D2 dopamine receptor antagonism is postulated to be the key to antipsychotic efficacy in the treatment of schizophrenia. Yet the D1 dopamine family of receptors is far more prevalent in the cortical areas of the brain, such as the prefrontal cortex, which have frequently been implicated in schizophrenia. Moreover, the prefrontal cortical D1 sites have recently been shown to be down-regulated by chronic treatment with several commonly used antipsychotic drugs (Lidow and Goldman-Rakic, 1994). To provide further insight into the pharmacological regulation of the D1 class of dopaminergic receptors, we have now used ribonuclease protection assays to examine the regulation of D1 and D5 dopamine receptor mRNAs in the prefrontal cortex and the neostriatum of nonhuman primates after chronic treatment with eight different drugs representing a wide structural and pharmacological spectrum of antipsychotic medications. The medications were administered for 6 months twice daily at doses that fall within the therapeutic range recommended for human patients. The study also included a substituted benzamide, tiapride, which is a D2 antagonist like the eight aforementioned drugs but reportedly lacks antipsychotic activity. Remarkably, all drugs used in this study, including tiapride, down-regulated the levels of both D1 and D5 mRNAs in the prefrontal cortex by 30% to 60% compared with a vehicle control group, whereas mRNAs in the neostriatum were not affected. This observation indicates that a reduction in the levels of prefrontal cortical dopamine receptors of the D1 class may be an obligatory consequence of D2 receptor antagonism and thus may be a pharmacological property of antipsychotic drugs.