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