Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics

Abstract

Quantitative in vitro receptor autoradiography was used to examine changes in three ionotropic glutamate receptor subtypes using ³H-MK801 (NMDA-R antagonist), ³H-CNQX (AMPA-R antagonist) and ³H-kainic acid (kainate-R agonist) following subchronic (28 days) and chronic (8 months) treatment of rats with a typical antipsychotic, haloperidol (1.5 mg/kg per day), atypical antipsychotic, clozapine (25 mg/kg per day), the dopamine D₂/D₃ receptor antagonist, raclopride (10 mg/kg per day), and the dopamine D1 (D₁/D₅) receptor antagonist SCH23390 (0.5 mg/kg per day). Subchronic and chronic drug treatments did not significantly alter ³H-CNQX or ³H-kainate binding in any of brain regions examined. Subchronic SCH23390 treatment elevated ³H-MK801 binding in the hippocampal formation with significant increases in the CA₁ and dentate gyrus, suggesting a specific role for dopamine D1 receptors in the regulation of hippocampal NMDA receptor function. Subchronic, but not chronic, haloperidol and clozapine treatment significantly reduced ³H-MK801 binding in the medial prefrontal cortex. This suggests that typical and atypical antipsychotics may exert some of their clinical effects by affecting NMDA receptors in the medial prefrontal cortex. Both subchronic and chronic clozapine treatment decreased ³H-MK801 binding in the caudate putamen. The minimal extrapyramidal side effects produced by clozapine may result, in part, from the reduction in NMDA receptor binding in the caudate putamen.