Abstract The mechanism by which 3,4-methylenedioxymethamphetamine (MDMA) produces serotonin (5-HT) neurotoxicity is unknown but considerable evidence suggests that endogenous brain dopamine (DA) is involved. However, it has recently become apparent that some of the data implicating brain DA in MDMA neurotoxicity may be confounded by drug effects on thermoregulation. The purpose of the present studies was to examine the role of DA in MDMA neurotoxicity, while controlling for possible confounding effects of drug- induced changes in core temperature. Rats were treated with reserpine, alone and in combination with alpha-methyl-p -tyrosine (AMPT), to deplete vesicular and cytoplasmic stores of DA. When drug-induced hypothermia was averted (by raising ambient temperature), the 5-HT neuroprotective effects of reserpine and AMPT were no longer apparent. The lack of neuroprotection by AMPT and reserpine, alone and in combination, in studies that control for the effects of these drugs on core temperature, suggests that DA per se is not essential for the expression of MDMA-induced 5-HT neurotoxicity.