Huntington's Disease (HD) is an hereditary degenerative disorder of grey matter characterized by abnormal movements, psychiatric symptoms and degeneration of striatal intrinsic and efferent neuronal systems. During the previous period of support, we have demonstrated that intra-striatal injection of kainic acid (KA) in the rat reproduces the neurochemical and histologic pathology of HD. We have also demonstrated the existence of specific receptors for KA in brain and that the neurotoxic action of KA involves activation of these receptors in cooperation with the release of endogenous excitatory neurotransmitters. In the proposed studies, we will examine pre- and post-synaptic mechanisms involved in the neurotoxic action of KA, with a particular focus on endogenous substances that interact with putative glutamate receptors and KA receptors. 1. We will characterize the regional distribution, neuronal localization, ontogeny, metabolic disposition and receptors of N-acetylaspartyl-glutamate, an endogenous excitatory peptide with high affinity for glutamate receptors. 2. The pharmacology of the nerve terminal high affinity uptake processes for glutamate and aspartate will be characterized as we have found regional differences in drug specificity for these transport systems. 3. The mechanisms involved in the pre-synaptic release of endogenous glutamate and aspartate by KA will be defined wih regard to receptor specific effects. 4. The role of acute alterations in the levels and turnover of endogenous norepinephrine and GABA in the convulsant and neurotoxic action of KA will be examined. 5. We will use the KA-receptor to identify substances in the brain that might serve as endogenous ligands for the KA-receptor. The physiologic effects of the purified compound(s) will be determined in those systems known to be sensitive to KA and their regional subcellular and neuronal localization will be assessed.
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