Inhibition of methylphenidate-induced gene expression in the striatum by local blockade of D1 dopamine receptors:...

Psychostimulants change the function of cortico-basal ganglia circuits. Some of these effects are mediated by altered gene regulation in projection neurons of the striatum which participate in these circuits. Psychostimulant-induced changes in gene expression in these neurons are a consequence of excessive stimulation of G-protein-coupled receptors, particularly the D1 dopamine receptor subtype. Recent findings show that the psychostimulant methylphenidate, which causes dopamine overflow in the striatum, produces changes in striatal gene regulation similar, but not identical, to those induced by psychostimulants such as cocaine and amphetamine. We investigated, in rats, the role of striatal D1 receptors in methylphenidate-induced gene expression, by intrastriatal administration of the D1 receptor antagonist SCH-23390. Effects on the expression of two plasticity-related molecules, the transcription factor zif 268 and the synaptic plasticity factor Homer 1a, in the striatum and cortex were assessed. Intrastriatal infusion of SCH-23390 (2-10 microg) attenuated zif 268 and Homer 1a mRNA expression induced by methylphenidate (10 mg/kg, i.p.) in a dose-dependent manner. Moreover, this unilateral SCH-23390 infusion not only inhibited gene induction at the infusion site in the central striatum, but also in distant striatal regions including the nucleus accumbens, as well as throughout the entire contralateral striatum. These results indicate that striatal D1 receptors are critical for gene induction by methylphenidate. Moreover, the ipsilateral and contralateral effects of local SCH-23390 administration suggest that D1 receptor-stimulated striatal output exerts robust control over widespread striatal activities/gene expression via regulation of input to the striatum.