Enhancement of antipsychotic-like effects by combined treatment with the alpha(1)-adrenoceptor antagonist prazosin and the dopamine D-2 receptor antagonist raclopride in rats

Blockade of central alpha (1)-adrenoceptors has been implicated as a possib le factor contributing to the atypical antipsychotic profile of clozapine. Thus, in the present study we examined the effects of concomitant alpha (1) -adrenoceptor and dopamine D-2 receptor blockade on conditioned avoidance r esponse 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 alpha (1)-adrenoceptor a ntagonist prazosin (0.2 mg kg(-1) s.c.) caused an enhancement of a suppress ion of conditioned avoidance response in the presence of the dopamine D-2 r eceptor antagonist raclopride (0.05-0.20 mg kg(-1) s.c.). The effect was mo st prominent at a sub-threshold dose of raclopride (0.05 mg kg(-1)). At the se 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 D -2 receptor occupancy, additional alpha (1)-adrenoceptor blockade might imp rove antipsychotic efficacy, and thereby improve the therapeutic window wit h regard to parkinsonism.