Huntington's disease (HD) is a devastating neurodegenerative disease presently lacking effective therapy. Striatal excitotoxic lesions in rats have served as useful models for HD but do not mimic the movement abnormalities of dyskinesia and chorea seen in HD. The development of a non-human primate-model of HD by excitotoxic caudate-putamen lesions, is necessary to determine underlying mechanisms for dyskinesias following basal ganglia lesions, and potential of new therapeutic approaches, such as neuronal transplantation. We will produce unilateral caudate-putamen neuropathology similar to Huntington's disease using a novel CT-guided stereotaxic infusion-method of quinolinic acid (7 x 8 mul; 120 nmoles/mul) developed for the cynomolgus monkey. This lesion results in a movement disorder, which is quantifiable and highly reproducible under dopamine-agonist drug stimulation (apomorphine 1 mg/kg i.m., 40 min. test). We will determine if stereotaxic implantation of dissociated primate striatal neuroblasts (7 x 8 mul; 105 cells/mul) into the degenerated caudate-putamen can ameliorate the induced movement disorder. In this primate-model we will carefully determine the neurochemical and anatomical basis for the movement disorder observed. We will also assess the neuronal mechanisms causing the improvements by implanted neural tissue, by investigating (a) neuroanatomical connections, (b) neurochemical changes and (c) the effects of implanted control tissue. This primate work will demonstrate the utility of neuronal replacement as a potential treatment strategy for Huntington's disease and significantly improve our understanding of the pathophysiology of the movement disorder accompanying this illness.
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