Mechanisms of (dopaminergic) MDMA neurotoxicity in mice were explored in a series of studies examining the role played by dopamine and its metabolites. Body temperature, brain dopamine content and presence of free radicals in microdialysate were measured after administering MDMA alone, or with the dopamine uptake inhibitor GBR 12909. Mice were given saline or 3 injections 30 mg/kg MDMA, with injections given at 3 h intervals, with injections of saline or GBR 12909 given immediately before each drug (MDMA or saline) dose. Presence of free radicals in microdialysate was assessed via salicylic acid probe (salicylic acid combines to produce 2,5-DHBA in presence of free radicals). The possibility that GBR 12909 might possess antioxidant effects was examined in vitro by assessing its ability to attenuate lipid peroxidation produced by ascorbic acid. Both MDMA and GBR 12909 increased dopamine release in striatal tissue, but through apparently independent mechanisms, since GBR 12909 did not reduce MDMA effects. MDMA apparently released dopamine through a calcium-dependent process not involving the DA transporter, since MDMA-induced DA release was attenuated when mice were perfused through microdialysis with low-calcium artificial CBF. However, the dopamine uptake inhibitor (GBR 12909) did attenuate MDMA-induced reduction in striatal dopamine after treatment. GBR-12909 significantly decreased the formation of 2,5-DHBA in microdialysate after MDMA administration, but was less potent than another free radical scavenger (BHT) in reducing lipid peroxidation in vitro. GBR 12909 did not alter body temperature after MDMA. Taken together, study findings suggest that the neuroprotective effects of GBR 12909 are not due to inhibition of MDMA-induced dopamine release, as MDMA does not compete with the compound for transporter in mice, nor are they chiefly due to reducing MDMA-induced hyperthermia. Instead, they seem to be due at least in part to antioxidant properties of GBR 12909. Hence although the exact mechanisms behind MDMA neurotoxicity in mice affect different target cells (dopaminergic instead of serotonergic cells), oxidative stress in involved in both mouse and rat models of MDMA neurotoxicity. While a dopamine metabolite may still be involved in producing oxidative stress, these findings do not support a direct link between dopamine release and MDMA neurotoxicity in mice.