Mice from the inbred strains C57BL/6 and DBA/2 are characterized by striking differences in their behavioral response to addictive drugs. We used Fos expression as a tool to reveal strain differences in the postsynaptic effects of amphetamine (AMPH; 2.5 mg/kg) within the nucleus accumbens (NAc) (core and shell) and the dorsal caudate (dorsomedial and dorsolateral). AMPH stimulated Fos expression in all striatal regions of mice from both strains. However, while C57BL/6 showed a higher Fos response than DBA/2 mice in both NAc shell and core, the opposite was true for the dorsolateral caudate. The effects of AMPH were prevented by D1 blockade in all striatal regions of both strains and mimicked by the D1 agonist, SKF82958 (0.1 mg/kg), in both regions of the caudate and in the NAc shell, but not in the core. Our results suggest that the functional heterogeneity of the striatal complex is under genetic control and that this control may implicate DA transmission and corticostriatal interactions.