Enhancement of antipsychotic-like effects by combined treatment with the α₁-adrenoceptor antagonist prazosin and the dopamine D₂ receptor antagonist raclopride in rats

Summary.

Blockade of central α₁-adrenoceptors has been implicated as a possible factor contributing to the atypical antipsychotic profile of clozapine. Thus, in the present study we examined the effects of concomitant α₁-adrenoceptor and dopamine D₂ receptor blockade on conditioned avoidance response performance, as an index of antipsychotic-like activity, and on the induction of catalepsy, as a test for extrapyramidal side effect liability, in rats. It was found that pretreatment with the α₁-adrenoceptor antagonist prazosin (0.2 mg kg⁻¹ s.c.) caused an enhancement of a suppression of conditioned avoidance response in the presence of the dopamine D₂ receptor antagonist raclopride (0.05–0.20 mg kg⁻¹ s.c.). The effect was most prominent at a subthreshold dose of raclopride (0.05 mg kg⁻¹). At these doses, prazosin or raclopride by themselves, or in combination, did not produce catalepsy. In addition, pretreatment with prazosin (0.2 mg kg⁻¹ s.c.) did not alter the catalepsy produced by a higher dose of raclopride (1.0 mg kg⁻¹ s.c.). It is suggested that, in the presence of low dopamine D₂ receptor occupancy, additional α₁-adrenoceptor blockade might improve antipsychotic efficacy, and thereby improve the therapeutic window with regard to parkinsonism.