GABA-B RECEPTORS AND PARKINSON'S DISEASE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该项目的主要目标是表征正常和帕金森病条件下基底神经节GABA-B受体的解剖和功能组织。在过去的资助期间，一直致力于了解GABA转运蛋白（GATs）在调节正常和帕金森病非人灵长类动物苍白球复合体中GABA-B受体激活中可能发挥的作用。这些实验与大鼠脑切片中的体外电生理学研究相补充，以进一步了解GAT阻断调节苍白球中突触前和突触后GABA-B受体活性的突触机制。 结果表明：（1）苍白球内、外段GATs的亚细胞定位在帕金森病状态下不受影响。使用在清醒的猴子结合局部药物输送在GPe和GPi的体内电生理记录程序，我们证明了GAT-1或GAT-3的封锁的影响是类似的，在正常的猴子在GPe中看到的，但不像在正常状态下的调查结果，大多数神经元的放电不受任何转运蛋白在GPi的封锁。 这些结果表明，多巴胺能耗尽后，GPi中GABA转运蛋白的功能发生改变;其亚细胞定位没有重大变化。(2)使用体外切片电生理学，我们还证明了GABA转运蛋白，GAT-1和GAT-3，显着调节GABA受体介导的GABA能突触传递在大鼠GP，从而提供证据的高表达水平和功能的重要性，GAT在调节GABA能纹状体-苍白球传递。已知纹状体GABA能流出增加到GP在帕金森病的病理生理学中的重要性，GAT可以被认为是未来开发抗帕金森病药物的潜在靶点，所述抗帕金森病药物可以在病理条件下增加GAT-1或GAT-3介导的GABA再摄取功能。

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.