The symptoms of Parkinson's disease are associated with a degeneration of dopaminergic nigrostriatal neurons in the central nervous system. We propose to evaluate the biochemical changes that occur in nigrostriatal neurons of rats that have been lesioned with 6-OHDA, a chemical that destroys dopaminergic neurons, thereby producing an animal model for Parkinson's disease. Four groups of animals will be evaluated, these include animals with 1) lesions of greater than 90%, 2) lesions of approximately 50% to 60%, 3) lesions of greater than 90% plus treatment with L-dopa and carbidopa, 4) lesions of greater than 90% plus tissue transplants. The brain areas examined will include the striatum and substantia nigra. Catecholamine function will be evaluated in these brain regions from the four groups of animals to establish the compensitory biochemical changes that take place in dopaminergic neurons in lesioned animals and the ability of the L-dopa treatment and transplants to affect these changes. Catecholamine synthesis will be evaluated by performing kinetic analysis of the enzyme tyrosine hydroxylase, as well as examining the in vivo regulation of catecholamine synthesis be measuring the accumulation of dopa in the brain regions following the intraperitoneal injection of NSD-1015. The responsiveness of dopaminergic neurons will be examined by administering treatments to the rats that are known to enhance dopamine synthesis in the striatum. These treatments include haloperidol injection and electroconvulsive shock treatment. Catecholamine turnover and tyrosine hydroxylase activity will be evaluated in these animals after these treatments. Cofactor availability will be measured by determining the levels tetrahydrobiopterin metabolites in the brain regions of these animals. Release of endogenous dopamine and GABA will be measured from superfused brain minces in vitro and in the intact brain in vivo using microdialysis. The regulation of this release by compounds that are known to affect the release of dopamine and HABA will be examined. Dopamine receptor function will be evaluated by measuring the accumulation of cyclic AMP in brain minces treated with D1 and D2 agonists. Three groups of transplanted rats will be evaluated, these include rats transplanted with fetal tissue chromaffin cells and pheochromocytoma PC8B cells. These studies will provide useful information on the biochemical compensitory changes that occur in the 6-OHDA lesioned animal model of Parkinson's disease and allow us to examine the effectiveness of L-dopa treatment and transplantation of catecholamine neurons in correcting the dopaminergic deficit produced by these lesions.
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