RATIONALE: Mice lacking the gene for the dopamine transporter (DAT) show a unique behavioral phenotype characterized by locomotor hyperactivity and repetitive circling in a novel environment. The hyperactivity of DAT (-/-) mice can be attenuated by psychostimulants and by serotonin uptake inhibitors, suggesting an important role for serotonin in the attenuation of locomotor hyperactivity in these mice. OBJECTIVES: These studies characterized the effects of 3,4-methylenedioxy-N-methylamphetamine (MDMA), a serotonin releaser, on the amount and patterns of locomotor activity in DAT (+/+) and (-/-) mice. We compared the locomotor patterns produced by MDMA to those observed in DAT (-/-) mice, and examined whether MDMA altered the hyperactivity and perseverative locomotor patterns in DAT (-/-) mice. METHODS: The effects of MDMA (10, 30 mg/kg) on locomotor activity in DAT (+/+) mice were measured for 90 min in a video tracker system to determine the optimal dose for subsequent studies in DAT (+/+) and (-/-) mice. The effects of 20 mg/kg MDMA on patterns of locomotor activity in DAT (+/+) and (-/-) mice were measured for 90 min. RESULTS: In DAT (+/+) mice, MDMA increased locomotor activity and induced repetitive straight movement patterns. In DAT (-/-) mice, however, MDMA (20 mg/kg) attenuated the characteristic locomotor hyperactivity seen in these mice. In contrast, MDMA potentiated the thigmotaxis and decreased entropy observed in the DAT (-/-) mice. CONCLUSIONS: The effects of MDMA observed here demonstrate that the different aspects of the abnormal locomotor behavior exhibited by DAT (-/-) mice can be independently manipulated by pharmacological treatments.