A hypothesized link between MDMA-induced hyperactivity and action at 5HT2c receptors was tested in rats through a crossed comparison of the effects of 3 mg/kg MDMA alone, MDMA + 5HT2C antagonist (2 mg/kg SB 206553), and this drug combination paired with pretreatments intended to antagonize 5HT2A (2.5 mg/kg GR 127935) and 5HT1B/D receptors (1 mg/kg M100907). The effects of 5HT2A and 5HT1B/D antagonists were also tested, with substances given singly and in combination. Each pretreatment was also tested with saline-treated animals for effects on locomotor behavior. Central activity (general, center of chamber), peripheral (wall-edges, specific to MDMA) and rearing were considered as separate measures of hyperactivity, with peripheral activity associated with MDMA administration. MDMA-induced hyperactivity was exacerbated by the 5HT2C antagonist. While peripheral activity elicited by MDMA + 5HT2C antagonist was reduced by the addition of a 5HT2A antagonist, it did not significantly reduce MDMA-induced rearing or central (general) activity. Pre-treatment with a 5HT1B/D agonist significantly reduced peripheral and rearing activity after treatment with MDMA +5HT2C antagonist, but rearing and activity were not reduced to levels below those produced by MDMA alone. A combined pretreatment of the 5HT2A antagonist + 5HT1B/D antagonist significantly attenuated peripheral activity, central activity and rearing after MDMA + 5HT2C antagonist, with activity equal to or below that produced by MDMA alone. Studies assessing hyperactivity were also performed with fenfluramine, amphetamine and amphetamine + fenfluramine combination serving as treatments. Fenfluramine and amphetamine alone had the expected effects on hyperactivity (none with fenfluramine, mostly central activity after amphetamine), and fenfluramine + amphetamine produced peripheral and central activity. The 5HT2C antagonist increased peripheral, but not central, activity when combined with amphetamine alone or with amphetamine + fenfluramine. Overall, the series of studies suggests that MDMA-related activity at 5HT2C receptors (either directly or indirectly) suppresses dopaminergically mediated hyperactivity, though action at 5HT2a and 5HT1b/d receptors may contribute to MDMA-induced hyperactivity as well.