The loss of dopamine terminals in the striatum in response to high doses of methamphetamine has been well established. Although toxicity has been shown to be dependent upon the methamphetamine-induced release of dopamine into the extracellular space, the exact mechanism by which dopamine induces toxicity remains unclear. One mechanism often proposed is that dopamine can oxidize to form reactive metabolites such as free radicals and DA quinones that may attack cellular components resulting in toxicity. Although some evidence exists to support this theory, the relation between the oxidation of dopamine and drug-induced toxicity has not been examined directly. Thus, the goal of this study is to rigorously test the hypothesis that dopamine oxidation plays a role in the mechanism of methamphetamine-induced neurotoxicity. The proposal aims to examine specific measures of dopamine oxidation during and after exposure to methamphetamine: the formation of free and protein-bound cysteinyl-catechols, and salicylate trapping of hydroxyl radicals. Pharmacological manipulations of dopamine synthesis and metabolism will be used to correlate dopamine oxidation with the resulting toxicity. Antioxidant levels in tissue and extracellular fluid also will be monitored during exposure to methamphetamine. Pharmacological manipulations that increase or decrease brain levels of antioxidants will be used to examine the effect of brain antioxidant status on dopamine oxidation and the resulting toxicity. Finally, the hypothesis that dopamine-induced oxidative stress can influence extracellular levels of potentially toxic neurotransmitters via disruption of the dopamine and/or glutamate transporters will be examined. The findings may suggest that individuals who abuse amphetamines are at risk for the development of permanent damage to the CNS. Therapeutic intervention in the form of antioxidant supplementation may be warranted to prevent permanent-damage to the CNS and to reduce the potential predisposition of these individuals for the development of Parkinson's disease later in life.
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