RESTORATION OF DOPAMINE FUNCTION IN PARKINSON'S DISEASE

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The neuroestorative and neuroprotective tropic actions of GDNF on midbrain dopamine (DA) neurons provide a promising therapeutic approach for the treatment of Parkinson's disease. As with many tropic factors, optimum success of this tropic factor depends on focal and controlled delivery of the protein to affect the function of DA neurons, without producing unwanted side effects. It is our central hypothesis that chronic intracerebroventricular or intraputamenal GDNF willproduce effects on damaged DA neurons with greater efficacy, potency and reduced side effects as compared to other methods of delivery. 1. We propose to use a novel indwelling pump that can deliver GDNF chronically in the freely-moving MPTP-lesioned monkey to evaluate two sites of delivery: the lateral ventricle and the putamen. 2. We will also investigate washout of GDNF and re-instatement of the trophic factor in both infusion paradigms. The different highly integrated Projects and Cores will provide key data regarding the functional effects of chronic GDNF treatments to DA neurons, and form the foundation for a Parkinson's Disease Center of Excellence. Project 1 will use microdialysis, in vivo electrochemistry and postmortem HPLC-EC methods to study the nigrostriatal pathway of unilateral MPTP-lesioned monkeys that have received chronic infusions of GDNF. Project 2 will investigate the behavioral consequences of the GDNF infusions and study potential functional changes to DA neurons using fMRI methods. Project 3 will carryout tract tracing and immunohistochemical measures of DA neurons in the same groups of chronically treated monkeys. The Cores A-D will all provide needed support for the experiments outline in Projects 1-3. These studies will answer key questions regarding the chronic delivery of a trophic factor in freely-moving and behaving rhesus monkeys. Such data could lay the foundation for the use of trophic molecules for the treatment of Parkinson's disease in humans.