Adjunctive α2 adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission.

Abstract

Compared with typical antipsychotic drugs (APDs) clozapine shows superior efficacy in treatment-resistant schizophrenia. However, in contrast to most APDs clozapine possesses high affinity for α₂ adrenoceptors, and clinical and preclinical studies provide evidence that the α₂ adrenoceptor antagonist idazoxan enhances the antipsychotic efficacy of typical D₂ receptor antagonists as well as olanzapine. Risperidone has lower affinity for α₂ adrenoceptors than clozapine but higher than most other APDs. We here examined, in rats, effects of adding idazoxan to a low dose of risperidone.
We used conditioned avoidance response (CAR) to assess antipsychotic efficacy, a catalepsy test to examine extrapyramidal side-effect (EPS) liability, in vivo microdialysis technique to measure brain dopamine efflux, in vitro intracellular electrophysiological recording to analyze cortical NMDA receptor-mediated transmission, and ex vivo autoradiography to assess the in vivo α_2A and α_2C adrenoceptor occupancies by risperidone.
The dose of risperidone needed for antipsychotic effect in the CAR test was ~0.4 mg/kg, which produced 11 and 17% in vivo receptor occupancy at α_2A- and α_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 enhanced cortical dopamine release and NMDA receptor-mediated responses were obtained.
These data propose that the effectiveness of risperidone in schizophrenia can be enhanced, and its EPS liability reduced, by adjunctive treatment with an α₂ adrenoceptor antagonist, such as idazoxan, concomitant with a reduction in dose of risperidone.