The effect of L-3,4-dihydroxyphenylalanine (L-DOPA) on dopamine receptor gene expression in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys was investigated using in situ hybridization histochemistry with measures of changes in relative absorbance. In MPTP-lesioned monkeys, a decrease of D1 dopamine receptor mRNAs was observed in the rostral part of the caudate and putamen compared with control animals (-20% and -17%, respectively, in the lateral axis). Chronic treatment of MPTP-lesioned monkeys with L-DOPA returned their D1 receptor mRNA values to near those of control monkeys in the caudate and putamen (92% and 91% of control values, respectively). No lesion or drug-induced changes of D1 receptor mRNAs were observed in the more caudal parts of the striatum. A decrease of D1 receptor mRNAs was observed in the olfactory tubercule (-22%) in MPTP-lesioned monkeys compared with control animals but no change was seen in the nucleus accumbens. D1 receptor mRNAs in the anterior cerebral cortex were decreased in MPTP-lesioned monkeys (-19% compared with control animals). D1 receptor mRNAs in olfactory tubercle and in cerebral cortex of L-DOPA-treated MPTP-lesioned monkeys were not significantly different from control animals. For D2 receptor mRNAs, we observed an increase in the caudal part of the caudate and putamen (+24% and +23%, respectively, in MPTP-lesioned monkeys compared with control animals). Chronic L-DOPA treatment corrected this elevation to control values. No variation of D2 receptor mRNAs was seen in the more rostral parts of the striatum and in the nucleus accumbens in MPTP-lesioned monkeys as well as in MPTP-lesioned monkeys treated chronically with L-DOPA. Our results show for the first time that L-DOPA can influence gene expression of D1 and D2 receptors in MPTP-lesioned monkeys and correct the lesion-induced increase in the expression of D2 receptors, whereas the correction of the D1 receptor expression decrease is only partial. Furthermore, the changes in gene expression of D1 and D2 receptors in MPTP-lesioned monkeys are regional: they are restricted to the anterior striatum for the D1 receptors and the posterior striatum for the D2 receptors.