Why does clozapine stimulate the motor activity of reserpine-pretreated rats when combined with a dopamine D1 receptor agonist?

Abstract The aim of the present experiments was to investigate the locomotor stimulant effects of the atypical antipsychotic agent, clozapine, in rats depleted of their dopamine by reserpine and α-methyl- p -tyrosine pretreatment. Clozapine itself induced a slight but never significant stimulation of locomotor activity which was enhanced by the addition of the selective dopamine D 1 receptor agonist, SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H -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 antagonist, SCH23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H -3-benzapine 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-HT 2 receptor antagonist, ritanserin, nor the dopamine D 2 receptor antagonists, haloperidol and remoxipride, caused locomotor activation when given alone or in combination with SKF38393. The indirectly 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, scopolamine, alone did not alter locomotion, but produced marked stimulation when combined with SKF38393 but not with quinpirole. This stimulation was not affected by haloperidol. However, the scopolamine plus SKF38393-induced stimulation was partially blocked by SCH23390 or by a combination of haloperidol and SCH23390. The data indicate that clozapine, in rats depleted of their dopamine stores, exhibits properties consistent with those of a dopamine receptor agonist. The pharmacology of this behavioural stimulation was similar but not identical to that seen with the muscarinic receptor antagonist, scopolamine. The behavioural effects of clozapine reported here might be explained by a dual effect: antagonism of muscarinic receptors and agonist-like activity at dopamine receptors.