Since the recognition that Parkinson's disease is associated with dopamine depletion in the caudate and putamen and cell loss in the substantia nigra, there has been steady progress in understanding the role of dopamine in movement disorders. L-dopa therapy has offered partial relief by increasing brain dopamine and relieving symptoms in the Parkinsonian patient. However after several years of disease, drug therapy becomes less effective with patients often showing a more brittle response. Transplantation-of fetal mesencephalic dopamine cells may be able to restore motor function and drug responsiveness to the Parkinson patient-. Human fetal dopamine cell transplants are already being tested in patients. This grant proposal will address several questions designed to improve the effectiveness of fetal cell implants in rat models of Parkinson's disease. In rodent and primate experiments, fetal dopamine cell implants have been shown to have behavioral effects. Despite clear evidence that fetal mesencephalic dopamine neurons can survive and grow neurites in striatum and can influence amphetamine and apomorphine behaviors, there are few experiments showing that transplants alter spontaneous motor activity or are functionally activated during voluntary motor behavior. Previous experiments by us have shown that animals trained to run in circles for a water reward show increased dopamine metabolism in a number of brain nuclei, increased firing of dopamine cells in substantia nigra pars compacta, and increased firing in striatal neurons during movement. The present experiments will examine whether rats with unilateral dopamine depletion followed by dopamine cell implants in striatum have movement related activation of dopamine cell firing in the implant, dopamine release from the striatum and changes in striatal and pallidal cell firing. Studies of movement related release of dopamine will be done by in vivo dialysis. Electrophysiological studies of nigral, striatal and pallidal cell firing will also be performed in the moving animal.
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