We examined the effects of an interruption of dopamine neurotransmission, by either dopamine receptor blockade or degeneration of dopamine neurons by 6-hydroxydopamine, on the levels of D2 receptor mRNAs. In addition, we evaluated by the polymerase chain reaction (PCR) the relative abundance of the two D2 receptor isoform mRNAs generated by alternative splicing. Daily injections of 4 mg/kg of haloperidol to rats elicited in striatum a rapid and progressive increase in D2 receptor mRNA levels, which reached 70% after a 15-day treatment. By contrast, there was no apparent change in D2 receptor mRNA levels in cerebral cortex and pons-medulla, in spite of an increased density of D2 receptor in the former tissue. Using the PCR with primers flanking the alternative exon, we observed that the relative proportion of the shorter receptor isoform (D2S) mRNA was slightly but significantly enhanced in cerebral cortex (17%) and pons-medulla (18%) after a 15-day haloperidol treatment. Unilateral degeneration of dopamine neurons induced by local injection of 6-hydroxydopamine resulted in a marked decrease in levels of total D2 receptor mRNAs in substantia nigra (-79%) and ventral tegmental (-63%) area, two cell body areas. In the substantia nigra, the longer isoform (D2L) mRNA was significantly more decreased in content than the D2S isoform mRNA, so that there was a large enhancement in the relative abundance of the latter (81%).(ABSTRACT TRUNCATED AT 250 WORDS)