The role of serotonin 5-HT(2) receptors (5-HT(2)R) in the hyperactivity induced by (+)-3,4-methylenedioxy-methamphetamine ((+)-MDMA; 3 mg/kg) was investigated. Hyperactivity induced by (+)-MDMA was robustly potentiated by the 5-HT(2B/2C)R antagonist SB 206553 (1.0, 2.0, and 4.0 mg/kg). Administration of the 5-HT(1B/1D)R antagonist GR 127935 (2.5 mg/kg) or the 5-HT(2A)R antagonist M100907 (1.0 mg/kg) partially suppressed the potentiated hyperactivity seen following SB 206553 plus (+)-MDMA; a blockade to activity levels seen with (+)-MDMA alone was observed following the combination of GR 127935 plus M100907. A modest potentiative interaction was seen when SB 206553 was combined with the DA releaser amphetamine (0.5 mg/kg) or amphetamine plus the 5-HT releaser fenfluramine (4.0 mg/kg). SB 206553 (1-4 mg/kg), GR 127935 (2.5 mg/kg) and M100907 (1 mg/kg) did not alter spontaneous activity upon administration singly or in combination. These data suggest that activation of 5-HT(2C)R exerts a strong inhibitory influence on the hyperactivity induced by (+)-MDMA, and that 5-HT(2C)R blockade unmasks hyperactivity mediated through several mechanisms.