科研之友
微信
新浪微博
Facebook
分享链接
摘要
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 alpha(2)-adrenoceptors, and clinical and preclinical studies provide evidence that the alpha(2)-adrenoceptor antagonist idazoxan enhances the antipsychotic efficacy of typical D-2 receptor antagonists as well as olanzapine. Risperidone has lower affinity for alpha(2)-adrenoceptors than clozapine but higher 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 N-methyl-D-aspartate (NMDA) receptor-mediated transmission using intracellular electrophysiological recording in vitro, and ex-vivo autoradiography to assess the in-vivo alpha(2A)- and alpha(2C)-adrenoceptor occupancies by risperidone. The dose of risperidone needed for antipsychotic effect in the CAR test was similar to 0.4 mg/kg, which produced 11% and 17% in-vivo receptor occupancy at alpha(2A)- and alpha(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 alpha(2)-adrenoceptor antagonist, and generally support the notion that the potent alpha(2)-adrenoceptor antagonistic action of clozapine may be highly important for its unique efficacy in schizophrenia.
- 出版日期2010-8
