A series of studies employing various pretreatments is used to demonstrate that MDMA neurotoxicity in the mouse is probably not produced by the same form of oxidative stress involved in MDMA neurotoxicity in rats. (MDMA damages dopamine axons, not serotonin axons, in the mouse). All mice in drug-combination studies were given 25 mg/kg MDMA ip 3 times in 1 day, with dosing every 3 hours; microdialysis studies used 20 mg/kg MDMA injected on the same schedule. Striatal DA assessed 7 days after treatment. Two NMDA-receptor antagonists (MK-801 and AR-R15896AR) did not attenuate decreased striatal dopamine or decrease MDMA-induced hyperthermia. The GABAergic agonist clomethiazole failed to decrease striatal DA decline, and failed to reduce MDMA-induced hyperthermia. PBN, a free-radical trapping agent, also surprisingly failed to reduce striatal dopamine loss, but did produce hypothermia. The NOS inhibitor 7-NI produced substantial neuroprotection (retention of striatal DA) but it also produced hypothermia. Two other NOS inhibitors, 5MTC and AR-R17477AR both prevented striatal DA loss without inducing hypothermia. Microdialysis was used to measure the ability of AR-R17477AR to trap or prevent oxidative stress after MDMA administration via salicylate challenge. (Salicylate is converted into 2,3-DHBA on exposure to free radicals). Pre-treatment with AR-R17477AR abolished the increase in 2,3-DHBA produced by MDMA. However, when tested for the ability to inhibit the oxidatively driven reaction between ascorbate and FeCl2 in synaptosomes, AR-R17477AR proved ineffective in preventing this reaction. The authors interpret this series of studies to mean that in mice, the oxidative substance is a peroxinitrite produced by reactions between nitric oxide, MDMA and/or dopamine metabolites (similar to a model of MDMA neurotoxicity proposed by Nichols). There is evidence that MDMA-induced oxidative stress in rats may be governed by a different set of processes, leading to reduction in 5-HT rather than DA. It seems likely that the process in primates will be more similar to that of rats rather than mice, as primates undergo selective long-term serotonergic (but not dopaminergic) changes after MDMA.