GABA-B RECEPTORS AND PARKINSON'S DISEASE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在过去的资助期间，人们致力于了解GABA转运体(GATS)在调节正常和帕金森病非人类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。这些实验还辅之以大鼠脑片的体外电生理研究，以进一步了解GAT阻断调节苍白球突触前和突触后GABA-B受体活性的突触机制。从这些研究中可以得出以下结论：(1)GABA-B受体的GABA-BR1亚单位在帕金森病猴和正常猴的GPE和GPI中的定位相似。然而，在MPTP治疗的动物中，微量注射GABA-B受体激动剂巴氯芬引起的GPE和GPI中的放电减少比正常猴子更大，而注射GABA-B受体拮抗剂CGP55845A在帕金森病患者中产生的GPI中放电的减少比正常动物更常见。 此外，在GPE和GPI中注射巴氯芬，或在GPI中注射CGP55845A，可显著增加帕金森病动物反弹爆发中的尖峰比例，但在正常猴子中没有。因此，GABA-B受体介导的传递在GPI中发生改变，并可能有助于帕金森状态下的突发性活动。(2)在体外，GAT抑制剂可显著延长刺激纹状体(15-20伏)诱发的大鼠大脑皮层eIPSCs的衰变时间，但对其幅度无明显影响。这些数据表明，GAT-1和GAT-3代表不同的靶点，通过这些靶点，GABA的再摄取可能有助于大鼠GP中GABA能传递的互补调节。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 localization of the GABA-BR1 subunit of the GABA-B receptor in GPe and GPi was similar in parkinsonian and normal monkeys. However, the reduction in firing in GPe and GPi produced by microinjections of the GABA-B receptor agonist baclofen was larger in MPTP-treated animals than in normal monkeys, and injections of the GABA-B receptor antagonist CGP55845A produced more commonly decreased firing in GPi in the parkinsonian than in the normal animals. In addition, the injections of baclofen in GPe and GPi, or of CGP55845A in GPi lead to a significant increase in the proportion of spikes in rebound bursts in parkinsonian animals, but not in normal monkeys. Thus, GABA-B receptor mediated transmission is altered in GPi and may contribute to bursting activities in the parkinsonian state. (2) In vitro, GAT inhibitors significantly prolonged the decay time, but did not affect the amplitude, of eIPSCs induced by striatal stimulation (15-20 volts) in the rat GP. These data indicate that GAT-1 and GAT-3 represent differential target sites through which GABA reuptake may subserve complementary regulation of GABAergic transmission in the rat GP.