Compared to both first-and second-generation antipsychotic drugs (APDs), clozapine shows superior efficacy in treatment-resistant schizophrenia. In contrast to most APDs clozapine possesses high affinity for a 2 -adrenoceptors, and clinical and preclinical studies provide evidence that the a 2 -adrenoceptor antagonist idazoxan enhances the antipsychotic efficacy of typical D 2 receptor antagonists as well as olanzapine. Risperidone has lower affinity for a 2 -adrenoceptors than clozapine but

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... her than most other APDs. Here we examined, in rats, the effects of adding idazoxan to risperidone on antipsychotic effect using the conditioned avoidance response (CAR) test, extrapyramidal side-effect (EPS) liability using the catalepsy test, brain dopamine efflux using in-vivo microdialysis in freely moving animals, cortical Nmethyl-D-aspartate (NMDA) receptor-mediated transmission using intracellular electrophysiological recording in vitro, and ex-vivo autoradiography to assess the in-vivo a 2A -and a 2C -adrenoceptor occupancies by risperidone. The dose of risperidone needed for antipsychotic effect in the CAR test was y0.4 mg/kg, which produced 11 % and 17 % in-vivo receptor occupancy at a 2A -and a 2C -adrenoceptors, respectively. Addition of idazoxan (1.5 mg/kg) to a low dose of risperidone (0.25 mg/kg) enhanced the suppression of CAR, but did not enhance catalepsy. Both cortical dopamine release and NMDA receptor-mediated responses were enhanced. These data propose that the therapeutic effect of risperidone in schizophrenia can be enhanced and its EPS liability reduced by adjunctive treatment with an a 2 -adrenoceptor antagonist, and generally support the notion that the potent a 2 -adrenoceptor antagonistic action of clozapine may be highly important for its unique efficacy in schizophrenia.