Arch.Int.PL R Acodyn. 127, 2 C?-25C:(19/O0)- LSD 815

J Arch.int.PL_r_acodyn. 127, 2_c?-25c:(19/o0)- LSD 815

ANTAGONISM OF PSYCHOTOMIMETIC AGENTS IN THE CONSCIOUS CAT

W. B. RICE AND J. D. McCOLI.

(Receh'ed fi_r publication 5 - t - 1960 ).

INTRODUCTION

The antagonism of psychotomimetic agents has been considered as a screening method for ataractic agents (see RILEY and SPINKS, 1958 , for references). The rationale for this is based largely on the observations that certain neuroleptics counteract chemically induced hallucinations in man (FABING, 1955, DENBER& MERLIS, 1954) and the EEG changes in animals (RINALDI & HIMWlCH, 1955). The injection of small doses of mescaline and I.SDz5 into the lateral ventricle of the conscious cat and dog produces characteristic behavioural, somatomotor and autonomic effects. (HALEY & McCoRMICK, 1956; HALEY, I957; HALEY & DASGUPTA, I958 ). STURVESANTand DRILL (1956) observed modification of a mescaline response in the cat following the intracerebral injection of chlorpromazine, reserpine and azacyclonol. This study was undertaken to quantitatively compare the effects of different psychotomimetic agents in the conscious cat when administered by the intraventricular route. Also of interest was a study of the antagonism of these induced changes by some neuroleptic agents.

M ETHODS

Collison cannulae were implanted under sterile conditions into the lateral ventricle of the adult cat after the method of I'EI.DBER(; and

SHERWOOD (1953). The psychotomimetic compounds were injected in a volume of o. 3 mis

I 250 W.B. RICE AND J. I). MC COI.I. followed by 0.2 mls saline to wash the solution through the cannula. All animals were first tested by an injection of o. 5 mls of saline to assure patency of the system, and that the change in the cerebro-spinal fluid pressure would not alter the behaviour of the animal. Animals were allowed two to three weeks rest between trials. Final results were not tabulated until the location of the cannula in the lateral ventricle was confirmed by autopsy. The effects produced by the intraventricular injection of the psycho- tomimetics were tabulated according to the items listed in Table I. The table also summarizes the possible central sites of action of these different effects. (HALEY, X956; HESS, X956). Results were recorded as the percentage of animals responding with the particular effect following a standard dose of a given psychotomimetic. Rage was classified as unprovoked, repeated periods of spitting and snorting with flared nostrils and extended claws. Hostility consisted of spitting and growling when the animal was approached by the observer or another cat. Mescaline sulphate (x), LSD25 (-.), and adrenochrome (a), were the psychotomimetic agents chosen for study. The action of the following compounds on the mescaline-induced response was studied : benactyzine, meprobamate, chlorpromazine, reserpine, phenobarbital, scopolamine, chlorphenoxamine (fl-dimethylaminoethyl-p-chloro-_-methyl benzhydryl ether HCI) and nonyl methyl dioxolane _2-nonyl-2-methyl- 4- hydroxy-methyl- i ,3-dioxolane).

RESULTS

The various effects produced by the psychotomimetic agents injected into the lateral ventricle of the conscious cat are summarized in "Fable II. Mescaline (x mg/kg) produced a high incidence of autonomic, somatomotor and behavioural changes. The onset of these signs occurred within minutes following the injection. Convulsions occurred within ten minutes. Less autonomic and somatomotor effects were observed with LSI)2s (5 ° _,/kg) than with mescaline. The most significant and outstanding effect of this compound was the appearance of pronounced hostility. This was the only psychotomimetic studied which did produce a hostility reaction.

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S()MAT()M()'I'()R ('onvulsi.ns :66 ",, o ",, _oo Tremors 5° ",, z5 ",, Ioo Ataxia tOO ",, 0 ",, tOO Pav.' Elevation Ioo ",, noo ",, 50 Circlin_ 7t ",, o ". o Facial Twitch xoo "., o ".. t oo .'klescaline Fact' xoo ".,

BI':I IAVI()L'RA[, Yowlin_ 86 ".. o ",. o '.. I labit Chance too ".. o %. too ",, Hostility o ",, ioo ",, o ".,

The injection of adrenochrome (0.6 mgkg) resulted in a higher incidence of sympathetic rather than parasympathetic stimulatior,. A high incidence of somatomotor effects, including convulsions, was also observed. The action of adrenochrome resembled that produced by mescaline rather than I,SD.._. Four minutes following the injection ,,f adrenochrome the animals began growling, meowing and spitting. Eight minutes after the injection a severe tonic seizure dcveh,ped which became tonic-chmic in nature, l:ollowin¢ these convulsions the animal was immobile with flaccid muscles and appeared semi-stupor,,us. The effect on the mescaline rcsp,,nse fifth,wing prctrcatment ,,f the animals with the various agents tested is summarized in Table ili. Reserpine (zo y, kg, subcutaneous 2 4 hours pretrcatment) had little effect on the sympathetic comp,,nents, although it did reduce sumc I',_Y('I I()T()M I M I-TI(' A(;I'N'I'S 253

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•,_ _. ,_- 254 W.B. RICE AND J. D. MC COLL of the parasympathetic effects. Rage and emesis were completely blocked by this compound. The incidence of convulsions and tremor were markedly decreased while paw elevation and circling were antagonized. Meprobamate (20 mgkg intraperitnneally 3° minutes pretreatment) abolished man)" of the autonomic effects induced by mescaline and markedly decreased the incidence of others. The somatomotor components were also modified by this compound, in particular, convulsions and tremor. Chlorpromazine (2 mgkg subcutaneously 3° minutes pretreatment) produced little effect upon the sympathetic mediated components, but did reduce the incidence of many of the parasympathetic features and somatomotor effects. Chlorpromazine had no influence on convulsions or ataxia, but did reduce to some extent the incidence of the others. It also decreased the behavioural effects induced by mescaline. Atropine (o.6 mg, kg subcutaneously 3° minutes pretreatment) and scopolamine (o. 5 mgkg subcutaneously 3° minutes pretreatment) had no effect upon sympathetic induced elements, while the parasympathetic components were affected. There was no influence of these compounds on the somatomotor effects produced by mescaline and little effect on the behavioural components. Phenobarbital (uo mgkg intraperitoneally 3° minutes pretreatment) failed to modify any of the sympathetic elements, had some effect upon the parasympathetic components, and little significant action upon the somatomotor components or the behavioural changes. The modification of the mescaline response was also studied fl)llowing pretreatment with nonyl methyl dioxolane, benactyzine, chlorphenoxamine and a combination of these compounds administered together. These were studied as the dioxolane represented the central relaxant type of ataractic, while the other two compounds represented the anti- phobic type. These results are summarized in Table IV. Benactyzine (xo mg kg intraperitoneally 3o minutes pretreatment) markedly antagonized many of the autonomic-mediated effects, parti- cularly the parasympathetic components. There was also a decrease in the somatomotor features and although convulsions were not prevented, the time of onset was significantly prolonged. Benactvzine also modified the behavioural parameters. Nonyl methyl dioxolane (lo mg kg intraperitoneally 3° minutes pretreatment) abolished rage produced by mescaline, and completely antagonized all parasympathetic elements with the exception of salivation. There was little effect on the snmatomotor components. It did, I'SY ('II()TO_I I M El"I(" A(;ENT_ 2_

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-- II 2_6 W.B. RICE AND J. D. MC COLA. however, completely eliminate the behavioural changes induced by mescaline. Chlorphenoxarnine (io mg/kg intraperitoneally 3° minutes pretreatment) had little effect on the autonomic parameters. Of the somatomotor components the only two affected were paw elevation and circling. There was no modification of the behavioural pattern. The combination of nonyl methyl dioxolane with benactyzine (xo mgkg each intraperitoneally 3o minutes pretreatment) completely abolished all autonomic and somatomotor signs induced by mescaline. The simultaneous administration of chlorphenoxamine with nonvl methyl dioxolane at the same dose also markedly modified the various components. When the dose of the dioxolane was reduced to 5 mg kg the degree of antagonism of the various components decreased. Benacty- zine was more effective than chlorphenoxamine at this lower dose level of the dioxolane.

DISCUSSION

The in_racerebral injection of mescaline, adrenochrome and LSD_5 in the cat produced a variety of autonomic, somatomotor and behavioural changes which could be quantitated. The effects so induced did not appear to be correlated with other pharmacological action of the psycho- tomimetics. Mescaline and adrenochrome are chemically related to vasoconstrictors, but the effect in the cat was different from that produced by adrenaline or noradrenaline (FELDBERG and SHERWOOD, I954). Those compounds which antagonized the mescaline reaction did not appear to accomplish this by virtue of secondary pharmacological activity. Benactyzine, for example, has anticholinergic properties, but atropine or scopolamine did not modify the mescaline response. Phenobarbital had little effect upon this reaction as a consequence of its sedative activity. In general those compounds which modified the mescaline effect were those reported to be active as neuroleptic ataractic agents. These results should not be interpreted to suggest that compounds active against mescaline in the cat will antagonize mescaline hallucinations in man. Many workers have employed mescaline given systemically for bio- assay of potential ataractic agents (SPEcKs, i957; PLOTNIKOFFand W_HXNCTON, i958 ; MAd'Eli and SONCIN, x958 ; DEEC;ANand CooK, n958). The comparative results vary somewhat with the different end I',",;Y('111YI( ) M ] M If]'l (" A(;ENTS 2_'_"

points rce_wded which ranged from spontaneous motor activity to death. _l.st workers report that chlorpromazine and reserpine were the most effective antagonists while phenobarbitone, meprobamate and atropine had little eflect, l_l.O'rYltCOF}:and \VAsIIIN_;'IO.X (1958) found benactvzine had no significant protection in mice against mescaline-induced mllrtality. The difference betxvecn their results and our own is likeh" due to the extreme differences in the dose of mescaline employed. The results we have observed bv the injection i1f LSI).,_, are qualita- tivelv similar to those effects observed bv HAI.m and I)AS_;t!P3"A (I958). I.ike HAH'Y, but unlike STt'RVI-:SANTand DRH_L (1956), no true catatonia was observed in the cat. No catatonia was observed with mescaline or with adrenochrolne. .Mescaline and adrenochrome appeared to affect predominantly various regions of the hypothalamus, diencephalon, medulla, the higher brain stem and motor cortex. I_SDz5, on the other hand, had considerably less effect on the hypnthalamus and also affected the medulla and higher brain centres. This is only an approxilnate assessment of the possible sites of action, as much of the brain was brought into contact with the compounds via the cerebro-spinal fluid. These potential sites, however, agree well as compared with EEG studies. I_INALI)I and Hl.xlxwcll (i955) observed that I_SD,,., and mescaline produced arousal patterns via the mesodiencephalic activating svstem. KILLA.XI (1956) fi}und in the cat that the thalamus was inw)lved in CNS response to I.SD.,-,. MERLIs (1955) considered that mescaline acted primarily on diencephalic structures. .'_IARRAZZI and HART (1953) reported that chlnrpr.mazine and reserpine blocked mescaline in a two neurone transcallosal (cortical-visual) system. Consideration has been given the problem of penetration of the blood- brain barrier bv psychotomimetic agents and by neuroleptic agents ((;RELY; and (;I_BONS, i959). The intracerebral injection of mescaline, adrenochrome and LSD.,,_ produced a distinct pattern of action at doses which are generally ineffective when given by a peripheral route. Our results demonstrate that many of the centrally mediated effects produced by the intracerebra[ injection of mescaline could be antagonized by compounds administered by a peripheral route. This strongly suggests that these antagonists are exerting this action at the level of the central nervous system. 258 W.B. RICE AND J. D. MC COLL

SUMMARY

The action of mescaline, adrenochrome and LSD25 following the intraventricular injection in the conscious cat has been studied. Mescaline produced a high incidence of autonomic, somatomotor and behavioural changes. Adrenochrome produced a pattern of effects similar to that of mescaline, but less intense. LSD25 considerably less affected the autonomic and somatomotor parameters, while its main action was on behaviour. Benactyzine, chlorpromazine, reserpine, nonyl methyl dioxolane, chlorphenoxamine and meprobamate were found to antagonize various components of the mescaline-induced behaviour. The simultaneous administration of nonyl methyl dioxolane with benactyzine or chlorphenoxamine demonstrated an enhancement of antagonism against mescaline. Scopolamine, atropine and phenobarbital had very little action on the mescaline response.

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