by "B" receptor type (5~ finity to TRH receptors. I. Knoll,J. 1976, Eur. J.Pharm. 39, 403. These findings suggest the possible interaction between 2. Illes,P. et al., 1985, J. Pharmacol. Exp. TRH receptors and a certain type of DA receptors having a Ther. 232, 526. high affinity to DA agonists, like DA autoreeeptors. Al- 3. Von Kugelgen etal., 1985, Eur. J.Pharm. 118, though the binding study cannot identify the function of 97. receptors, it is possible to speculate that this type of 4, Knoll,J. 1977, Pol. J.Pharmacol.Pharm. 29, 165. DA receptors are DA autoreceptors that are present On the 5. Kovaes,A. et al., 1985, Varna, Symp. of Phy- nerve-ending and that TRH potentiates the release of DA siol. Pharmacoi. of Smooth Muscle p 70. through the inhibition of DA autoreceptors. (Ref.) Funatsu and Inanaga, Peptides 8, 319-325, 1987. Semmelweis University of Medicine, Dept. of Department of Psychiatry. Kurume University Hospital, Pharmacology, Budapest, Nagyvarad ter 4. Asahi-machi 67, Kurume 830, Japan. P.O.B. 370, 1445-Hungary. 34.05.18 34.05.19 EFFECTS OF NALTREXONE ON INFANTILE AUTISM Nerve growth factor ootentlates the hormone M. LESOYEI~*. M P BOUVARD**. M DUGAS** stimulated intracellular accumulatlon of It h~ r.~_n su&~ted that abnormaht~ of the endogeneousopioid s,/stem may inosltolphosDhates and Ca2+ In rat underhe someof the devianced~spi~veo by auhstic children. Indirect support for pheochromocytoma cells. Comparison wlth the an er,3orphin theory of autism cem~ from the foilowing two observations : effects of epidermal arowth factor. I ) Ben~ioural features of autism ~?e similar to features in opiateaddiction and Dietrich van Calker *. Kyoya Takahata $ and anai.ogoustc symptoms observed Jr,op,ate treated animals ( PANKSEPP 1979); Roll Heumann # 2) Peri~,nera]measures of opiaid levels in autisticchildren suggest the presence of abnormalitiesi GILLBE~G 1980). This hypothesis can be further *Psychiatric Hospital of the University of explc'~ from a therapeutical perspective :Opiate antagonist therapy with a long Munich l~sting c-ally eff~tive.drug,NALTPEXONE(Du Pont De Nemours Pharmaceutical). NuBbaumstr. 7 D-8000 M~nchen 2 F.R.G. 'Naltrex~e has been specificellyt~.edon self-iniur]ousbelqaviours of # Max Planck Institut of Psychiatry ment~,ly retarded subjacts(GERM/~4 ~987) and on one autisticboy( BERNSTEIN Am Klopferspitz I, D-8033 Martinsried F.R.G. 1987). in an open and ecute-Oose range trial,we tested the response of naitr~xone on two autisticgirls, 12 &nrl I0 years old. Both of them met DSM-Ill cmtema for autism.They displayed ~mous self-injuriousbehaviours (BIB) The effects of nerve growth factor (NGF) and since the age of 7, pain insensitwity,and reducedcrying. During the present epidermal growth factor (EGF) on the intracellular aocumulation of inositolohos- exper,,ment, neurolepticswere-not discontinued.After 2 days placebo, each phates and Ca2+-ions were studied in rat PC-~2 child received a single dose of naltrexonewhich was increa~%~devery two days pheochromocytoma cells. Both NGF and EGF ( i m~!Kg/dav, 1 ,B mglkg/day ; 2 mg/KglG~iy ). Behavlour w~ assessedby potentiate in these cells the increase in the ratine me B$E ("Behavioral Summ&-L-~. Evaluation" )(LELORD, in press) one accumulation of inositolphosphates and Ca2+- hour d~er oral administration of placebo, of naltrexone, three days and six days ions that is elicited by bradykinin and after L~4"nning of therapy. Sessions wee videotapedfor assessment. carbachol. The effect of NGF. but not that os Naltrexore had a strikingly similar profile af action on the two children : a EGF. is abolished, when the cells are remd and marked reduction af hyperactivity and an improvment ]n social preincubated with 5'-deoxy-5'-methylthiosdeno- bandY,our(eye contact, smiles and inte?actions). The reduction of BIB was sin. an inhibitor of S-adenosylhomocystein anly cieer at the beginning of treatm~t ( ! and 1.5 mg/kg/doy), but this effect hydrolase. These results suggest that an dic no~ lest at 2 mg/kg/day. No Side effects were observed. As a whole, increased response to hormones, which act via naltre. 391 34.05.20 34.05.21 ELEVATED CSF LEVELS OF DYNORPHIN A [1-8] IN TOURETTE'S NEUROPHYSIOLOGICAL EFFECTS OF SYNTHETIC COMPETI- SYNDROME TIVE ANTAGONIST OF CORTICOTROPIN RELEASING J.F. Leckman. M.A. Riddle. W.H. Berrettini. G.M. FACTOR. Anderson, M Hardin. P. C~u~Doell. G. Bissette. C.B. A.Tartara,F.Savoldi,E.Marchioni,M.Maurelli Nemeroff. W.K. Goodman. and D J Cohen A recent neuropathological study has reported Corticotropin Releasing Factor (CRF), a 41 - decreased levels of dynorphin A immunoreaotivity in residue peptide, has been documented to induce striatal fibers projecting to the globus pallidus in Electroencephalographic (EEG), behavioral and the brain of a patient with severe Gilles de la autonomic effects when intracerebroventricularly Tourette's syndrome (TS). This observation taken with (i.c.v.) administered in various animal species the neuroanatomic distribution of dynorphin and its including rabbit. broad range of motor and behavioral effects has led to speculation concerning its role in the pathobiolog~ of A CRF competitive antagonist synthetized by TS. We report on the presence of elevated levels of Rivier et al has been found to be active in vivo dynorphin A [1-8] in the CSF of 7 adult, dzt~g-free TS on ACTH secretion in the rat (Science,224,889, patients (Mean + SD: TS: 294 + 57 fmol/ml vs. Ctrls: 1984). 223 +_ 64 fmol/ml, p =.036). Three of four drug-naive In the present study we have tested in 12 New patients had distinctly elevated levels of 372, 324, and 322 fmol/ml. The increase in CSF dynorphin was Zealand rabbits the effects of a CRF antagonist found to be associated with the severity of the (alpha-Helical CRF 19,41 - Sigma),injected into obsessive con~olusive sy~toms but not the level of tic the mesencephalic ventricle on EEG,behavior and severity in these patients. Although CSF su~dies lack autonomic parameters. The cortical EEG activity the precision necessary to address questions of has been quantified on line by means of Fast selective involvement of neuronal systems in specific Fourier Transform; the behavior has been CNS locations, these findings suggest that endogenous opioids are involved in the pathobiolog~ of TS and evaluated by counting EMGraphically recorded related disorders. movements and heart rate, respiratory rate and Child Study Center and the Departments of colonic temperature have been continuously Psychiatry and Pediatrics Yale University School of recorded on a polygraph. Medicine, New Haven, C'f 06510 CRF antagonist induced a significant increase in the total power of the cortex; the EEG pattern was opposite to the cortical changes we observed in the same species after CRF administration. The autonomic parameters were not significantly modified. Neurological Institute, University of Pavia, 27100 Pavia, Italy 34.06.01 INFLUENCE OF GROWTH HORMONE RELEASING HORMONE (GHRH) ON THE GROWTH HORMONE (GH) SECRETION IN ENDOGENOUS DEPRESSED FEMALE PATIENTS IN COM- PARISON TO HEALTHY FEMALE SUBJECTS POSTER A. Hinz, G. Laakmann, F. Krupp PRESENTATION Pharmacoendocrine studies showed a significan- tly lower GH-stimulation after desimipramine 34.06 (DMI) administration in endogenous depressed female patients compared with healthy female subjects. The pituitary GH secretion is controlled by (GHRH) and released by the hypothalamus. The aim of our study was to find out whether there is a difference in the GHRH induced GH Pharmacoendocrinology stimulation between endogenous depressed female patients and healthy female subjects. We examined 15 endogenous depressed female in- patients of normal weight (mean age 44.7 years) who had been given GHRH 100 ~g i.v. and 13 healthy female subjects (mean age 24.5 years) GHRH 100 ~g i.v. The comparison of the GH peaks shows a higher GH increase (32.5 • 7.4 ng/ml) in healthy female subjects than in endogenous depressed patients (12.0 • 2.4 ng/ml). From these groups we selected 6 female patients (mean age 26,7) and 6 age matched healthy female subjects (mean age 23.3 years) and compared the GH stimulation. The GH stimulation in the group of endogenous depressed female patients (n=6) is smaller (13.6 • 5.0 ng/ml) than in the group of healthy female subjects (n=6, 32.2 • 8.5 ng/ml). This study shows that GH stimulation after GHRH in healthy female subjects (n=13) as well as in the group matched for age (n=6) is clearly higher than in endogenous depressed female patients. 392 34.06.02 34.06.03 THE I~FI/JENCE OF CLZ~,~fTEROL, A BETA-ADRE~RGIC AGONIST NEUROENDOCRINE EFFECTS OF BUSPIRON ON DESIPRAME~E ]]';EI,~'C=~_DGP~3~fH HOP~;3NE ((~), PI~3LACTIN (PRL) AND CORTISOL (COH) STI/~IATION H. Neuhauser, G. Laakmann, A. Knossalla U. Voderholzer, T. M.~.z, A. Hinz, G. LasMnann Buspiron is a ,novel anxiolytic substance with Previous studies on pituitary hormone secretic~q in heal- moderate affinity to dopamine and 5-HT-recep- thy subjects using desimipramine (DMI) in conbir~tion tots (Am. J. Med. 80,1, 1986; J. Clin. Psychi- with the beta-adrenergic antagonist propranolol sug- atry 43, Ii, 1982). Endocrinologically, a sti- gested that beta-receptors are inhibitory to [~-induced mulation of prolactin and growth hormone has GH and PRL release t~Jt have no influence on F~]-induced been described (J. Clin. Psychiatry 43, 76, AC~- and COR secretion (Laakmann et al., PsycF~neuro- 1982). endocs ii, No. 4. 447-461, 463-474, 475-489. We examined the effect of buspiron 60 mg p.o. 19@6). on plasma levels of prolactin, growth hormone To further clarify the role of noradrenergic beta-recep- and cortisol in 6 healthy male subjects aged tors we investigated ~ effect of a pretreatment with 18-35 years. We also examined the effect of the the beta-adrenoceptor agonist clenbuterol (0.04 mg p.o serotonin antagonist methysergide on buspiron given 60 rain prior to i.v.-infusion of 50 ~ F2#J) on G~, induced release of prolactin. PRL and COR release in comparison to I~tI alone in 12 We found that buspiron leads to a marked rise young healthy male subjects (18-35 years). of plasma prolactin (peak value x • SE 802.17 • ~an AUC (x • SE~.:) of ~ secretion follow~ D~[I 205,75 ~g/ml; area under the curve AUC • SE (1127 :~ 226 nglml x 120 rain) was significantly inhibited 90512.50 • 18322.78 ~g/ml x 180 min). After by clenbuter01 pretrea~ent (465 + 93 nglml x 120 rain; pretreatment with methysergide prolactin sti- p --< 0.01; student t-test). Clenbuterol had no effect on mulation was markedly reduced (x • SE 326.50 • PRL secretion which ~s nearly identical after combined 110.70 ~g/ml; AUC • SE 46075.00 • 7668.35 ~g/ml application of clenbuterol and DMI (30789 :~ 442 ~Ulml x 180 min). The difference is statistically x 120 rain) when com~su~ed to D~tI alone (29188 :h 2761 signficicant (p S 0.05). - Buspiron also leads ~/UIml x 120 rain). Similar results were observed for C0R to a moderate stimulation of plasma growth release following D~LI ,nich was not affected by clenbu- hormone (AUC • SE 601.80 • 268~ ~g/ml x 180 terol pretrealnent (1988:hi05 ~gllOO ml x 120 rain) in min) and to a moderate rise of plasma cortisol ccn~parison to E~tl aior~ (1966~i05 ~gIl00 n~ x 120 m/n). (AUC • SE 2232.82 • 136.05 ~g/1O0 ml x 180 These results cor~irm that noradrenergic beta- min). receptors play an ir~nibit0ry role with regard to (~- Our results indicate that the stimulation of stimulation and are not involved in C0R stimulation prolactin by buspiron is mediated through cen- after E~[[ . The lack of influence of clenbuterol on [~LI- tral nervous serotonin receptors. The stimula- induced PRL secretion is unexpected and in opposite to tion of growth hormone and cortisol is an indi- the suggestion that noradrenergic beta-receptors are cation that buspiron also effects central ner- in~libitory to PRL release. vous receptors other than those of the seroto- Psychiatrische K1 ~_~k der Universi t~t t,i~chen, nergic system. NuBbaumstr. 7, D-8000 Mt~chen 2 Psychiatrische Klinik der UniversitAt M~nchen, NuBbaumstraBe 7, 8000 M~nchen 2 34.06.04 34.06.05 GH- PRL- AND CORTISOL STIMULATION BY DMI SOL- EFFECTS OF TRIMIPRAi41NE ON SLEEP-EEG, NOCTURNAL PENILE VENT IN COMPARISON TO VERUM IN TWELVE HEALTHY TUMESCENCE (NPT) AND NOCTURNAL HORMONAL SECRETION IN SUBJECTS. NORMAL CONTROLS M. Ortner, A. Hinz, G. Laakmann, W. Sch6n S. W~hrmann A. Steiger, O. Benkert and F. Holsboer An investigation by Laakmann et al. (1985) She antidepressive properties of trimipramine (TR) are showed that Desipramine i.v. stimulated GH, well documented. Previous studies showed that, in PRL and Cortisol. Doubts arose concerning the contrary to most other antidepressants, this substance methodology in regard to if DMI caused the does not suppress rapid-eye-movement-(REM-)sleep. To stimulation or if it was the result of the further elucidate the way of action of TR, a long-term- invasive intervention based on the action of study was performed in 3 normal controls (23-26 years the solvent in the substrate. Therefore we old). They were investigated during 21 consecutive nights investigated GH, PRL and cortisol stimulation with sleep-EEG and nocturnal penile tumescence (NPT) and by DMI solvent in comparison to DMI. received: (I) placebo for 3 days; (2) then increasing Twelve healthy age-matched male subjects dosages of TR up to 200 mg for I0 days; and (3) placebo received DMI 50 mg i.v. or DMI solvent 50 mg again after withdrawal for 8 days. During the last night i.v. the examination was carried out under of each of the 3 parts of the study a hormone secretory basal metabolic conditions, beginning at 8.00 profile was collected simultaneously with sleep between h • 30 min (t = 0 min) at t = 60 min the trial I0 pm and 7 am to measure the course of the plasma substances were administered. The GH, PRL ~ concentration of cortisol, growth hormone, prolactin cortisol plasma levels were determined at the (PRL), testosterone, LH and FSH. Under TR sleep structure beginning of the examination and then every 30 did not change; especially REM sleep was not affected. min up to t = 120 min. The results are i~PT activity was not disturbed, in one subject NPT depicted in the following table: increased. PRL was enhanced under TR and normalized after drug cessation. Under 200 mg TR the cortisol concen- AUC (120 min) GH PRL Cortisol tration decreased and the cortisol increase occurred (ng/ml) (~U/ml) (~g/100 ml) markedly delayed. After withdrawal of TR the cortisol Solvent concentration exceeded baseline values, while the Mean value 64.3 20013 1133.4 nocturnal cortisol increase was found advanced. No SD 21.4 1539 73.0 systematic effect on the other endocrine variables was DMI observed. Mean value 1704.4 31044 2322.4 The results suggest: (I) there is a low risk of erectile SD 334.4 3712 160.6 dysfunction under TR; and (2) the way of action of TR is different from the majority of antidepressants, which In contrast to the stimulation elicited by DMI suppress REM sleep, while TR acts by a suppression of no significant hormone stimulation was found cortisol, which is known to be increased in acute after the administration of DMI solvent alone. depression. Nervenklinik der Ludwig-Maximilians- Department of Psychiatry, University of Freiburg, Universit~t M~nchen, Nuflbaumstra~e 7, 8000 Hauptstrasse 5, D-7800 Freiburg, West-Germany M~nchen 2. 393 34.06.07 BLUNTED RESPONSE OF TSH IN pANIC DISORDER 1 = i 2 ~ I R.Martfn-San~os+~ , C.Udin~ , J.Rodrfguez , _.Alvarez , R. Guillamat , M.Torrens-. In the last years it has been reported that ~ne TRH test 34.06.06 has abnormal results in some psychiatric disorders and there is so~e evidence suggesting that the hipothalamic- pituitary-t~yroidaxis play a role in their ethiopathoge- nesis. Between 30-4C% of panic disorders show ablmnted thyroid- estimulating hormone (TSH) response to thyrotropin-rele• sing hormone (TRH) (Roy Borne et al., Psychopha.~nacol. Withdrawn Bull., 21,546-60, 1985). The interpretations of the results of the TRH test de-- pends on I) the thecnique use to measure the TSH, 2) the criterion of ! max TSH used, and 3) the ade~aa%e control. Twenty-seven outpatients with panic disorder (DSM-III) participated in the TRH test study (i0 male and 18 fema- le rangering in age from 21-59, with a mean age of 37). All patients had normal plasma levels of T and FT and 4 were not taking any medication for two wee{s prlor to testing and they were free of medical and others psychia tric illnesses. The TRH test was measured by inmunoradio metric assay (IRMA), using a criterion of ~Eax TSH<5mU/u from the normal controls (sex-age-matched wi~_/nout psy- chiatric and endoerinologic personal and family history). Seven of twenty-seven (26%) had ablunted TSE response. This findings and their significance in order to predict treatment response in considered. Departments of Psychiatry I and Biochemistry 2. Hospital de la Santa Creu i Sant Pau (Medical Szhool). Avda. S.A.M. Claret 167. 08025 BARCELONA. SPAIN. 34.06.08 34.06.09 CH~gNIC DEX~NE AND CSF MONfI~MINE METABO~. LEVELS OF PRL POST-DOM IN SCHIZOPHRENICS: DIFFERENT G. Santagostino, S. Schinelli, P. Frattini, M.L. O/cchi, RESPONSES AS A FUNCTION OF THE TIME-SPAN OF THE G.L. Corona and G. Spanu ILLNESS AND CLINICAL RESPONSE TO HALOPERIDOL. There is strong reason to suspect an interaction between J.., A. Cabranes, I. Almoguera, C. V~zquez, J. A. Ramos, and glucocorticoids and biogenic amines (B.S. McE~n, Biochem. & L. Santos. Phanmacol., 36,1755,1987). Recently, various authors have The response of PRL to 4 rag. of DOM l.v. was determined. re~orted modifications of the concentrations of monoamines Subjects were-35 schizophrenics (DSM-III) and 15 and their metabolites in plasma and cerebrospinal fluid normal controls. 9 patients were classified as (CSF) of subjects acutely treated %ith de_xanethasone (O.M. subchronic (SS) and did not receive any neuroleptic (NL) Wolkowitz et al., Arch.Gen.Psychiatry, 44,782,1987; C.M. Banki et al., Phazn~copsychiatry, 16,77,1983). In order to treatment ever before. 26 patients were classified as examine the effect of a chronic treatment with gluoocorti- chronic (SC) and were free of NL at least 10 days before coids on catecholanir~ and serotenin metaholisa, we measu- the study began. red levels of 3nme~-4-hydroxy phenylglycol C-IYLPG), ho- The analyses of data (ANOVA) showed that the response movanillic acid (HVA~ and 5-hydroxy indolacetic acid (5- of PRL to DOM (area under the curve) was nigher in SC HIAA), the main metabolites of noradrenaline, dopamine and than in SS patients [/-(2,47) -- 3.25, p < 0.048). seroten/_n, in ventricular CSF of hydrocephalic patients Furthermore, non-repondent patients (N-23) did show, either untreated (n=21) or treated with dexamet~sone (n= after 21 days of treatment, a higher response than 21, 4 mg twice daily, i.m.) for at least 15 days: in sc~e respondent patients did [F(2,47) = 3127, p < 0.047]. patients pla~na ~ was also determined. Metabolite ana- Thus, the two following conclusions may be drawn: lyses were carried cut by liquid chranatography with elec- I) Normal response to DOM is associated to both a good trochemical detection (G.M. Anderson et al., J. Cb~samatogn clinical response and the absence of previous NL 142,501,1979; S. Schinelli et al., J.Chromatogr.Bic~aed. treatment Appl., 338,396,1985). No significant differences were no- 2) The higher response of PRL to DOM observed in the SC ted in metabolite concentrations of untreated and treated and the non-respondent subgroups suggests a dysfunction subjects: only slightly lower MHPG levels (alx~t 8%) were of the dopaminergic post-synaptic receptor (TIDA) as a found in CSF and plamma of dexarrethasone treated patients. likely result of either the illness itself or the effects of These results indicate that effects of a chronic treatment previous NL treatments. with dexame~ on monoamine metabolism may be quite different frQm those observed after administration of a single dose of the drug. Hospital Unlversltario San Carlos. 28040-Madrid. Institute of Phazmacology, University of Pavia, Via Tara- melli 14, 27100 PAVIA (Italy) 394 34.06.10 34.06.11 EL-rf AND THE h~LFHO~NDOCRINE WINDOW CHANGES IN NOCTURNAL SECEETION OF ANTERIOR PITUITARY M. Steiner,J.R.PeILettier,R.N.Gupta and E,S.Werstiuk HORMOhYS FOLLOWING A SERIES OF SIX ECTs Preclinical data irdicate that repeated ECS in anirmls indtre J.D.Bergiannaki, C.R.Soldatos, P.N.Sakkas,C.Christodoulou, in central mmcsmirergic system.. 2he purpose of the present study was A.Botsis,C.N.Stefanis. to further ewaluate ~ether ~f prcduces similar changes in man. ~%is Previous studies have reported on changes of anterior pi- was ck~e indire~ztly by determining the effects of ~ire challef~es tuitary hormonal secretion as an immediate effect of ele- to prc~dde infozmation about ~ated central ev~ts ctroconvulsive treatment (ECT).They included only daytime (the "neurseodocrire wir6~v'). plasma samples of pituitary hormones although the secreto- ry peaks of these hormones occur during nocturnal sleep. To date t~e~ty acutely depressed i~patie~ts were studied, htieats Therefore,we studied the effects of ECT on nocturnal plas- ~_re given a structured inte~rie~ (S~:~C) and were imh~led only if m~ concentrations of prolactin (PRL),growth hormone(GH), they qualified for the diagnosis of M~jor Depressive Disorder. thyroid stimulating hormone (TSH) and cortisol(F). Following a se~m day m.=dicatic~t free period the q]~flX~q, 13st and In six male drug free schizophrenics blood samples were clonidiee/~ ~ challenge tests were ;w~-mnlstrered in succession over hourly (S.00p.m. to 8.00a.m.) collected through a continu- a period of 3 days. Patients ~P_re then treated with ~. No other ous withdrawal pump,the nightbefore the first and the m-~dications ~ used through~t the study, qhe ~ of ECTs v~re nights after the first and the sixth of a series of ECTs. detezrained by clinical status v.hich was assessed ~ee/dy using the Hormonal levelswere determined using radioimmunoassay Hamilton Depression Scale. 2he challenge tests ~-re repeated 11-14 days methods. after the last ECT treammnt. T~4, cortisol and Od~m_rerm_as~ed Ourresults show that nocturnal PRL secretion did not sig- using RIA. ~aam M-l~as mel~ured by }~_C-~D. nificantly change following the first ECT (NS),while there Besu]ts: ~ ~ession reflected severity of depression and was a trend towards a decrease following the sixth (p~0.1) "nozrrelizatioa" of DST cccured in all EITs responders. The Erowth Total amount of GH secretion was not markedly affected by homxre, level of sedation and blc~d pressure r~ to clonidine either the first or the sixth ECT (both NS),although the did not chan~ with treatment v~ereas the M-~G.r~ to clc~idine latter caused a 2-hour phase advance of GH peak.TSH secret- decreased following treatment in ECT r~s. A anrl~d increase in ion increased after the first ECT and even more after the T~t resporu~ to 3~-Ivas:also noted in ]~Yr r~s. sixth (both p~O.001),whereas T3 and T4 secretion was not significantly affected. Finally,secretion of F did not show Cur data suggest that ECT might cause c_~ in central noradrenergic any sZatistically significant change either after the sensitivity. Tse possibility that ~ of the observed changes in first or the sixth ECT(boZh NS). neuroendocrine responses are attrib,-table to the effects of a course The findings regarding the effects of ECT on pituitary- of ECT itself rather than to clinical recover7 ~41] be discussed. thyroid axis suggests that ECT may cause a degree of hypo- responsiveness of the thyroid gland.Our results will be Stpportcd by a 8rant frcm The Chtario Mental Pealth Fotr~ation. further discussed in terms of their relation to clinical E.S.W. is also the recipient of an ~ career a~ard. characteristics of our patients as well as their tzeatment outcome. Clinical Studi~ Program, IvhVester Psychiatric Unit, St. Jaseph's Sleep Research Unit of the Department of Psychiatry,Univ. }bspital, and D~ts of Psychiatry and N~urosciences, M/Vaster of Athens,74,Vas. Sophias Ave. Athens 115 28,Greece. Lhi~.rsity, }~iltan, Chtarin, Canada. 34.07.01 SEASONAL VARIATION OF DEPRESSION:DIAGNOSTIC ASPECTS A.J.H.T. de Bie~A.L.van Ben~nel and R.van Diest The seasonal variation of affective disorders has been deduced from both case- and population-studies. Elaborate POSTER criteria to define seasonal affective disorders (SAD) have been put forward by Rosenthal et al.(*). The aim of PRESENTATION this study is twofold. Firstly: what is the occurrence of seasonal variation of depression in a psychiatric out- 34.07 patient population. Secondly: how well do Rosenthal's criteria apply to these patients. 362 Outpatients were screened for seasonal variation of depression by means of a questionnaire. Of the 112 patients who filled out this questionnaire 54 reported seasonal variation of depression. Subsequently, 32 of these 54 patients were interviewed to further investigate Miscellaneous the applicability of the criteria for SAD. Only 13 patients met all criteria for SAD. 9 out of these 13 SAD patients reported a life event characterized by loss just preceding their first depressive episode. Rosenthal's definition for SAD excludes patients with clear-cut seasonally changing psychosocial circumstances that would account for the seasonal variability in their mood and behavior. Such circumstances, however, can be interpreted as originating from environmental and/or psychological sources. We wonder, therefore, the necessity of the psychosocial exclusion criterium for any definition for SAD. More knowledge, e.g., about the influence of single life events just preceding the first episode of SAD is needed. (*)Rosenthal et el ,Arch.Gen.Psychiat.,41, 72-80, 1984 Department of Clinical Psychiatry, State University of Limburg, PO Box 616, 6200 MD Maastricht, The Netherlands. 395 34.07.02 34.07.03 A NON-24-HOUR SLEEP-WAKE CYCLE: FREE-RUNNING RHYTHMS SEASONAL VARIATIONS IN HOSPITAL ADMISSIONS AND THEIR RESPONSIVeneSS TO BRIGHT LIGHT PULSES K__t. Honma~ S__~. Honma~ *M___~.Kosaka~ *N__~.Fukuda~ and *Y. Asano (~ Voll, $ Kasper. Th Nicdermeyer. A non-24-hour sleep-wake cycle is characterized by a fail- ure of stable entrainment of the circadian sleep-wake Circannual rhythms in biochemical, endocrine, and physiological rhythm to environmental time cues in persons with normal activity have been reported for various psychiatric diseases. In order vision, and by a unique pattern of the rhythm known as a to determine if these changes are also reflected in the pattern of relative coordination. This state is thought to be caused circannual hospital utilization, we studied the seasonal variation of by an altered function of the underlying circadian clock; admission rate.s to the Psychiatric Department of the University either the endogenous period or the sensitivity to envi- Hospital of Heidelberg (FRG). We obtained the date of contact and ronmental time cues. We examined this hypothesis in a further variables for 4371 patients with different diagnoses who student who has been suffering from a periodic insomnia requested psychiatric inpatient care during a five year period from since his childhood. His illness was diagnosed as a non- 1980-1985. This total population consisted of schizophrenic 24-hour sleep-wake cycle from a three month record of his disorders (40%), affective disorders (28%), neuroses (17%), and sleep-wake cycle in a normal environment and the medical other disorders (15%). Seasonal patterns in the frequency of contacts examinations such as sleep EEG and ophthalmological tests. were compared for these patient groups. Affective disorders as a The free-running period of the rectal temperature and group and uhipolar depressions did not show a clear pattern, but sleep-wake rhythms, and the responsiveness of the circa- admissions for bipolar depression and also for mania occurred dian rhythms to a bright light pulse were studied in this significantly (p < 0.01) more in spring and summer. Psychosomatic subject under temporal isolation. The latter attempt was syndromes were significantly (p < 0.01) more diagnosed in winter based on our recent observations that the free-running and there was also a fall/winter peak for depressive neuroses and circadian rhythms in these variables phase-advanced in schizoaffecfive psychoses. Higher adunission rates in summer could response to a bright light pulse given at the early sub- be detected for acute schizophrenia whereas chronic schizophrenic jective morning, which is thought to be the basis of the patients were si~cantly (p < 0.01) more likely to be admitted in light entrainment. The subject (22 yr old) spent alone in winter. These reported changes could be seen more clearly in patients an isolation unit for 3 weeks without knowledge of time. with first admissions compared to the group with repeated After one week in the unit, a light pulse (5,000 ix) of 3 admissions. The finding of an interaction between seasons of the year hr duration was applied one hr after he awoke spontaneous- and the prevalence of selected psychiawic disorders suggests a role for ly. One week later, a light pulse was given at the same climatological factors, such as temperature and photoperiod. This circadian phase with extending the duration to 6 hr. His might contribute to our understanding of the etioIogy and course of free-running period ~as 25.9 hr, which was longer than the psychiatric disorders. In groups of patients with a seasonal occurance average of healthy Japanese subjects (25.2 hr). Noteworthy of the symptomatolog3, it seems worthwhile to study the effects of was the absence of phase-advance shift of the circadian treatments which include principles of the physicai environment which rhythms after the bright light pulses. From these results, might trigger the illness episodes, like phototherapy or temperature it is surmized that a non-24-hour sleep-wake cycle in this manipulations. particular subject is mainly due to the lack of response of the circadian clock to the environmental light. Psychiatric Department of the University of Heidelberg Department of Physiology, ~Department of Psychiatry, D-6900 HEIDELBERG, Vogstr.4, FRG Hokkaido University School of Medicine, Sapporo, Japan. 34.07.04 34.07.05 THE F/FECT OF BRIGHT LIGHT ON DEPRESSIVE SYMPTC61@ BRIGHT LIGHT TREATMENT OF PREMENSTRUAL AND ST,FrRP DISTORBANCES DEPRESSION Y.ASANO, K. HoD/ra*and S. Honma* B.L. Parry, S.L. Berga, D.F. Kripke, J.C. Gillin Th~ effect of bright artificial light on depressive Bright light has been used to treat Seasonal symptoms and sleep disturbances was examined in this Affective Disorder, Seasonal Premenstrual study. In the first experiment, an entrainment of human Syndrome and Major Depression. In this study, Circadian rhythms by a bright light pulse was examined we tested the efficacy of morning vs. evening in the temporal isolation unit. Bright light of 5000 Lux bright light (> 2500 lux) in patients with was emitted by a metal reflex fixture in the u~tit, where nonseasonal PMS. Based on some of our previous a subject lived for three weeks without kno~5.ng the time work, we hypothesized that some patients with of day. To avoide the behavioral effect of the complete PMS, like some patients with affective darkness, he %~s allowed to use another light ( 500 Lux ). disorders, have an abnormal phase-advance of When bright light was introduced at the early subjective certain circadian rhythms with respect to the day(n=8), the circadian rhythm in body temperature sleep/wake cycle. This model would predict that phase-advanced almost immediately, but the rhyth~ of patients would respond more to evening light sleep-wakefulness shifted sometimes one day later. On the (which delays circadian rhythms) than to morning other hand, when the light pulse was applied to the late light (which advances these rhythms). subjective day(n=2) and early subjective night(n=8), Subjects underwent a 2-3 month initial the circadian rhythms did not show a distinct phase shift. diagnostic evaluation. Patients then were There was a transcient internal desynchronization between phase-typed by obtaining overnight circadian the circadian rhythm in body temperature and in sleep-wak- profiles of melatonin at four specific endocrine efulness. This phase-r phase s~lltt ot the phases of the menstrual cycle. In the treatment circadian rhythm indicates that bright light is an effect- studies patients were randomized to morning vs. ive zeitgeber of the hlanan circadian pacemaker. Based on evening bright light for 7 days during the these findings,patients with major affective disorders or premenstural period. After each intervention, seasonal affective disorders were exposed to +~he bright raters blind to the treatment condition assessed light pulse during the morning hours frc~n 6 to 9 a.m., the patients' mood using the Ham-D, and patients in order to phase-advance their circadian rhy~hn~. The completed the Beck Inventory. light therapy was done during winter time.~e bright light Initial results showed a significant was dramatically effective to a case of seasonal affective reduction in Hamilton(p<.0003) and Beck (p<.01) disorder and 4 major affective disorders out of 6 examined depression ratings after evening, but not judging from HRS and Sleep Observation Inventory. The morning light treatment. Futher trials with a bright light th=_rapy was effective to depressive symptoms dim red light control condition are being and sleep disturbance on affective disorders. T~e bright conducted and will be presented in conjunction light may also be helpful to anither circadian disorders. with the melatonin data. Department of Psychiatry, University of Shukuzu Mental Hospita~ , Shukuzu 3-16-i0, Muroran 051, california, San Diego, T-004, La Jolla, JAPAN. * Department of Physiology, Hokkaido Univ=_rsity California 92093 USA. School of Medicine, Sapporo 060, JAPAN. 396 34.07.06 34.07.07 BIOLOGICAL CORRELATES OF SOME DRUG IkOlE~ PSYCHOLOGI- SOME RESULTS CON~ERhqN~ INDICATORS OF SCI~CJLUS- FREB CAL CHANGES. PSYCHOLOGICAL EVEh~ S ~.Sim~es da Fonseca, M. Puri~icaq~o Horta, Isabel Bara- Isabel Barahona da Fonseca r Jos~ Ba2ahona da Fonseca, h2na da Fonseca~ N.F~!ix da Costa. M. Purifica~o Horta The problem of ~he choice os biological indicators for As most of the psychophysioiogical indiza~ors which normal psychological as well as psychopathological pr~ are used in the domain in which we are interested co~ cesses as well as For their changes u~der the actioS cern stimuli-bound responses, and their biological i',,n-- of psychopharmaca is iiscussed taking as a reference dicators, such as E~Fs of the Brain, we have tried to some advances in the methodo!ogy which was used and in overcome the limitation of having to use a stimulus. one case developed by the Lisbon group. For this purpose we have developed an a.~e.na~ive~-- ~' tech Drug effects in Normal Volunteers as well as in Para- nique in which subjects are required to fency, with noid Schizophrenics are reported and their signi.mican- closed eyes, some agreable or else disagreable situa- ce is reconsidered, taking into account the approach tion, or to perform some mental task, as a control, which are proposed both at the biolo~cal and at the and to signal the beginning of the state whizh is re- psychopathological levels. quired to them. Dept. os Medical Psychology, Faculty os Medicine os Conventional bipolar EEG recording was m~de during Lisbon, Hospi=al de Sta, Maria, 1600 Lisbon, Portugal. those states. Periodic waveForms extraction was perFo~ med through cross-correlation and afuerwards took pla- ce an averaging procedure. In the final comparisons between different subjective states, were used the amplitudes of some components of the Power Spectrum, (concerning each wave~orm charact~ ristic for a given _~requency). In normal volunteers a significant difference was found in the amplitudes of components 3, 6, 9, 12 and 15, of waveforms of frequency 3 c/s, when agreable states were compared "~_th another state. Data concerning paranoid and depressive subjects under or not under therapy are reported. Dept. of Medical Psychology, Faculty of Y~iicine of Lisbon, Hospital Sta. N~ria, 1600, Lisbon, Portugal. 34.07.08 34.07.09 ~HE CHOLINERGIC SYSTEM /CH/ AND THE EPILEPSY THE POSSIBLE CIIOLINERGIC SYSTEM/CE/ DISTURBANCE M.~vejdovl, I. Rektor IN EARLY MENTAL IMPAIR~ENT A review is presented and confronted with own I.Rektor,M.~vejdov~,C.Silva Barrat,C.M4nini results. The cholinergic activation is generally The role of CH disturbance in Alzheimer's demen- accepted to be proconvulsive. For example it has tia is known.Authores hypothetise that CH dis- been proposed that the cholinergic modulation turbance is involved also in genesis of mental may be involved in the initiation of the focal impairment due to an early cerebral lesion. discharges and in the transition from the inter- CH was pharmacologically tested in acute tests ictal to ictal stage. There are more exoeriment- in 30 patients with and after infantile eoilep- al models using the proepileptic effects of the tic encephalooathy. All were mentally severly CH activation /e.g. Turski et al.,Fariello eta!. impaired. A significant reduction of CEG paroxy- Sooe et al./. Especially in the temporal epilep- smal activity after i.v. Dhysostigrnine and its sies the CII activation may be proconvulsant. The increase after atropine was disn!ayed. Persis~ role of CH in the chemically induced "choliner- tent startle resnonse was also blocked by phy- gic" kindling seems to be imnortant /Wasterlain/. sostigmine.The results were similar regardless In humans isolated information about antie~ilep- of the actual type of EEG,clinical seizures or tic properties of anticholinesterases are doubt= actual age.The CH disturbance seems to be tyoi- ful /ikonomoff/lazars/. On the contrary, the cal for infantile epileptic enceohalopathies be- antiepileptic effects of anticholinergics were cause in the cases of eDileosies appearing later more orobable /Millichap/. the effects of both of the tested drugs are ~ Our results in adults with partial and secondary rather opposite.However,this effect of CH acti- generalized epilepsies conform with other litera- vation seems to be linked with the mental defe- ture data. Physostigmine acts mainly as a nrocon- cts because the response of paroxysmal activity vulsant. However,there is also a recently des- was diferent in the infantile epileptics with cribed group of infantile eDilentic encenhalo- normal mental develonment.A direct relation be- paties with comoletely opposite CH actionphyso- tween EEG paroxysmal activity and other epilep- stignine acts as an antieoileptic and atronine as tic features on the one hand and the degree of proepileptic agent /Rektor et al./. It seems mental impairment on the other, is not probable. that CH plays a specific role in the epilentic More probable is the situation when the CH dis- encenhalooathies due to early cerebral damage. turbance influences both factors-EEG and also t~eurclogical Clinic KUI~Z and Purkynje University, the occurence of mental defect. The presumed 656 91 Brno, Peka~sk~ 53, Czechoslovahia therapeutic effect of CH ACTIVATION is discussed Neurological Clinic, Purkynje University, PekaFskl 53, 656 91 Brno, Czechoslovakia 397 34.07.10 34.07.11 CYTOGENETIC INJURY IN SCHIZOPHRENIC PATIENTS Enhanced Pressor Sensitivity to Oral Tyramine Challenge JoKo~i~ov~, Go~iriBan, R.Jo~r~m Following High Dose Selegiline Treatment Psychiatric Research Institute, 181 03 Prague, Czechoslovakia A. PRASAD, V. GLOVER, B.O. GOODWIN, M. SANDLER, M. SIGNY, S.E. SMITH Some recent hzpotheses expect the injury of cell and nucleus membrane due to the long-term Blood pressure and heart rate responses to oral tyramine therapy with neuroleptics and by the disease have been measured in healthy volunteers before and after itself in schizophrenics~ Therefore,we analysed administration of the selective monoamineoxidase the cytogenetic injury in a group of schizo- B-inhibitor, selegiline, at high dosage {30 mg/day). phrenics (n=Yl) and in group of patients with Treatment brought about a two- to four-fold increase in other psychiatric diagnoses (oligophrenics and tyramine sensitivity and a concomitant small, but personality disorders, n=8)o The cytogenetic significant reduction in plasma 4-hydroxy-3-methoxyphinyl- analysis of chromosome aberrations in periphe- concentration, pointing to the emergence of some degree ral lymphocytes and the determination of micro- of monoamineoxidase A-inhibition. It is suggested that nuclei in buccal epithelium cells were used for the patients treated with selegiline, 30 mg/day or more, the detection. The samples were collected on should be placed on a tyramine-free diet. day O, on day 28 and on day 56o In the second period the basic therapy was supplemented with A. Prasad, Consultant Psychiatrist, Claybury Hospital, antioxidants - vitamin E (400mg per day) and Woodford Bridge, Essex, England vitamin C (IO00mg per day)~ The frequency of aberrant cells in peripheral lymphocytes did not differ in both of these groups, but was higher than the frequency of aberrant cells in healthy population~ The frequency of micro- nuclei in buccal epithelium cells in both of these groups was higher than the frequency of micronucleatedcells in healthy volunteers~ After 4 weeks administration of vitamins E and C we did not find any significant decrease either in micronucleated cellap or in aberrant cells in peripheral lymphocyteso 34.07.12 34.07.13 METHYL FOLATE ENHANCES RECOVERY FROM The acceleration of antidepressants's effects by using PSYCHIATRIC ILLNESS photoherapy in endogenous depression Toone B,K., P. Godfrey, M.W.P. Carney, 3. Pras~o, Czechoslovakia T. Flynn, T. Bottiglieri, M. Laundy, E.H. Reynolds The combined therapy composed of antidepressants and We'bave reported that approximately one quar- light exposure was carried out, covering three groups ter of acute psychiatric inpatients have low of depressive patients. red cell folate levels (less than 200 ng/ml). We have undertaken a double blind placebo All patients were treated with the antidepressants and controlled trial of methyl folate, the the light exposure (5000 tux for 1 hour daily), the first transport form of folate in the nervous group ~11 patients) at 5 a.m., the second group (9 patients) system, as add on therapy to psychiatric at 9 p.m.. The control group consisted of 9 patients was patients with low red cell folate levels. only treated with tricyklic antidepressants. Patients were stratified according to psychiatric diagnosis, i.e. affective illness The best improvement, according to the Montgomery and or schizophrenia. The methyl folate 15 mg Asberg Depression Rating Scale, was recorded in the First daily or placebo was added to standard group, Lhough there was a tendency of mood worsening at the psychiatric medication and the 23 patients end of phototherapy. In the second group there was not so were followed for 6 months. At 3 and 6 months good improvement comparing with the results achieved in of follow up the clinical and social recovery the first one, but still significantly better than in the of the patients on vitamin replacement were control group. The worst results were ascertained in the significantly better than those on placebo. third group (evening phototheray). However, all three groups by combined therapy showed better results than control group. 398 34.07.14 34.07.15 DOTHIEPIN VERSUS TRAZODONE ~N MAYOR DEPRESSION INELDERLY Subtypes of Neurometric Profiles in C. Cocconcelli, R. Caso]i and G. Turrini Schizophrenia and Relationship to Drug A double-blind s-tudy in 40 old depressives (12 M and 28 F, Response mean age 68,5 + I SEM) has been performed in order to eva- luate the effectiveness and safety of dothiepin compared L.S. prichep 1,2, E.R. John1,2, J. Volavka 1,2, to trazodone in elderly. Patients were selected according R. Chabot l, T. Essig-Peppard t , K. Alper1 to DSM-III diagnostic criteria for Major Depression and evaluated by means of the Hamilton Psychiatric Rating Sca- le for Depression (~HRSD), the Cassano-Castrogiovanni Self- Egg recordings were obtained from schizophrenic patients Evaluation Scale for Depression (SAD) and a visual analo- during a drug free period, and a period whih on medication. gue scale of the severity of the depressiv e symptomatolo- gy (VAS). All the patients were randomly treated with Neurometric features were extracted from these recordings and dothiepin (D) 75 mg or trazodone (T) lO0 mg p.o. at night for 4 weeks. The HRSD scores significantly decreased at subjected to cluster analysis. PreLiminary results suggest at least the 2rid (-43% with D and --31,8% with T) and at the 4th (-60,7% with D and -49,4% with T) week. So did the SAD three major subgroups in this sample of patients, with markedly scores (-24,7% with D and -18% with T at the 2nd week; different profiles of pathophyslology. Members of these sub- -32,1% with D and -25,3% with T at the 4th week) and the VAS (-38,3% with D and ~ with T at the 2nd week; groups appear to display different responses to drugs. -63% with D and -54,9% with T at the 4th week). The ANOVA difference between treatments within times showed a significant trend for dothiepin compared to tra- zodone (p~-.O,Ol) on all the Depression Scales used. Side effects were foreseeable and mild; two patients on dothiepin dropped out for dizziness. Dothiepin showed a more quick and incisive action than trazodone in old patients affected by Mayor Depression. S. Maria Nuova Hospital - 42100 Reggio Emilia - Italy IDep~tment of Psyc.hlatry, New York University Msdlcal Center, New York, NY 2N~th~n S. ICllneIr~titute for Psychlstrle Research, Ora~geburg, NY 399