The respective roles played by sympathetic activity and corticosterone release in MDMA neurotoxicity were investigated in a series of studies on Fischer 344 (F344) rats. This strain was selected because it has a hyperactive corticotropic axis. Rats in all studies received 1 s.c. injection of MDMA on two consecutive days (2 injections overall) and rats were killed 6 days after receiving the second dose. Body temperature was assessed every half-hour for 2 (in dose-response study) or 3 hours. Serotonergic function was measured via assessment of tritiated serotonin uptake (5-HT), serotonin transporter binding (assessed via radiolabeled paroxetine), and measuring concentrations of 5-HT and its metabolite 5-HIAA with EC-MS. The first study compared doses of 5 and 10 mg/kg MDMA, whereas 10 mg/kg only was administered in studies examining effects of adrenalectomy on MDMA neurotoxicity. After establishing hyperthermic response in this rat strain, adrenalectomized rats were compared with sham-operated rats, and the effects of corticosterone supplementation in adrenalectomized rats were also examined. Lastly, the ganglionic blocker (antagonizes peripheral nicotinic receptors) chlorisondamine (2.5 mg/kg) was given 30 min prior to each MDMA injection in order to determine the effects of sympathetic activity on MDMA neurotoxicity. The dose regimen used in this study increased body temperature and reduced serotonin uptake, serotonin transporter binding, and concentrations of 5-HT and 5-HIAA in hippocampus and striatum. In adrenalectomized rats, MDMA produced hypothermia followed by hyperthermia, but hyperthermia was significantly weaker than in sham-treated rats, and MDMA-induced reductions in 5-HT transporter binding were not observed, while other markers of 5-HT function were still affected by MDMA. (However, adrenalectomy alone influenced several markers of 5HT function, including transporter binding.) Corticosterone supplementation in adrenalectomized rats attenuated hypothermic response after the second, but not first, MDMA injection, and countered effects of adrenalectomy on MDMA-induced reduction in 5-HT transporter binding. Administration of chlorisondamine produced hypothermia in saline-treated and MDMA-treated rats, and though rats given chlorisondamine showed a delayed increase in body temperature, it was below that produced by MDMA alone. In contrast with adrenalectomy, chlorisondamine attenuated MDMA effects on all markers of 5-HT function in hippocampus and striatum. Taken together, it appears that the corticotropic and sympathetic system may both play a role in MDMA neurotoxicity, though mainly through attenuating or preventing MDMA-induced increase in body temperature. However, since chlorisondamine did not entirely eliminate hyperthermia but still attenuated MDMA-induced reduction in 5HT, it is possible that either the compound or the sympathetic system independently reduce MDMA neurotoxicity. Study results can be considered along with those of Johnson and colleagues (Johnson et al. 2002) that suggest a role for stress hormones in MDMA neurotoxicity. Since anti-oxidant activity of chlorisondamine was not assessed, it is not possible to rule out the possibility that these antioxidant properties, and not reduced sympathetic activity, reduced MDMA neurotoxicity.