RGS mRNA expression in rat striatum: Modulation by dopamine receptors and effects of repeated amphetamine administration

Single injections of cocaine, amphetamine, or methamphetamine increased RGS 2 mRNA levels in rat striatum by two- to fourfold. The D1 dopamine receptor -selective antagonist SCH-23390 had no effect by itself but strongly attenu ated RGS2 mRNA induction by amphetamine, in contrast, the D2 receptor-selec tive antagonist raclopride induced RGS2 mRNA when administered alone and gr eatly enhanced stimulation by amphetamine. To examine the effects of repeat ed amphetamine on RGS2 expression, rats were treated with escalating doses of amphetamine (1.0-7.5 mg/kg) for 4 days, followed by 8 days of multiple d aily injections (7.5 mg/kg/2 h x four injections). Twenty hours after the l ast injection the animals were challenged with amphetamine (7.5 mg/kg) or v ehicle and killed 1 h rater. In drug-naive animals, acute amphetamine induc ed the expression of RGS2, 3, and 5 and the immediate early genes c-fos and zif/268, RGS4 mRNA levels were not affected. Prior repeated treatment with amphetamine strongly suppressed induction of immediate early genes and RGS 5 to a challenge dose of amphetamine. In sharp contrast, prior exposure to amphetamine did not reduce the induction of RGS2 and RGS3 mRNAs to a challe nge dose of amphetamine, indicating that control of these genes is resistan t to amphetamine-induced tolerance. These data establish a role for dopamin e receptors in the regulation of RGS2 expression and suggest that RGS2 and 3 might mediate some aspects of amphetamine-induced tolerance.