Partial agonistic action of clozapine at dopamine D2 receptors in dopamine depleted animals

 In the present experiments, the locomotor and stereotypic stimulant effects of the atypical antipsychotic agent, clozapine were studied in mice depleted of their brain dopamine by reserpine and alpha-methyl-p-tyrosine pretreatment. Clozapine at a dose of 1mg/kg produced slight stimulation of locomotor activity, but failed to produce any stereotypy. However, clozapine at 0.5 or 2 mg/kg failed to show increase in locomotor activity or stereotypy. Clozapine potentiated the locomotor activity and stereotypy induced by selective dopamine D₁ receptor agonist, SKF 38393 but blocked locomotor activity and stereotypy induced by dopamine D₂ agonist, B-HT 920 (1 mg/kg) and stereotypy induced by higher dose of B-HT 920 (2 mg/kg). The synergistic action of clozapine and SKF 38393 was partially blocked by the dopamine D₁ selective antagonist SCH 23390 and the dopamine D₂ selective antagonist, sulpiride, respectively. Clozapine potentiated the stereotypy induced by apomorphine (0.5 and 1 mg/kg) but did not affect locomotor stimulating activity of apomorphine. These behavioral effects of clozapine suggested that it has partial agonistic action at dopamine D₂ receptors. Received: 22 July 1997/Final version: 17 August 1997