Restoration of Dopamine Function in Parkinson's Disease

A. Specific Aims - Project I The specific aims of this project have not changed since the review of this grant For clarity they are detailed as follows: Hypothesis: Combined putamenal and substantia nigra delivery of GDNF will contribute to enhanced improvement of MPTP-lesioned monkeys. In these studies, chronic parenchymal catheters will be placed in both the substantia nigra and the putamen, and chronic delivery of GDNF will be compared in these animals to monkeys receiving a single catheter placement into the putamen. A battery of behavioral (Project 2), neurochemical (Project 1), histopathological (Project 3), immunocytochemical (Project 3) and biochemical (Projects I and 3) measures will be used to investigate the functional consequences of five months of delivery of GDNF. Hypothesis: Using an optimized delivery approach, GDNF will more completely restore nigrostriatal DA functions in milder versus severely impaired MPTP-treated monkeys. In these studies, stable milder-impaired versus stable severely impaired unilateral MPTP-treated monkeys will be used to investigate the effects of chronic delivery of GDNF. An optimized cannula delivery system will be used to chronically deliverGDNF in these animals. Hypothesis: GDNF administration will affect glutamate regulation in the striatum, substantia nigra and globus pallidus of severely parkinsonian rats. This is new direction of the Center, which embodies collaborations with other Udall Centers. A newly developed but well characterized glutamate microelectrode recording system will be used to study basal and potassium-evoked release and uptake of glutamate in the striatum, substantia nigra and globus pallidus of severely parkinsonian rats (6-ONDA-treated animals) that have received injections of GDNF into the substantia nigra.