The current study compares the acute and long-term effects of GBR 12935 and cocaine on locomotor activity and stereotypy in two genetically distinct strains of mice. Although cocaine stimulated locomotor activity maximally in both strains at 32 mg/kg, a single injection of cocaine stimulated locomotion to a greater degree in DBA/2J mice than in C57BL/6J mice. In contrast, GBR 12935 elevated locomotion to a greater extent in C57BL/6J mice at the maximally active dose of 10 mg/kg. The stimulant effects of cocaine diminished to near control levels in DBA/2J mice upon repeated injections, whereas cocaine-induced locomotion remained relatively consistent in C57BL/6J mice. Locomotor stimulation by GBR 12935 remained consistent in both strains with repeated injections. DBA/2J mice became sensitized to cocaine-induced stereotypy with repeated injections. Cocaine induced no stereotypy in C57BL/6J mice on any test day. No stereotypies were induced by GBR 12935 in either strain on any test day. Moreover, no cross-sensitization between cocaine and GBR 12935 was observed. These results demonstrate differences in the behavioral effects of two dopamine uptake inhibitors, and suggest that genetically controlled factors other than dopamine uptake inhibition contribute to the acute and adaptive behavioral responses to cocaine.