Recent investigations indicate that dopaminergic (DArgic) neurons in the substantia nigra (SN) secrete dopamine not only in their axonal terminals within the striatum but also via their dendrites within the SN pars reticulata (SNr) and that loss of dopamine in the SNr may have a role in the development of parkinsonism in primates. As a corollary, restoration of both nigral and striatal dopamine inputs may produce better recovery of function in Parkinson's disease than restoration of dopamine inputs in the striatum alone. Therefore, the PI proposes to examine the effects of combined DArgic fetal ventral mesencephalic (FVM) cell transplantation into the SN and the striatum in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated hemiparkinsonian (HP) monkeys and compare the results with FVM transplants in the striatum or SN alone. Animals will be periodically assessed by investigators blinded to the type of transplantation using a behavioral battery of tests (BBT). All animals will be treated with intracarotid MPTP injections to cause a stable HP state and briefly treated with oral levodopa to verify responsiveness to DArgic therapy prior to randomization into 4 equal groups (1-4). Microelectrode recordings of neuronal activity and magnetic resonance imaging (MRI) will be used to guide all transplantation procedures.
In specific aim 1 (SA 1), group 1 animals will receive simultaneous FVM transplants into both striatum and the SN, group 2 animals will receive striatal FVM transplants, group 3 animals will receive FVM transplants into the SN and group 4 animals will receive """"""""control"""""""" fetal tissue transplants into the SN. Periodic BBT assessments and immunochemical assessment of the transplanted animals compared across groups 1-4 will be used to test the hypothesis that combined striatal and nigral FVM transplants ameliorates parkinsonism to a greater extent than striatal FVM or nigral FVM transplants alone. In SA 2, neuronal recordings will be obtained before and after tissue transplantation from all 4 groups of animals from the SNr and the subthalamic nucleus (STN) and compared. This experiment will examine the hypothesis that striatal FVM transplantation will alter neuronal discharge patterns in both SNr and in the STN, while nigral FVM transplantation will alter neuronal discharge patterns in the SNr only. In SA 3, dopamine levels will be measured in vivo using microdialysis before and after nigral FVM transplantation from the SN and STN in group 3 and group 4 animals. This experiment will test the hypothesis that nigral FVM transplants restore dopamine content in the SN but do not effect dopamine content in the STN. These 3 experiments will objectively evaluate the role of restoring DArgic inputs into the SN in addition to restoring DArgic inputs into the striatum to ameliorate parkinsonian behavioral signs in primates and will help to understand the role of SNr in the pathophysiology of primate parkinsonism.
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