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The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitotoxicity and Environmental, Metabolic and Oxidative Stress

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Final rept. 1 Jul 1999-14 Jun 2005

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Degeneration of the nigrostriatal dopamine system is linked to the pathophysiology of Parkinsons disease. Similarly, the psychostimulant drug, methamphetamine also produces relatively selective damage to nigrostriatal dopamine neurons and is a widespread problem and drug of abuse throughout the U.S. However, the neurochemical underpinnings that mediate methamphetamine toxicity and Parkinsons disease are unknown. Several variables common to methamphetamine toxicity and Parkinsons disease, each of which may be important but alone are insufficient, may account for the neurodegeneration of the nigrostriatal dopamine path. It is hypothesized that the convergence of excitotoxicity, free radicals and a depleted bioenergetic state produces damage to dopamine neurons. Moreover, environmental stressors, which also increase free radicals and excitatory amino acids predispose dopamine neurons to damage. Consequently, environmental stress may be synergistic with oxidative and metabolic insults as well as glutamate to culminate in dopamine cell death. The major objective is to examine the interaction between environmental stress and methamphetamine and the convergent action of excitotoxicity and bioenergetic and oxidative stress to produce damage to nigrostriatal dopamine neurons. A multidisciplinary approach will be used as well as pharmacological strategies that we posit to be neuroprotective against methamphetamine, excitotoxicity, and bioenergetic and oxidative stress will be examined.

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  • Anatomy and Physiology
  • Medicine and Medical Research
  • Organic Chemistry

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