The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitotoxicity and Environment, Metabolic and Oxidative Stress
Abstract
Degeneration of the nigrostriatal dopamine system is linked to the pathophysiology of Parkinson's disease. Similarly, the psychostimulant drug, methamphetamine also produces relatively selective damage to nigrostriatal dopamine neurons and is rapidly becoming a widespread problem and drug of abuse throughout the U.S. However, the neurochemical underpinnings that mediate methamphetamine toxicity and Parkinson's disease have escaped definition. We propose that several variables common to methamphetamine toxicity and Parkinson's disease, each of which may be important but alone are insufficient, 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, excitatory amino acids, and alter energy metabolism, 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 in rats the interaction between environmental stress and methamphetamine and the convergent action of excitotoxicity, bioenergetic stress, and oxidative stress to produce damage to nigrostriatal dopamine neurons. A multidisciplinary approach of in vivo and in vitro biochemical and histochemical methods will be used. In addition, pharmacological strategies that we posit to be neuroprotective against methamphetamine, excitotoxicity, and bioenergetic and oxidative stress will be examined.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA398119
Entities
People
- Bryan Yamamoto
- Kristan Burrows
- Leslie Matuszewich
- Wendy Nixdorf
Organizations
- Case Western Reserve University