DOWN-REGULATION OF THE D1 AND D5 DOPAMINE-RECEPTORS IN THE PRIMATE PREFRONTAL CORTEX BY CHRONIC TREATMENT WITH ANTIPSYCHOTIC-DRUGS

D2 dopamine receptor antagonism is postulated to be the key to antipsy chotic efficacy in the treatment of schizophrenia, Yet the D1 dopamine family of receptors is far more prevalent in the cortical areas of th e brain, such as the prefrontal cortex, which have frequently been imp licated in schizophrenia, Moreover, the prefrontal cortical D1 sites h ave recently been shown to be down-regulated by chronic treatment with several commonly used antipsychotic drugs (Lidow and Goldman-Rakic, 1 994). To provide further insight into the pharmacological regulation o f the D1 class of dopaminergic receptors, we have now used ribonucleas e protection assays to examine the regulation of D1 and D5 dopamine re ceptor mRNAs in the prefrontal cortex and the neostriatum of nonhuman primates after chronic treatment with eight different drugs representi ng a wide structural and pharmacological spectrum of antipsychotic med ications. The medications were administered for 6 months twice daily a t doses that fall within the therapeutic range recommended for human p atients. The study also included a substituted benzamide, tiapride, wh ich is a D2 antagonist like the eight aforementioned drugs but reporte dly lacks antipsychotic activity. Remarkably, all drugs used in this s tudy, including tiapride, down-regulated the levels of both D1 and D5 mRNAs in the prefrontal cortex by 30% to 60% compared with a vehicle c ontrol group, whereas mRNAs in the neostriatum were not affected. This observation indicates that a reduction in the levels of prefrontal co rtical dopamine receptors of the D1 class may be an obligatory consequ ence of D2 receptor antagonism and thus may be a pharmacological prope rty of antipsychotic drugs.