3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug. Despite an increase in the number of fatalities related to its use, no definite therapeutic method has been established thus far. In the present study, risperidone's ability to attenuate MDMA-induced hyperthermia and its mechanism of action were investigated in rats. The pharmacological effect of MDMA was evaluated using microdialysis. In the body temperature experiment, administration of risperidone before and after MDMA administration significantly suppressed MDMA-induced hyperthermia in a dose-dependent fashion. Furthermore, risperidone completely inhibited MDMA-induced hyperthermia at a low ambient temperature. Moreover, pretreatment with ritanserin, ketanserin, or R-96544, all of which are 5-HT(2A)-receptor antagonists, significantly prevented MDMA-induced hyperthermia. On the other hand, pretreatment with WAY-100635 (a 5-HT(1A) receptor antagonist), SB 206553 (a 5-HT(2B/2C) receptor antagonist), or SB 242084 (a 5-HT(2C) receptor antagonist) did not prevent MDMA-induced hyperthermia. Pretreatment with haloperidol, which blocks the dopamine (DA) receptors D(2) and D(1), significantly prevented MDMA-induced hyperthermia. However, sulpiride and L-741626, which are D(2) receptor blockers, did not prevent MDMA-induced hyperthermia. Pretreatment with SCH 23390 (a D(1) receptor antagonist) significantly prevented MDMA-induced hyperthermia. Furthermore, postadministration of ritanserin, haloperidol, and SCH23390 reversed MDMA-induced hyperthermia. These results demonstrate that the mechanism underlying the suppression of MDMA-induced hyperthermia by risperidone is primarily based on the drug's potent 5-HT(2A) receptor blocking effect, and to a lesser extent, on its D(1) receptor blocking effect. A microdialysis study showed that when MDMA (10mg/kg) was subcutaneously (s.c.) injected into the rats, the DA and serotonin (5-HT) levels in the anterior hypothalamus of the rats increased approximately 10- and 50-fold, respectively, as compared to their preadministration levels. These increases in the DA and 5-HT levels after MDMA injection were significantly suppressed by pretreatment with risperidone (0.5mg/kg). This suggested that both the DA and 5-HT systems were involved in the induction of hyperthermia by MDMA. Taken together, the present study's results indicate that risperidone may be an effective drug for the treatment of MDMA-induced hyperthermia in humans.