The hypothesis of this proposal for a CIA is that excessive dopamine release in the neostriatum may contribute to the cerebral damage incurred in neonatal hypoxic-ischemic encephalopathy. This is based on recent studies indicating that CNS ischemia is accompanied by a 30-fold increase in extracellular dopamine which, in these circumstances, May be neurotoxic. Two phases of study are proposed. In vivo studies (phase 1) will utilize a neonatal rat model. Neurochemical and histologic methods (including GFAP immunocytochemistry, calculation of striatal area and volume, autoradiography of dopamine DI receptors and of peripheral benzodiazepine binding sites) will be employed to quantitate the degree and extent of brain damage. The potential neuroprotective effects of a depleter of endogenous dopamine (alpha-methyl-ptyrosine), of dopamine antagonists, both non-selective (fluphenazine and flupenthioxl) and selective (SCH 23390; sulpiride), and of antioxidants will be assessed in this model. Mechanisms of dopamine-induced neuronal damage will next be examined (%phase 2"""""""") in vitro using striatal tissue culture to determine if dopamine-induced brain injury is mediated through stimulation of specific receptors, or through the generation of oxygen free radicals. The ability of dopamine antagonists versus free radical scavengers to protect neurons in culture from excess dopamine will be determined. The results of the proposed research should contribute to the understanding of the pathophysiology of CNS injury in neonatal hypoxic-ischemia, and may suggest therapeutic interventions in the human neonate. Dr. Filloux will be supervised in this research endeavor by Dr. Thomas N. Parks, a well-known, respected developmental neurobiologist with documented expertise in excitotoxic cellular effects and in CNS tissue culture techniques. All the laboratory space and equipment as well as ancillary assistance necessary for the successful completion of this project will be made available to Dr. Filloux by Dr. Parks and through the unified support of the Departments of Pediatrics, Neurology, and Psychiatry at the University of Utah.
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