WHY DOES CLOZAPINE STIMULATE THE MOTOR-ACTIVITY OF RESERPINE-PRETREATED RATS WHEN COMBINED WITH A DOPAMINE D-1 RECEPTOR AGONIST

The aim of the present experiments was to investigate the locomotor st imulant effects of the atypical antipsychotic agent, clozapine, in rat s depleted of their dopamine by reserpine and cr-methyl-p-tyrosine pre treatment. Clozapine itself induced a slight but never significant sti mulation of locomotor activity which was enhanced by the addition of t he selective dopamine D-1 receptor agonist, SKF38393 trahydro-7,8-dihy droxy-1-phenyl-1H-3-benzazepine), but not by the selective dopamine D- 2 receptor agonist, quinpirole. The stimulation produced by clozapine plus SKF38393 was blocked by the selective dopamine D-1 receptor antag onist, SCH23390 (7-chloro-8-hydroxy-3-methyl-l-phenyl-2, hydrochloride ), while the selective dopamine D-2 receptor antagonist, haloperidol, was ineffective. A combination of SCH23390 and haloperidol blocked the clozapine plus SKF38393-induced locomotion. Unlike clozapine, neither the selective 5-HT2 receptor antagonist, ritanserin, nor the dopamine D-2 receptor antagonists, haloperidol and remoxipride, caused locomot or activation when given alone or in combination with SKF38393. The in directly acting sympathomimetic amine, d-amphetamine, was inactive in the monoamine-depleted rats, indicating that no dopamine was available for release by d-amphetamine. The muscarinic receptor antagonist, sco polamine, alone did not alter locomotion, but produced marked stimulat ion when combined with SKF38393 but not with quinpirole. This stimulat ion was not affected by haloperidol. However, the scopolamine plus SKF 38393-induced stimulation was partially blocked by SCH23390 or by a co mbination of haloperidol and SCH23390. The data indicate that clozapin e, in rats depleted of their dopamine stores, exhibits properties cons istent with those of a dopamine receptor agonist. The pharmacology of this behavioural stimulation was similar but not identical to that see n with the muscarinic receptor antagonist, scopolamine. The behavioura l effects of clozapine reported here might be explained by a dual effe ct: antagonism of muscarinic receptors and agonist-like activity at do pamine receptors.