The hypothesis being examined suggests 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. There are two phases of study. In vivo studies (phase 1) utilize a neonatal rat model. Neurochemical and histologic methods (including GFAP immunocytochemistry, calculation of striatal area and volume, autoradiography of dopamine D1 receptors and of peripheral benzodiazepine binding sites) are employed to quantitate the degree and extent of brain dama ge. The potential neuroprotective effects of a depleter of endogenous dopamine (a-methyl-p-tyrosine), of dopamine antagonists, both non-selective (fluphenazine and flupenthixol) 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.
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