This study examined mRNAs encoding regulators of G protein signaling (RGSs) expressed within the striatum and determined whether their expression in the caudate putamen was altered by amphetamine. RT-PCR techniques were used to clone cDNA probes of RGSs expressed within the rat striatum. Northern blot analysis of caudate putamen and nucleus accumbens RNA determined the relative abundance of RGS mRNA expressed within the caudate putamen and adjacent nucleus accumbens to be RGS 2 > RGS 5 > RGS 16 > RGS 4 = RGS 9 > RGS 8 = RGS 3. A single injection of amphetamine rapidly and transiently induced RGS 2 mRNA. The temporal pattern of induction of RGS 2 strongly resembled that of the immediate early gene c-fos. Levels of mRNAs of RGS 3 and 5 steadily increased over a 4-h interval, as did that of the 6.6-kb transcript of RGS 8. The level of RGS 9 mRNA, which shows strong striatal-specific expression, steadily decreased over a 4-h interval, whereas RGS 4 and 16 and the 3.9-kb transcript of RGS 8 were not significantly affected at any point examined. The ability of amphetamine to alter RGS mRNA expression within the caudate putamen suggests these proteins may play an important role in adaptive processes to psychostimulant exposure.