The neurorestorative and neuroprotective tropic actions of GDNF on midbrain dopamine (DA) neurons provide a promising therapeutic approach for the treatment of Parkinson's disease. It is our central hypothesis that chronic intracerebroventricular or intraputamenal GDNF will produce effects on damaged DA neurons with greater efficacy, potency and reduced side effects as compared to other methods of delivery. We propose to use a novel indwelling pump that can deliver GDNF chronically in the freely-moving unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesions monkey to evaluate two sites of delivery: the lateral ventricle and the putamen. Prior studies have shown that single infusions of GDNF produce neuroprotection and neurorestorative effects to DA neurons, which are localized to the substantia nigra and not the striatum of rats and monkeys. We hypothesize, based on preliminary studies, tha chronic delivery of GDNF will restore DA function in regions of the substantia nigra and striatum, producing a greater reversal of parkinsonian behavior than previously seen with single injections. Project 1 of this program project grant application will perform quantitative neurochemical assessments using in vivo micordialysis, in vivo electrochemical, and high performance liquid chromatography coupled with electrochemical detection (HPLC-EC) to study DA neuronal systems in the striatum (putamen and caudate nucleus) and substantia nigra of young adult Rhesus monkeys that have received chronic GDNF infusions. Washout studies will be performed to determine the longevity of the chronic GDNF effects. Re-instatement studies will also be performed to determine if GDNF can sustain or increase DA funciton following washout and be safely re-administered. These neurochemical changes to the monkey striatum during chronic delivery of GDNF will be performed in conjunction with behavioral, immunohistochemical, tract tracing and functional MRI (fMRI) studies of the same monkeys in conjunction with Project 2 and 3. These studies should lead to a greater understanding of the effects of focal and sustained delivery of a potent DA tropic factor to damaged DA neurons. They will likely lay the foundation for focal and chronic delivery of trophic factors to patients with Parkinson's disease.
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