Similar to other amphetamine analogs 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"), a currently popular illicit drug, has been characterized recently as a serotonergic neurotoxin due to its ability to cause long-lasting deficits in markers of central serotonergic function in animals. Because the serotonergic toxicity associated with the MDMA analog methamphetamine has been linked previously to endogenous dopamine and because MDMA, like methamphetamine, elicits pronounced dopamine release in vitro, we have examined the role of endogenous dopamine in both the immediate (3 hr) and longer-term (3 days) central serotonergic deficits induced by systemic MDMA administration to rats. Depletion of central dopamine content with alpha-methyl-p-tyrosine or reserpine, or selective destruction of nigrostriatal dopamine projections with bilateral 6-hydroxydopamine-induced substantia nigral lesions, partially blocked the immediate MDMA-induced reduction in rat striatal tryptophan hydroxylase (TPH) activity. In addition, the longer-term TPH deficits caused by a high single dose of MDMA were completely prevented by prior alpha-methyl-p-tyrosine or reserpine, and attenuated significantly by inhibition of dopamine uptake with the selective dopamine-uptake blocker GBR 12909. These results implicate endogenous drug-released dopamine as a partial mediator of the initial decrease in TPH activity caused by MDMA and as an important prerequisite to the development of long-term MDMA-induced neurotoxicity. Potential mechanisms of dopamine-mediated toxicity are discussed.