GABA-B RECEPTORS AND PARKINSON'S DISEASE

这个子项目是许多研究子项目中的一个 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。 本研究的主要目的是：（1）研究MPTP治疗后帕金森病猴GABAB受体的定位和功能变化;（2）阐明GABA转运蛋白在苍白球（GP）GABAB受体活化调节中的作用。 在过去的一年里，两只猴子每周注射MPTP，导致帕金森病。然后，我们研究了单个神经元在GPe的活动，之前，期间和之后，局部注射GABA-B受体激动剂和拮抗剂或GAT-1或GAT-3阻断剂。GABA-B激动剂的作用与我们以前在正常猴子中发现的相似，即所有测试的GPe神经元的放电都大大减少。与此相反，GABA-B受体的阻断诱导可变的反应，最明显的是增加射击。解释这一意外结果的一种可能方式是，GABA-B突触前受体在帕金森病中上调，因此其阻断产生了GABA能传递的增加，以及随后的放电减少。GATs阻断剂获得的效果与正常猴中观察到的效果不同，即GAT-1和GAT-3阻断剂均使正常猴的细胞放电持续减少，而GAT-1阻断后对GPe细胞的放电率通常没有影响，而GAT-3转运蛋白阻断后对帕金森病患者的GPe细胞的放电率影响更小。最后，在脑片上使用膜片钳记录方法，我们显示了GABA转运体阻断对大鼠GP神经元中GABAB介导的传递的强大影响，表明非突触GABA溢出在介导GP中GABAB受体激活中的重要性。 总之，这些发现为更深入地了解基底神经节中GABAB受体的功能提供了坚实的基础，并有助于表征这些受体作为帕金森病新治疗靶点的潜在意义。

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 goals of this project are: (1) To characterize changes in the localization and function of GABAB receptors in MPTP-treated parkinsonian monkeys and (2) To elucidate the role of GABA transporters in the regulation of GABAB receptor activation in the globus pallidus (GP). Over the past year, two monkeys were rendered parkinsonian with weekly injections of MPTP. We then studied the activity of single neurons in GPe, before, during and after local injection of GABA-B receptor agonist and antagonist or GAT-1 or GAT-3 blockers. The effects of the GABA-B agonist were similar to what we found previously in normal monkeys, that is, a profound decrease in the firing of all GPe neurons tested. In contrast, blockade of GABA-B receptors induced variable responses, most noticeable an increase in firing. A possible way to interpret this unexpected result is that the GABA-B presynaptic receptors are upregulated in parkinsonism so that their blockade produced an increased GABAergic transmission, and a subsequent decrease in firing. The effects obtained with the GATs blockers were different from those observed in normal monkeys, ie both GAT-1 and GAT-3 blockade produced consistent decrease in the cell firing in normal monkeys, while there was often no effect on the firing rate of GPe cells after blockade of GAT-1 and even less after GAT-3 transporter blockade in parkinsonians. Finally, using patch clamp recording method in brain slices, we showed powerful effects of GABA transporter blockade on GABAB-mediated transmission in rat GP neurons, suggesting the importance of non-synaptic GABA spillover in mediating GABAB receptors activation in the GP. Together, these findings provide a solid basis for a deeper understanding of GABAB receptor function in the basal ganglia, and help characterize the potential significance of these receptors as new therapeutic targets for Parkinson's disease.