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.