The effects of dopamine receptor agonists on the levels of the striatal serotonin 5-HT2A receptor and its mRNA were investigated in rats lesioned with 6-OHDA as neonates. The mRNA encoding for the 5-HT2A receptor was detected by in situ hybridization histochemistry and the binding of 5-HT2A receptors was revealed with [125I](2,5-dimethoxy-4-iodophenyl)2-aminopropane ([125I]DOI). In adult control unlesioned rats, labeling with the 5-HT2A cRNA probe and with [125I]DOI was concentrated in medial sectors of the striatum. In 6-OHDA-lesioned rats, labeling with the 5-HT2A cRNA probe or with [125I]DOI was increased in the striatum, particularly in its lateral subdivisions. These increases were abolished after chronic systemic administration of the dopamine receptor agonists apomorphine or SKF-38393. The mRNA levels encoding for the 5-HT2A receptor were further measured in individual striatal neurons after double-labeling of sections with a 5-HT2A and a preproenkephalin (PPE) cRNA probe. In control unlesioned rats, 5-HT2A mRNA labeling was distributed in PPE-labeled as well as in PPE-unlabeled striatal neurons. In 6-OHDA-lesioned rats, increased 5-HT2A mRNA labeling was found only in PPE-unlabeled neurons and it was abolished after apomorphine or SKF-38393 administration. These results demonstrate that agonists of dopamine receptors inhibit the expression of 5-HT2A receptors in a subpopulation of presumed striato-nigral neurons. We propose that this regulation plays an important role in the control of motor activity by dopamine and 5-HT in the basal ganglia.