Pharmacological studies have shown that blockade of the dopamine D1 receptor attenuates locomotor behaviors and prevents sensitization to psychostimulants. However, due to possible cross-reactivities of the D1 receptor antagonists, the exact role of the D1 receptor in response to psychostimulants is still not definitive. To address this issue, we used D1 receptor mutant mice and tested locomotor responses of the mutant mice and wild-type control mice after cocaine and amphetamine treatments. We found that the D1 receptor mutant mice exhibit significantly reduced locomotor responses to repeated cocaine administration compared to wild-type mice. Moreover, D1 receptor mutant mice were less sensitive than the wild-type mice to acute amphetamine administration over a dose range, although they exhibited apparently similar behavioral responses to those of the wild-type mice after repeated amphetamine administration at the 5 mg/kg dose. These studies suggest that the D1 receptor plays an essential role in mediating cocaine-induced locomotor responses in mice. In addition, the D1 receptor also participates in behavioral responses induced by amphetamine administration. Further molecular studies are in progress to address the intracellular signaling mechanisms in response to D1 receptor activation by psychostimulants.