The combined effects of chronic corticosterone administration, intended to mimic chronic stress and S(+)-MDMA on dopaminergic neurotoxicity was investigated in female C57BL/6J mice. Placebo, 5 or 15 mg 21-day release corticosterone pellets were centrally implanted in mice 7 days prior to saline or neurotoxic S(+)-MDMA regimen (4 injections of 20 mg/kg s.c. every 2 h). Brains were removed 72 h after last treatment. Concentration of neurotransmitters (DA, DOPAC, NE and 5-HT) were measured in L striatum with HPLC, and glial fibrillary acidic protein (GFAP) and tyrosine hydroxylase (TH) were measured via immunoassay in L and R hippocampus. S(+)-MDMA reduced thymus weight (indicator of corticosterone release) on its own, and S(+)-MDMA exacerbated corticosterone-induced reduction in thymus weight. Spleen weight was only effected by corticosterone, and adrenal weight was unaffected by any treatment. Both alone and in combination with chronic 15 mg corticosterone, S-(+)-MDMA significantly reduced striatal DA, but not striatal 5-HT or 5-HIAA. Corticosterone pellets did not significantly exacerbate the depletion in striatal DA following S-(+)-MDMA; the additive effects of the highest dose of corticosterone (15 mg) and S-(+)-MDMA were not significant. However, 15 mg corticosterone did enhance S-(+)-MDMA induced depletion of the DA metabolites DOPAC and HVA. Hippocampal 5-HT, 5-HIAA, NE and GFAP were not altered by d-MDMA. 15 mg corticosterone did lower hippocampal 5-HT in both saline and S(+)-MDMA-treated mice. TH (DA neuron terminal marker) was decreased in all mice receiving S(+)-MDMA. Chronic treatment with 15 mg corticosterone, but not 5 mg corticosterone, further decreased hippocampal TH. Hippocampal GFAP was increased by S(+)-MDMA. Though corticosterone treatment did not increase GFAP when given alone, both chronic treatment with 5 mg or 15 mg corticosterone increased GFAP after S(+)-MDMA. Chronic treatment with 15 mg, but not 5 mg, corticosterone further elevated body temperature after S(+)-MDMA. Chronic stress, as simulated via chronic central corticosterone administration, appears to increase S(+)-MDMA-induced dopaminergic neurotoxicity in mice. It should be noted that humans administer racemic MDMA, and not one enantiomer only, and that interactions between the R-(-) and S-(+) enantiomers are possible. It is difficult to generalize these results to humans, as humans because MDMA produces serotonergic, but not dopaminergic, neurotoxicity in primates.