Abnormal interactions between the serotonin and dopamine systems may underlie the high prevalence of non-motor complications in Parkinson's disease (PD). Here, we demonstrate that the genes encoding serotonin 5-HT2A and 5-HT2C receptors are differently regulated by dopamine in the 6-hydroxydopamine (6-OHDA) rat model of PD. Nigrostriatal cell loss causes an up-regulation of 5-HT2AR mRNA, but a down-regulation of 5-HT2CR mRNA, in striatum. Repeated injections with L-DOPA/benserazide reverse the effect of 6-OHDA lesioning on 5-HT2AR, but not on 5-HT2CR, gene expression. Neither 6-OHDA-lesioning nor L-DOPA/benserazide treatment had any effect on 5-HT2AR mRNA in cortex or on 5-HT2CR mRNA in nucleus subthalamicus. These data suggest that the regulation of 5-HT2AR in striatum, in the 6-OHDA rat model of PD, is mainly dependent upon alterations in dopamine levels. 5-HT2CR, on the other hand, are regulated by nigrostriatal cell loss and by the accompanied reduction of factor(s), other than dopamine, that are normally co-expressed with dopamine. The apparent imbalance between 5-HT2AR and 5-HT2CR levels in this PD model indicates a potential role for these receptors in the pathophysiology of neuropsychiatric symptoms, such as depression and L-DOPA-induced hallucinations, which are co-morbid with PD. The fact that 5-HT2CR are differentially regulated as compared to 5-HT2AR to alterations in the dopamine tone predicts that pharmacological manipulations at 5-HT2CR, but not at 5-HT2AR, will result in similar effects in PD patients whether they are treated or not with dopamine replacement.