Abstract

Changes in members of the dopamine (DA) D₁-like (D₁, D₅) and D₂-like (D₂, D₃, D₄) receptor families in rat forebrain regions were compared by quantitative in vitro receptor autoradiography after prolonged treatment (28 days) with the atypical antipsychotics olanzapine, risperidone, and quetiapine. Olanzapine and risperidone, but not quetiapine, significantly increased D₂binding in medial prefrontal cortex (MPC; 67% and 34%), caudate-putamen (CPu; average 42%, 25%), nucleus accumbens (NAc; 37%, 28%), and hippocampus (HIP; 53%, 30%). Olanzapine and risperidone, but not quetiapine, produced even greater up-regulation of D₄ receptors in CPu (61%, 37%), NAc (65%, 32%), and HIP (61%, 37%). D₁-like and D₃ receptors in all regions were unaltered by any treatment, suggesting their minimal role in mediating actions of these antipsychotics. The findings support the hypothesis that antipsychotic effects of olanzapine and risperidone are partly mediated by D₂ receptors in MPC, NAc, or HIP, and perhaps D₄ receptors in CPu, NAc, or HIP, but not in cerebral cortex. Selective up-regulation of D₂ receptors by olanzapine and risperidone in CPu may reflect their ability to induce some extrapyramidal effects. Inability of quetiapine to alter DA receptors suggests that nondopaminergic mechanisms contribute to its antipsychotic effects.