The ability of various serotonergic and dopaminergic drugs to attenuate MDMA-induced hyperthermia was examined in Dark Agouti rats given 12.5 mg/kg MDMA IP (15 mg/kg in microdialysis studies). Rectal temperature and tail temperature were recorded in MDMA-treated and control rats. (MDMA increased rectal temperature, but tail temperature decreased from baseline 40-80 min after MDMA administration, and it never increased above tail temperature in controls). Most serotonergic drugs (methysergide, ritanserin and the specific 5HT2A antagonist MDL-100907) did not attenuate MDMA-induced hyperthermia. Exceptions were MDL-11939 (nonspecific 5HT2 antagonist) and SB-242084 (5HT2C antagonist); MDL-11939 completely abolished hyperthermia without reducing temperature in control rats, and SB-242084 moderately attenuated hyperthermia without altering temperature in controls. Fluoxetine did not reduce hyperthermia, though it did reduce 5HT release in hippocampus (measured via microdialysis). Several dopaminergic drugs also failed to reduce MDMA-induced hyperthermia, including remoxipride (D2 antagonist) and GBR-12909 (DA uptake inhibitor). However, the D1 antagonist SCH-23390 reduced hyperthermia without altering temperature in controls. However, microdialysis probes indicated that GBR-12909 did not alter DA release in the striatum. Taken altogether, it appears that MDMA-induced hyperthermia in rats is partially caused through direct or indirect dopaminergic activity, specifically as relates to D1, and not D2 receptors. The authors explain the reduction in body temperature seen in humans after ketanserin pretreatment with MDMA (Liechti et al. 2000) as arising from adrenergic effects. The authors conclude that D1 antagonists could be used to reduce ecstasy-related hyperthermia in humans.