Wild-type and MAO-B knockout mice were exposed to saline, DSP-4 (a norepinephrine neurotoxin) and with a large enough dose of MDMA (2 doses of 50 mg/kg 2 h apart) to produce both DA and 5HT neurotoxicity (MDMA normally only depletes DA in mice). Mice were sacrificed 7 days post-treatment, and neurochemical contents of cerebellum, frontal cortex, hippocampus, hypothalamus, striatum and substantia nigra were examined, and chemicals were detected with HPLC. Lack of MAO-B did not attenuate the neurotoxic effects of DSP-4. After treatment, MDMA produced significant DA depletion in the frontal cortex, substantia nigra and striatum that was not attenuated in MAO-B knockout mice; knockout mice given MDMA had exacerbated DA loss in the striatum. MDMA did not reduce DA in hypothalamus in either mouse strain, and MDMA slightly but not significantly reduced DA in hippocampi of MAO-B knockouts, but not wild-type mice. At this high dose, MDMA produced 5HT depletion in frontal cortex, hippocampus, striatum and substantia nigra in wild-type mice that was completely abolished or greatly reduced in MAO-B knockout mice. MDMA did not significantly modify 5-HT content in either mouse strain. Taken together, findings support a role for MAO-B activity in MDMA-induced serotonergic neurotoxicity in mice, but its role in MDMA-induced dopaminergic neurotoxicity in mice is uncertain. Since mice and rats differ in the form of neurotoxicity after MDMA, and since at least one recently published paper (Colado et al. 2001) suggests that MDMA toxicity in mouse and rat arise from different processes, the findings reported here may not be relevant for MDMA toxicity in humans.