PARTIAL AGONISTIC ACTION OF CLOZAPINE AT DOPAMINE D-2 RECEPTORS IN DOPAMINE DEPLETED ANIMALS

In the present experiments, the locomotor and stereotypic stimulant ef fects of the atypical antipsychotic agent, clozapine were studied in m ice depleted of their brain dopamine by reserpine and alpha-methyl-p-t yrosine pretreatment. Clozapine at a dose of I mg/kg produced slight s timulation of locomotor activity, but failed to produce any stereotypy . However, clozapine at 0.5 or 2 mg/kg failed to show increase in loco motor activity or stereotypy. Clozapine potentiated the locomotor acti vity and stereotypy induced by selective dopamine D-1 receptor agonist , SKF 38393 but blocked locomotor activity and stereotypy induced by d opamine D-2 agonist, B-HT 920 (1 mg/kg) and stereotypy induced by high er dose of B-HT 920 (2 mg/kg). The synergistic action of clozapine and SKF 38393 was partially blocked by the dopamine D-1 selective antagon ist SCH 23390 and the dopamine D-2 selective antagonist, sulpiride, re spectively. Clozapine potentiated the stereotypy induced by apomorphin e (0.5 and 1 mg/kg) but did not affect locomotor stimulating activity of apomorphine. These behavioral effects of clozapine suggested that i t has partial agonistic action at dopamine D-2 receptors.