Identification of the genetic factors that underlie stimulant responsiveness in animal models has significant implications for better understanding and treating stimulant addiction in humans. F(2) progeny derived from parental rat strains F344/NHsd and LEW/NHsd, which differ in responses to drugs of abuse, were used in quantitative trait locus (QTL) analyses to identify genomic regions associated with amphetamine-induced locomotion (AIL) and G-protein levels in the nucleus accumbens (NAc). The most robust QTLs were observed on chromosome 3 (maximal log ratio statistic score (LRS(max))=21.3) for AIL and on chromosome 2 (LRS(max)=22.0) for Galpha(i3). A 'suggestive' QTL (LRS(max)=12.5) was observed for AIL in a region of chromosome 2 that overlaps with the Galpha(i3) QTL. Novelty-induced locomotion (NIL) showed different QTL patterns from AIL, with the most robust QTL on chromosome 13 (LRS(max)=12.2). Specific unique and overlapping genomic regions influence AIL, NIL, and inhibitory G-protein levels in the NAc. These findings suggest that common genetic mechanisms influence certain biochemical and behavioral aspects of stimulant responsiveness.