CELLULAR TOXICOLOGY OF THE DOPAMINE NEURON

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The candidate is a pharmacologist and neurologist with research experience in behavioral pharmacology and clinical research training in movement disorders. His-special interests include extrapyramidal syndromes and neurotoxic consequences of drug use. Research proposed here concerns MPTP (l-methyl-4-phenyl-1,2,3,6- tetrahydropyridine), a meperidine analogue which produces changes that mimic the lesion of Parkinson's disease in primates and other species. Despite advances in understanding some aspects of the mechanism by which the drug causes neuronal degeneration, many basic questions remain unanswered due primarily to the complexity of in vivo research on the central nervous system. One approach to this problem is to elucidate the mechanism of action of MPTP in vitro by studying the effects of the toxin on cell cultures of dopaminergic neurons and upon striatal (or midbrain) slices. Specific aims of this research are: 1) to characterize the selectivity and irreversibility of MPTP and MPP+ toxicity towards dopamine neurons in culture, 2) to test the hypothesis that MPP+ acts primarily on neuronal fibers, with subsequent retrograde degeneration of the neuron, 3) to test the hypothesis that oxyradicals mediate MPP+ induced destruction of dopamine neurons, 4) to test the hypothesis that mitochondrial electron transport is inhibited by MPP+ in rat (or mouse) striatal and midbrain slices as measured with scanning spectrophotometer, and 5) to test the hypothesis that target tissue (striatal cells) influences MPP+ neurotoxicity and facilitates recovery of dopamine neurons from sub-lethal damage. The University of Miami Dept of Neurology provides outstanding resources for development of a clinical investigator: fully equipped laboratories, basic research staff, out-patient clinics, hospital neurology ward, students and housestaff.