SUSTAINED IMPROVEMENT OF MOTOR FUNCTIONS AND UPREGULATION OF DOPAMINE RELEASE PROCESSES WITH CHRONIC INTRAVENTRICULAR DELIVERY OF GDNF IN AGED MONKEYS.
Grondin R, Cass WA, Zhang Z, Stanford JA, Gerhardt GA, Gash DM
University of Kentucky Medical Center, Department of Anatomy & Neurobiology and Morris K. Udall Parkinson's Disease Research Center of Excellence, Lexington, KY 40536-0298, USA
The progressive slowing of motor functions and the development of parkinsonian signs are commonly seen in elderly humans and monkeys. As in Parkinson's disease (PD), the nigrostriatal dopaminergic system may be involved with these age-associated declines in motor functions. Interventions that would up-regulate this system could benefit elderly humans or PD patients. The present study was conducted to determine if the potent dopaminergic trophic factor GDNF can improve motor performance and dopamine (DA) release processes in aged rhesus monkeys. Using an indwelling catheter connected to a programmable infusion pump, five animals were chronically infused with 7.5 mg GDNF per day into the right lateral ventricle for two months. A two-month washout period with the vehicle was then instituted to determine the longevity of the chronic GDNF effects. Re-instatement of treatment for one month was also performed to determine if GDNF can sustain or further increase motor function following washout and be safely readministered. Concurrent in vivo microdialysis measurements of basal and stimulus-evoked release of DA were recorded in the basal ganglia to determine if functional changes in the nigrostriatal dopaminergic system paralleled changes in motoric behavior. Five vehicle-treated animals were used as controls. GDNF significantly improved behavioral performance. The effects were retained during the washout period and further increased following re-instatement of the treatment. Evoked overflow of DA in the striatum and substantia nigra were increased in the GDNF recipients compared to vehicle recipients. Basal levels of extracellular DA were also significantly increased in the substantia nigra of the GDNF-treated animals. Body weight loss was the main side-effect observed. The data suggest that GDNF improves motor performance by increasing striatal and somatodendritic dopamine release in the aging non-human primate brain. The data also support the hypothesis that chronic GDNF, delivered by programmable pumps, may be an efficacious approach to improve motor deficits in aged people or in patients with PD. Supported by USPHS grants NS39787, AG13494 and MH01245, Amgen Inc. and Medtronic Inc.
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