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Quantitative in situ hybridization was used to investigate the effect of prolonged striatal dopamine or monoamine depletion on the mRNA density of regulators of G-protein signaling (RGS) 2-12 proteins. Two types of treatments were studied: a 6-hydroxydopamine-induced unilateral lesion of the nigrostriatal pathway and a 5-day reserpine treatment. The results clearly show a selective increase in the mRNA levels of RGS2, 5 and 8 and a decrease in RGS4 and 9 mRNA levels following nigrostriatal denervation. In this model, we observed no change in the mRNA levels of RGS10 and other RGS proteins that are weakly expressed in the striatum (RGS3, 6, 7, 11 and 12). On the other hand, the mRNA levels RGS2, 4, 5, 8, 9 and 10 were found to be significantly decreased after prolonged reserpine treatment. In contrast, the densities of these transcripts (in particular, RGS2, 4 and 10) tend to increase after an acute administration of reserpine, used as control. These results provide further evidence for the influence of dopamine and/or other monoamines in the regulation of RGS protein expression in the striatum. In connection with the previously documented acute regulation of RGS proteins after modulation of the dopaminergic transmission [Geurts et al., Neurosci Lett 2002;333:146-50], the present study demonstrates that alteration in their genetic expression can be long-lasting and this could reflect the adaptation processes that occur in certain pathological states, such as Parkinson's disease.