MDMA and other psychostimulants continue to be popular drugs of abuse despite evidence in rodents and non-human primates that these agents produce a long-lasting depletion of brain serotonin (5-HT) and its major metabolite, 5-hydroxyindoleacetic acid. However, beyond this well-known finding, the mechanisms by which these agents produce 5-HT neurotoxicity remains unknown. There is evidence that the depletion of 5-HT in the brain is dependent, in part, upon the prolonged and excessive release of dopamine elicited by MDMA. The overall hypothesis that provides the basis for the studies proposed in this application is that the MDMA-induced depletion of brain 5-HT results from a) a MDMA-induced increase in the extracellular concentration of dopamine, b) the enzymatic or autoxidation of dopamine and the subsequent formation of hydroxyl-free radicals and c) the cellular damage (e.g., lipid peroxidation) associated with their formation. To provide evidence in support of the view that MDMA-induced 5-HT neurotoxicity results from oxidative stress to neurons following the generation of free radicals and depletion of endogenous antioxidants, the specific aims are to utilize in vivo microdialysis and biochemical assays to establish that 1) MDMA produces a dose- and time-dependent increase in the formation of hydroxyl free radicals in the brain, 2) MDMA-induced formation of hydroxyl free radicals is dependent, in part, upon the sustained increase in the extracellular concentration of dopamine, 3) MDMA-induced formation of hydroxyl free radicals is accompanied by free radical-mediated cellular toxicity, as evidenced by lipid peroxidation, decreased tissue concentrations of vitamin E and glutathione, and 4) MDMA-induced neurotoxicity of 5-HT neurons can be attenuated by prevention or inhibition of hydroxyl radical formation, treatment with free radical scavengers or treatment with iron chelators that diminish iron-facilitated autoxidation of dopamine. An understanding of the neurochemical substrates that mediate the neurotoxic effects of MDMA ultimately will assist in determining the risk to human health associated with its abuse and predicting neurotoxic consequences of other abused substances.
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