Accumulation of neurotoxic thioether metabolites of 3,4-(±)-methylenedioxymethamphetamine in rat

ABSTRACT 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 MDMA is N-demethylated to MDA and O-demethylenated to N-methyl-␣-methyldopamine (N-Me-␣-MeDA