The influence of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on the central serotonergic and dopaminergic systems of the rat after a single or multiple injections was studied. MDE (10 mg/kg) produced a significant decrease in the concentration of 5-hydroxytryptamine (5-HT) 1 hr later in the frontal cortex and the hippocampus without affecting the concentration of 5-hydroxyindoleacetic acid (5-HIAA) or tryptophan hydroxylase (TPH) activity. Hypothalamic and neostriatal concentrations of 5-HT, 5-HIAA, dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) remained unaffected, as well as the neostriatal TPH and tyrosine hydroxylase (TH) activities. However, 3 hr after the MDE injection, the serotonergic variables including TPH activity were decreased in most of the brain areas examined. The dopaminergic system remained unaffected, except for a significant reduction in neostriatal DOPAC concentrations. The changes in transmitter concentrations after a single injection were dose dependent; the maximum depletion in TPH activity was reached with a 10 mg/kg dose. The administration of multiple doses of MDE caused greater decreases in TPH activity and 5-HT concentrations 3 hr after the treatment than did a single injection; in addition, a partial recovery from multiple administrations occurred by 18 hr. The effects of MDE on DA and its metabolites were transient, and neostriatal TH activity was not altered. This study demonstrates that MDE primarily affects the central serotonergic system, as reported for its congeners 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine. It does, however, produce less neurotoxicity as judged by its lower potency on the dopaminergic and the serotonergic systems as well as the recovery occurring in these systems.