The serotonergic neurotoxicity of 3,4-(Ϯ)-methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism because direct injection of MDMA into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N-methyl-␣-methyldopamine (N-Me-␣-MeDA). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-␣-MeDA are neurotoxic and are present in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, the present study was designed to determine the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. The serotonergic neurotoxicity 3,4-(Ϯ)-methylenedioxymethamphetamine (MDMA, Ecstasy) and 3,4-(Ϯ)-methylenedioxyamphetamine (MDA) is dependent on the route of administration (O'Shea et al., 1998). Direct injection of MDMA and MDA into the brain fails to reproduce the acute or long-term neurotoxic effects evident following peripheral administration of these drugs (Schmidt et al., 1987;Paris and Cunningham, 1992), suggesting that systemic (liver) metabolism contributes to the neurotoxicity of MDMA and MDA. Indeed, although MDMA targets the serotonergic system in humans, nonhuman primates, and rats, the finding that MDMA does not affect the serotonergic system in mice but rather targets the dopaminergic system has been attributed to metabolic differences between species (Logan et al., 1988;Escobedo et al., 2005). Perhaps the most convincing evidence that peripheral metabolism of MDMA is required for neurotoxicity was provided by the work of Esteban et al. (2001). In this study, MDMA was perfused into the hippocampus in amounts sufficient to give rise to the range of concentrations observed following peripheral administration of neurotoxic doses of MDMA. After perfusion, acute monoamine release was observed in the absence of long term depletions in 5-HT levels. These data are consistent with the hypothesis that peripheral generation of neurotoxic metabolites contributes to MDMA-induced serotonergic neurotoxicity.MDMA is N-demethylated to MDA and O-demethylenated to N-methyl-␣-methyldopamine (N-Me-␣-MeDA) (Fig. 1) (Lin et al., 1992). N-Demethylation in humans is a minor metabolic pathway (ϳ10%), but ␣-MeDA is a metabolite of both MDMA and MDA. Isoenzymes belonging to the CYP2D subfamily, and the CYP2B or CYP3A1 isoforms, catalyze the low-and high-K m O-demethylenation reactions, respectively (de la Torre et al., 2004). The catecholamine metabolites are very unstable and are either conjugated with sulfate/glucArticle, publication date, and citation information can be found at

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