Terguride Stimulates Locomotor Activity at 2 Months but Not 10 Months After L-Methyl-4-Phenyl-L,2,3,6-Tetrahydropyridine Treatment of Common Marmosets

European Journal of Pharmacology, 212 (1992) 247-252 247 (c~ 1992 Elsevier Science Publishers B.V. All rights rcscrvcd 0014-2999/92/$05.00

EJP 52334

Terguride stimulates locomotor activity at 2 months but not 10 months after l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine treatment of common marmosets

Klaus W. Langc, Peter-A. L6schmann '~, Itclmut Wachtcl ~, Reinhard Horowski '~, Peter JS.hnig ~, Peter Jenner and C. David Marsdcn b Parkinson ~ Disease Society Experimental Research Laboratories, Pharmacology Group, Biomedical Sciences Dit'ision, King's College, Manresa Road, l.ondon S W3, U.K., ~ Research Laboratories of Schering A G, D- 1000 Berlin 6.5, I': R.G., t, Unit ersity Department of Clinical Neurolog3', Institute o/" Neurology, The National llo.spital, Queen Square, l.ondon WC1, U.K. and ~ A 1" B Comstat GmbH Berlin, Europacenter, D-IO00 Berlin 30, b:R.G.

Received 27 June 1991, revised MS received 16 October 1991, accepted 17 December 1991

The mixed dopaminc (DA) agonist/antagonist tcrguridc acts as a I)A antagonist on normosensitivc receptors but shows DA agonistic properties at supersensitive DA receptors. Such a compound could offer an alternative to the treatment of Parkinson's disease with indirect or direct DA agonists. The present study compares the actions of terguride, 4-12 mg/kg i.p., in naive common marmoscts with its effects in animals rendered parkinsonian by administration of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridinc (MPTP), 2 months or 10 months previously, in order to test its antiparkinsonian efficacy. Tcrguride reduced locomotor activity in naive common marmosets, similar to its effects in rodents and in line with the DA antagonistic activity of the compound. In marmosets treated with MPTP 2 months previously and exhibiting pronounced bchavioural motor deficits, terguride stimulated locomotor activity, showing DA agonistic properties under these conditions. In contrast, the locomotor activity of animals that had recovered from MPTP treatment 10 months previously was not altered by terguride. It is concluded that terguridc has anti-akinetic efficacy in this primate model of Parkinson's disease. In addition, terguride offers a unique opportunity to differentiate, pharmacologically, the extent of dopaminergic recovery from MPTP treatment in this primate species.

MPTP (1-methyl-4-phcnyl-l,2,3,6-tetrahydropyridinc); Parkinsonism; Tcrguride; Dopamine D 2 receptors (mixed agonist/antagonist); (Common marmoset)

I. Introduction Mixed DA agonists/antagonists, with terguridc be- ing the prototype compound, are promising for such an The current treatment of Parkinson's disease with approach. Tcrguride, a derivative of the dopaminergic indirect or direct dopamine (DA) agonists (i.e., L-Dopa, ergolinc lisuride, binds with high affinity to rat striatal lisuride, pergolide or bromocriptinc) is limited by side DA 1) 2 and to a lesser extent to DA D~ binding sites effects. Whereas somc initial adverse reactions such as (Valchfir ct al., 1987). The compound acts as a DA nausea and vomiting usually disappear due to rapid antagonist in normal rats but shows DA agonistic prop- tolerance, the incidence of others such as fluctuations erties in reserpine-treated rodents (Wachtcl and in motor performance and involuntary movements in- Dorow, 1983). In naive rats, terguride dose depen- creases after long-term treatment with L-Dopa (Mars- dently inhibits locomotor activity. However, stimulation den and Parkcs, 1976). Psychosis is another limiting occurs after subchronic prctreatment with reserpine. side effect of all dopaminergic therapies, especially in Similarly, terguride does not induce stereotypies in rats elderly patients. A balanced stimulation of DA recep- treated acutely with reserpine, but does so after sub- tc.rs, taking into account the differential status of DA chronic treatment with reserpine (Wachtel ct al., 1984). receptor sensitivity in the course of the disease, could Furthermore, and in common with classical DA ago- lead to a more specific therapeutic effect and reduc- nists, terguridc suppresses hyperprolactinaemia in fe- tion of side effects. male rats pretreated with reserpine and induces con- tralateral rotations in rats injected unilaterally with 6-hydroxydopaminc into the substantia nigra (Dlab~c Correspondence to: P.-A. lJJschmann, Schcring AG, Ncuropsy- and Krej(:i, 1980; lJSschmann et al., 1991a). chopharmacology, Postfach 65 03 11, D-1000 Berlin 65, F.R.G. Tel. Administration of 1-methyl-4-phenyl-l,2,3,6-tetrahy- 49.30.468 2162, fax 49.30.4691 6738. dropyridine (MPTP) to man or non-human primates 248

(Davis et al., 1979; Langston et al., 1983; Burns et al., 2.2. Measurement of locomotor actit:ity 1983) including common marmosets (Jenner ct al., 19841 induccs a parkinsonian syndromc duc to the Ix)comotor activity was measured simultaneously in selective destruction of nigrostriatal neurones, which four aluminium cages (50 × 60 × 70 cm) with stainless causes a substantial decrease in the DA content of the steel grid doors (50 × 70 cm) identical to thc animals' caudate nucleus and putamen and a corresponding home cages but equipped with eight horizontally orien- decrease in [~H]DA uptake (Jenner el al., 1984). The tated sets of infrared photocells. Across the cage three deficits in motor performance produced by MPTP beams wcrc located at floor level and one along each trcatmcnt of common marmosets respond to classical of the two pcrchcs. Other beams were directed from anti-parkinsonian drugs such as L-Dopa in combina- front-to-back of the cage at floor level and abc~ve each tion with a peripheral decarboxylase inhibitor (Jenner pcrch. The number of light beam interruptions due to et al., 1984), or DA rcccptor agonists such as (+)- the animal's movements were accumulated in 10-min PHNO (Nomoto et al., 19871, N-0437 (l.6schmann ct intervals and recorded for 360 rain, using a Com- al., 1989) or the ergoline derivative lisuridc (L6sch- modore CBM 4032 computer. The animals were al- mann ct al., 1991b). The MPTP-treated monkey ap- lowed to acclimatize to the test cage for a minimum of pears to be the most suitable pharmacological model of 30 rain prior to drug treatment. Parkinson's disease currently available. Common marmosets recover from the initial symp- 2.3. Behat:ioural obsercations toms induced by MPTP treatment over a period of several months. This bchavioural recovery, is associated In parallcl to the automated recording of locomotor with increased DA turnover in the caudatc-putamcn activity the animals were observed under blinded con- (Jenner et al., 1984; Rose ct al., 19891 and is not ditions through a one-way mirror. Motor behaviour was reverscd by further treatment with MPTP (Ueki et al., rated qualitatively to determine the presence or ab- 19891. The present study was designed to test the sence of stereotypy, head twitches, wet-dog shakes or hypothesis that the behavioural recovery in common grooming, oral movements, co-ordination of movement marmosets after MPTP treatment would be associated (good/impaired) and other obvious motor signs in 5- with a change in their behavioural response to a mixcd min intervals for 360 rain after drug administration. DA agonist/antagonist. Wc therefore compared the The maximal score for each item was 72. actions of terguride in naive common marmosets to its effects in groups of animals exposed to MPTP either 2 2.4. Drugs and solutions months or 10 months prior to the administration of terguride. The results obtained under these conditions The following compounds were used: MPTP (l- are discussed in view of the pharmacological effects of methyl-4-phenyl- 1,2,3,6-tetrahydropyridine hydrochlo- tcrguride in patients. ride; Schering AG) and tcrguride (Sobering AG). MPTP was dissolved in sterile physiological saline and tcrguridc was suspended in sterile physiological saline 2. Materials and methods containing 10(I g/1 polycthoxylated castor oil (Cremo- phor EL, BASF, FRG). All solutions were prepared 2.1. Animals immediately before administration.

Common marmosets (Callithrix jacchus) of either 2.5. MPTP treatment sex weighing 280-420 g and aged 6-10 years at the beginning of the study were used. The animals were The animals were treated with MPTP in doses of 2 housed in pairs or alone under standard conditions at a mg/kg s.c. daily for up to 6 days. Since the response of temperature of 27°C (+ I°C) and 50% relative humid- individual animals differed markedly, variable dose ity with a 12-h light-dark cycle (light on from 6:00 to regimes were applied to obtain comparable initial mo- 18:00 h). The animals had free access to food pellets tor deficits. Impairment of motor function was quanti- (Mazuri primate diet) and tap water, and in addition fied daily with a rating scale (L/ischmann ctal., 1989). received a daily ration of fresh fruit and Mazuri mar- The animals were treated until they reached a maximal moset jelly. During MPTP treatment and throughout disability score of 18 24 h after the last MPTP injec- the following weeks the animals were hand-fed with tion. The cumulative doses administered ranged from 8 Mazuri marmoset jelly and fresh fruit puree until they to 12 mg/kg. After MPTP treatment the animals re- were able to maintain themselves. Electrolyte, nutrient covered from acute effects over a period of some and fluid balance were maintained by s.c. infusion of weeks. During the following months a further gradual an electrolyte, amino acid and vitamin solution recovery, from the MPTP effects was obscrvcd. One (Duphalyte, Duphar, UK) when necessary. group of three animals was tested 2 months (group A) 249

aad a second group of thrcc animals 10 months (group TABLE 1 B) after exposure to MPTP. Median stereotypy scores with the range in parentheses over 360 rain after treatment of common marmosets with terguridc.

2.6. Drug treatments Treatment Normal 2 months 10 months post MPTP post MPTP A group of four marmosets was treated with vehicle Vehicle 0 (0) 0 (0) 0 (0) aad one of the three doses of tcrguridc (4.0, 8.0 or 12.0 4 mg/kg 0 (0) 4 (5) 3 (3) mg/kg i.p.) ovcr the following weeks, allowing 1 week 8 mg/kg 0 (0) 7 (5) 2 (3) recovery between experiments. Treatments wcrc ran- 12 mg/kB 0 (0) 21 (14) 4 (1) d~mizcd within the group. MPTP-trcatcd marmosets were tested either 2 months (group A, N = 3) or 10 months (group B, N = 3) after MPTP treatment with thereafter, little or no activity for up to 180 min. This vehicle or one of the three doses of tcrguride (4.0, 8.0 exploratory activity was dose dependently reduced by or 12.0 mg/kg i.p.) in a identical design. All experi- terguride 4.0, 8.0 and 12.0 mg/kg i.p. (figs. 1 and 4). At ments started at 11:00 a.m. and finished at 5:00 p.m. later times vehicle-treated animals were more active whereas terguride-treated animals showed almost com- 2. Z Data analysis plete akinesia. Prior to behavioural testing, all animals of group A The means _+ S.E.M. wcrc calculated for time (treatment with MPTP 2 months before the experi- courses and accumulated locomotor counts of the dif- ment) showed a reduction in basal locomotor activity ferent treatment groups. Statistical differences were and exhibited slower and less coordinated movements, calculated for accumulated locomotor counts by the reduced checking movements of the head and eye- non-parametric Page test for non-independent data. blinks as well as abnormal postures of some parts of lntraindividual monotone trends of treatment effects the body. The behavioural deficits were different in were detected using the ordered alternative: vehicle < group B (treatment with MPTP 10 months before 4.0 < 8.0 < 12 mg/kg, using exact distributions fol- testing). Locomotor activity was still reduced in one of lowed by sequential tests against two alternative hy- these animals whereas another showed signs of hyper- potheses (vehicle < 4.0 < 8.0 mg/kg) or (vehicle < 4.0 excitability and unrest. The behaviour of the third and 8.0 < 12.(I mg/kg) when appropriate. animal was not different from that of controls. Animals treated with MPTP 2 months prior to the experiment (group A) showed reduced locomotor activ- 3. Results ity when exposed to vehicle. Terguridc stimulated locomotor activity in the first I80 min after administration. When adapted to the environment of the test cages, Because stereotyped movements were elicited by the naive common marmosets showed very little locomotor higher doses tested, 4.0 mg/kg of tcrguride was most activity when not disturbed. Injection of vehicle was effective (fig. 4 and table 1). The stimulatory effect of followed by a 30-min period of exploratory activity but, tcrguride was more pronounced during the last 3 h of

~" 900 | ~ 300 ,~ Z ,~o 780 z 260 ]0~ ~LM 660 --~ 540

TTLI ~I ~ ~20 2 ~4o- 1 , lr ~ 300 ~ "[ 00 E 180 T . ., E 60 ~ so ~ 20 :~ -60 ~ -20 10 60 120 180 240 300 360 ~0 60 120 180 240 300 360 Time (rain) Time (rain) Fig. 2. Mean locomotor activity counts (_,'. S.E.M., N = 3) accumu- Fig. 1. Mean locomotor activity counts (+S.E.M.. N = 4) accumu- laled in 10-min inlcrvals for 360 rain of common marmosets pre- ]aled in 10-rain intervals for 180 rain of naive common marmosets treated with MPTP 2 months prior to the adminislration of vehicle treated with vehicle (.~) or 4.0 (e), 8.0 (/~) and 12.0 (•) mg/kg of (o) or 4.0 (e), 8.0 ( ,~ ) and 12.0 ( • ) mg/kg of terguride, respectively. tc:guride, respectively. Error bars for the treatment groups are Error bars for the higher doses are omitted for clarity but were omilted for clarity but were within the same range as those shown for within the same range as those shown for 8.0 mg/kg or vehicle i.p. the vehicle group. (note the difference in scale to fig. 1). 250

~ 900 r ] ~ " 8000 . z '~z" 780 l tu~ 660 ] 6000 1 c ~/×" .EE 540 i ~° 420 T ~ 4000 ~ ~ T~,~. ' E~ 8°°t~ '~,~~' ~ 2000 ,80

8 ~o j~.~] i~ , -~i~ " - , ~ -~o ~ ...... ~J ~ 0 - 10 60 120 180 240 300 360 Normal MPTP 2 MPTP 1 Time (min) Fig. 5. Mean locomotor activity counts (~S.E.M., N = 31 accnmu- Fig. 3. Mean locomotor activity counts (+ S.E.M., N 3) accumulated over 360 min for the data shown in figs. 2 aud 3. Both groups of lated in 10-min intc~,als for 360 min of common marmosets pro- common marmosets wcrc treated with vehicle (open columns), 4.0 treated with MPTP 10 months prior to the administration of vehicle (dense hatched columns). 8.0 (hatched colunms) and 12.0 (crossed (o) or 4.0 (~), 8.0 ( ~ ) and 12.0 ( ~ ) mg/kg of terguridc, respccti~ely. colunms) mg/kg of tcrguride. In animals treated with MPTP 2 Error bars for the higher doses are omitted lbr clarity but wcrc months prior to the experiment, tcrguridc clearly stimulated locomo- within the same range as those shown for 8.13 mg/kg or vehicle i.p. tor activity at ~he lower doses tested (4.0 and 8.0 mg/kg i.p.). Ilowcvcr, due to the variability of iudividual animal responses, this effect was not statistically significant. In common marmosets exposed to MPTP 10 months prior to the experiment, terguridc had no effect the observation period (fig. 2). Vehicle-treated animals upon locomotor activity. showed some activity at this time of day, when they are usually fed. Marmosets treated with 4.0 and 8.0 mg/kg of terguride were clearly stimulated. The presence of all doses tested, although the effect did not seem to be stcrcotypics (table 11 resulted in a smaller stimulation dose-dependent. During the second 3-h period, ter- of locomotion after administration of 12 mg/kg of guride showed a tendency to stimulate locomotor activ- tcrguridc i.p. (fig. 5). ity. Again, this effect was not significant (figs. 3 and 5) The basal locomotor activity of common marmosets for the 6-h observation period. None of the doses of treated with MPTP 10 months prior to the experiment terguride tested induced pronounced stereotyped (group B) was variable, leading to somewhat higher movements in this group of animals (table 1). activity counts after vehicle treatment as compared with controls and animals of group A (figs. 3 and 4). Treatment with terguride reduced locomotor activity at 4. Discussion

In rodents without lesions, terguride has DA antag- ~ 1500 onistic properties, resulting in a reduction of locomotor activity and in catalepsy when higher doses are admin- l istered. In line with these findings, the compound reduces exploratory locomotor activity of normal common marmosets. This depressant effect Iasts up to 6 h. ,000. i_i DA agonistic properties arc unmasked in rodents pretreated subchronically with reserpine (Wachtel et al., 1984). It is likely that the depletion of monoaminergic 8 8 terminals may lead to an increased sensitivity of postsy-

~ 0" ' ' naptic receptors. The anti-parkinsonian activity of ter- ~ Normal MPTP 2 MPTP 10 guride in the MPTP-treated primate, the most reliablc Fig. 4. Mcau locomotor activity counts ( = S.E.M.) accumulated over model fl)r Parkinson's disease at present available, has 180 in for the data shown in figs. 1-3. All groups of common been shown previously. The compound induces rota- marmosets wcrc treated with vehicle (open columns), 4.0 (dense tions in monkeys rendered hcmiparkinsonian by intrac- hatched columns), 8.11 (hatched columns) and 12.0 (crossed columns) mg/kg of terguride. In naive animals tcrguridc dose dependently arotid infusion of MPTP (Brihckc et al., 1988). In reduced locomotor activity (P < 13.01, Page test, ordered alternative: accord with these findings, our data indicate that DA vehicle > 4.0 > 8.13 > 12i1 mg/kg of tcrguride). In common mar- agonistic effects in the MPTP-trcatcd common marmoscts treated with MIrTP 2 months prior to the experiment, tel'- moset arc also critically dependent on the receptor guride stimulated locomotor activity at the lowest dose tested (4.0 status. A clear stimulatory effect was only seen in mg/kg i.p., P < 0.05, Page test; ordered alternative: vehicle < 4.0 and animals treated 2 months previously with MPTP when 8.0 < 12.0 mg/kg of terguridc). In animals exposed to MPTP 113 months prior to the experiment, terguride rednccd locomotor actMty they had not recovered bchaviourally from the MlrfP up the highest dose tested allhough the effect was not significant. treatment. In the first 3 h, 4 mg/kg of terguride 251 produced the greatest response (fig. 4) whereas in the levels in humans and produce endocrine effects identi- 6-h period 4 and 8 mg/kg stimulated locomotor activ- cal to those seen with bromocriptinc, but with less side il.y (fig. 5). In animals that had recovered from MPTP effects. In a double-blind cross-over study, subjects treatment given 10 months previously, tcrguride inhib- could not distinguish the lower tcrguridc doses from i,.cd locomotor activity in the first 3 h, as it did in placebo and 1 mg of tcrguridc was always preferred to formal marmosets, although this effect was not statisti- 2.5 mg bromocriptinc (Ciccarclli et al., 1988). Clinical cally significant, llowever, in the 6-h period, all doses observations confirm that terguride is useful in the tested slightly stimulated locomotor activity, a response treatment of hyperprolactinaemic conditions including consistent with the weak DA agonistic effects of tcr- prolactinomas (Dallabonzana et al., 1986). Antiparkin- guride under these conditions. We hypothesize that the sonian effects have been reported when terguride was bchavioural recovery of common marmosets is accom- used as monotherapy or combined with L-Dopa in panied by a normalization of receptor sensitivity duc to advanced disease (Corsini et al., 1985). In open clinical changes in either the binding affinity or the coupling of trials in paticnts with Parkinson's disease, especially in receptors to second messenger systems. Thus, in ani- elderly patients (Briicke et al., 1986), there was a low raals recovered from prior MPTP treatment, the in- frequency of typical dopamincrgic side effects such as creased I)A turnover (Rose et al., 1989) could lead to a nausea, cmcsis or orthostatic hypotension. However, in higher availability of DA and subsequent normalization a double-blind study in dc now) patients terguride was of the sensitivity of presynaptic autoreceptors. Under better tolerated but less active than lisuride after 3 these conditions tcrguride would act as autoreceptor months of therapy and its possible long-term effects agonist, resulting in a reduced I)A release and inhibi- are still trader investigation (U.K. Rinnc, personal tion of locomotor activity during the initial 3-h period. communication). In placebo-controlled double-blind In the second 3-h period, tcrguridc would exert weak studies in patients with motor fluctuations, terguridc DA agonistic properties at postsynaptic receptors. added to L-Dopa had a significant effect on disability An alternative explanation involves the partial DA and also improved wearing off and dyskinesias (E. agonistic properties of terguride. Thus, the increased Martignoni and G. Nappi, personal communication). DA turnover could lead to a higher availability of DA, In these studies antidyskinetic and anti-akinctic effects with terguride antagonizing the effects of endogenous of terguridc wcrc obse~'ed in the same patients. Tcr- I)A. The initial inhibition of locomotor activity could guridc had very pronounced anti-dyskinetic effects be explained by such a phenomenon. Since terguridc without interference with the anti-akinctic effects of did not reduce but slightly increased locomotor activity L-Dopa in parkinsonian patients with motor fluctua- in recovered common marmosets over the 6-h period, tions as shown in a double-blind placebo-controlled the latter hypothesis seems less likely. study (Baronti et al., 1989 and submitted for publica- Two faccts of the effects of tcrguridc arc of interest tion). Tcrguridc has positive effects on tardive dyskinc- when compared with the effects of direct DA agonists sia even in the presence of ncurolcptic drugs (Silk6 ct such as (+)-PHNO (Nomoto et al., 1987) in this animal al., 1987). Finally, in an open clinical trial, including 11 raodcl. First, tcrguridc did not cause a rapid and patients with chronic schizophrenia and marked nega- sustained locomotor hyperactivity even with the relative symptoms, tcrguride improved symptomatology in tively high doses used. Second, the normal diurnal eight patients on the scale for assessment of negative pattern of locomotor activity was preserved. Increased symptoms (SANS). In none of the patients were psy- activity after treatment with terguride was seen during chotic symptoms elicited and the compound was well periods of higher basal locomotor activity nnder con- tolerated (Olbrich and Schanz, 1988). trol conditions. Both observations contrast with the Mixed DA agonist/antagonists may have good anti- stimulatory effect on locomotor activity seen in reser- parkinsonian actions with fewer side effects, especially pinizcd-rodents and are compatible with the idea that in patients susceptible to motor fluctuations, dyskine- terguride 'enables' voluntary locomotion in the sias, psychosis or enhanced sensitivity towards MPTP-treated marmoset rather than causes hyperstim- dopamincrgic drugs. ulation. This atypical pharmacological profile, in which In conclusion, the MPTP-treated common mar- DA agonistic and DA antagonistic properties arc com- moset offers a useful pharmacological model and is of bined in one molecule, has been described as mixed predictive value for the characterization of not only DA agonism/antagonism in rodents. Our data show classical direct DA agonists but also mixed DA ago- similar effects of terguride in a primate species. nist/antagonists. Tcrguride can be used in a pharma- The unique pharmacological profile of terguridc cological in vivo test for the assessment of the sensitiv- suggests an interesting range of possible indications, ity status of central DA receptors in MPTP-trcated some of which have already been tested in clinical primates. Tcrguride could also be valuable for the trials. Like classical DA agonists, single doses of tcr- assessment of the function of dopaminergic cell trans- guride ranging from 0.25 to 1.0 mg lower prolactin plants. 252

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