Effect of haloperidol on expression of dopamine D2 receptor mRNAs in rat brain.

Chronic administration of the neuroleptic drug haloperidol previously has been shown to increase the density of striatal dopamine D2 receptor, which is believed to be the underlying factor in neuroleptic-induced tardive dyskinesia. To search for the mechanism of receptor upregulation, the expression of the isoforms of dopamine D2 receptor mRNA in rat striatum was analyzed by Northern, solution, and in situ hybridizations in haloperidol-treated rats (1-35 days). Northern blot analysis of poly(A)+ RNA hybridized with a probe common for both isoforms as well as an insert-specific probe for the long isoform of the receptor revealed no significant difference in hybridization signal between the control and any of the haloperidol-treated groups of rats. The receptor density, however, was increased by 30-40% in animals receiving haloperidol for 7-35 days. Solution hybridization with an antisense riboprobe specific for a consensus sequence as well as in situ hybridization with a consensus oligonucleotide probe similarly failed to detect any increase in the expression of receptor mRNA following haloperidol treatment. The results suggest that post-transcriptional mechanisms may be responsible for regulating the haloperidol-induced increase in dopamine D2 receptors.