Role of D1 and D2 dopamine receptors in the discriminative stimulus properties of the atypical antipsychotic clozapine in rats

Abstract

The purpose of the present study was to assess the role of dopamine D1 and D2 receptors in the discriminative stimulus properties of the atypical antipsychotic clozapine (CLZ). Two groups of rats were trained to discriminate either a moderate dose of clozapine (5.0 mg/kg) from vehicle or a high dose of clozapine (10.0 mg/kg) from vehicle in a two-lever drug discrimination paradigm. Generalization testing with clozapine yielded an ED50 of 0.9 mg/kg (95% confidence limits = 0.5–2.0 mg/kg) for the 5.0 CLZ group and 2.0 mg/kg (95% confidence limits = 1.4–2.8 mg/kg) for the 10.0 CLZ group. Substitution testing with the D1 antagonist SCH 23390 and the D2 dopamine antagonist haloperidol failed to produce clozapine-appropriate responding for either of the clozapine training doses. The antipsychotic drug thioridazine (which binds to a number of neurotransmitters in addition to dopamine) produced partial substitution (64.5% drug lever responding) in the 5.0 CLZ group at the 5.0 mg/kg dose. These results suggest that antagonism of D1 and D2 dopamine receptors alone is not sufficient to produce clozapine-appropriate responding, even with the higher training dose of 10.0 mg/kg. Drug Dev. Res. 46:139–147, 1999. © 1999 Wiley-Liss, Inc.