Vol. 283, Issue 2, 939-946, 1997

Differential Regulation of D₂ and D₄ Dopamine Receptor mRNAs in the Primate Cerebral Cortex vs. Neostriatum: Effects of Chronic Treatment with Typical and Atypical Antipsychotic Drugs¹

Michael S. Lidow and Patricia S. Goldman-Rakic

Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut

The RNase Protection Assay was used to examine the regulation of D₂ and D₄ dopamine receptor mRNAs in the cerebral cortex and neostriatum of nonhuman primates after chronic treatment with a wide spectrum of antipsychotic medications (chlorpromazine, clozapine, haloperidol, molindone, olanzapine, pimozide, remoxipride and risperidone). Tiapride, a D₂ antagonist that lacks antipsychotic activity, was also included. All drugs were administered orally for 6 months at doses recommended for humans. All antipsychotic drug treatments examined in this study caused a statistically significant up-regulation of both the long and short isoforms of the D₂ receptor mRNAs in the prefrontal and temporal cortex. Tiapride, in contrast, significantly up-regulated only the level of D₂-long mRNA in these areas. The same drug treatments produced less uniform effects in the neostriatum than in the cortex: clozapine and olanzapine failed to significantly elevate either D₂-long or D₂-short receptor messages in this structure unlike all other drugs, including tiapride. In both the cerebral cortex and striatum, D₄ receptor mRNA was upregulated by certain typical (chlorpromazine and haloperidol) and certain atypical (clozapine, olanzapine and risperidone) antipsychotic agents as well as by tiapride. Other drugs of the typical (molindone and pimozide) and atypical (remoxipride) classes had no effect on D₄ mRNA levels in either cortical or striatal tissue. The finding that up-regulation of D₂ dopamine receptor mRNAs was a consistently observed effect of a wide range of antipsychotic agents in the cerebral cortex but not in the neostriatum, coupled with the fact that the D₂-short isoforms in the cortex were not regulated by a nonantipsychotic D₂ antagonist, tiapride, draws attention to the importance of the D₂ dopamine receptor in the cerebral cortex as a potentially critical, common site of action of antipsychotic medications.