This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The main goal of this project is to characterize the anatomical and functional organization of basal ganglia GABA-B receptors in normal and parkinsonian conditions. During the past funding period, efforts have been devoted towards the understanding of the role GABA transporters (GATs) may play in regulating GABA-B receptors activation in the pallidal complex of normal and parkinsonian nonhuman primates. These experiments were complemented with in vitro electrophysiological studies in rat brain slices to further understand the synaptic mechanisms by which GAT blockade modulates activity of pre- and postsynaptic GABA-B receptors in the globus pallidus. The following conclusions can be made from these studies: (1) The subcellular localization of GATs in both the internal and external pallidal segments (GPi, GPe) is not affected in parkinsonian condition. Using in vivo electrophysiology recording procedures in awake monkeys combined with local drug delivery in GPe and GPi, we demonstrated that the effects of GAT-1 or GAT-3 blockade were similar to those seen in normal monkeys in the GPe, but unlike the findings in the normal state, the firing of most neurons was not affected by blockade of either transporter in GPi. These results suggest that, after dopaminergic depletion, the functions of GABA transporters are altered in GPi;without major changes in their subcellular localization. (2) Using in vitro slice electrophysiology, we have also demonstrated that both GABA transporters, GAT-1 and GAT-3, significantly regulate GABAA-receptor mediated GABAergic synaptic transmission in the rat GP, thereby providing evidence for the high expression level and functional importance of GATs in regulating GABAergic striatopallidal transmission. Knowing the importance of increased striatal GABAergic outflow to the GP in the pathophysiology of Parkinson's disease, GATs may be considered as potential targets for the future development of antiparkinsonian agents that could increase GAT-1- or GAT-3-mediated GABA reuptake functions in pathological conditions.
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