Abstract The effects of subcutaneous injection of 3,4-methylenedioxymethamphetamine (MDMA), a psychoactive amphetamine congener, on mouse central monoaminergic systems were assessed and compared to effects in rats. Whereas neostriatal concentrations of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in mouse were transiently decreased after a single moderately high dose of MDMA (15 mg/kg), mouse neostriatal or hippocampal tryptophan hydroxylase activity was not significantly affected, even after a dose of 60 mg/kg. These results are in contrast to effects in rats, in which a single 10 mg/kg dose of MDMA induced immediate and prolonged decreases in both central tryptophan hydroxylase activity and 5-hydroxyindole concentrations. Decreases in mouse central tryptophan hydroxylase activity, and prolonged decreases in mouse 5-hydroxyindole concentrations, were observed only after multiple doses of MDMA, suggesting that the duration of exposure may be an important determinant of toxic effects. These results show mice to be less susceptible than rats to MDMA-induced neurotoxicity, and are discussed in terms of possible interspecies differences in MDMA pharmacokinetics.