The effects of MDMA on striatal post-synaptic GABAergic neurons, and the potential role played by norepinephrine (NE) in MDMA neurotoxicity was investigated in mice. Mice were either administered vehicle or 50 mg/kg of the NE neurotoxin DSP-4, and afterwards given vehicle or 3 doses of 30 mg/kg MDMA every 2 hours, a regimen previously demonstrated to produce DA neurotoxicity in mice. (Unlike rats and non-human primates, MDMA damages dopaminergic, not serotonergic, neurons). Mice were killed 1 wk after treatment, and striatal slices were either examined via light microscopy or electronic microscopy, and neurochemical analyses were performed for DA, 5-HT, NE and their respective metabolites. MDMA reduced striatal DA and DOPAC content 1 wk after administration in mice not treated with DSP-4, and the effects of MDMA on striatal DA and DOPAC were enhanced after lesioning of NE neurons with DSP-4. Immunostaining for GFAP and TH was greater after MDMA administration, and was greatest in mice given both DSP-4 and MDMA. Both DSP-4 and MDMA given alone produced slight alterations in striatal ultrastructure, including whorls within the cytosol (cellular fluid) and nucleus. Combined DSP-4 pre-treatment and MDMA administration produced the same level of whorls in cytosol as did either treatment alone, but it produced a greater number of nuclear whorls. Immunoassays of whorls were positive for ubiquitin and DHA reductase in membranes, but not in surrounding cytosol. However, there was no indication of synuclein or dihydroxynonenal in striatal whorls. Finding DHA reductase and ubiquitin are interpreted as indicators of oxidative stress. The authors make comparisons with tissues found after stroke, HuntingtonÕs disease and AlzheimerÕs disease. Because the authors did not measure body temperature throughout this study, the possible effects of hyperthermia in producing these structural changes after MDMA is unknown. While these studies indicate that oxidative stress is likely involved in MDMA neurotoxicity, and that NE neurons may serve a protective function, the choice of a mouse model makes it difficult to generalize to effects in humans.