GABA-B RECEPTORS AND PARKINSON'S DISEASE

GABA-B 受体与帕金森病

• 批准号: 8357385
• 负责人: Yoland Smith
• 金额: $ 2.26万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357385
• 关键词: Affect; Agonist; Animals; Baclofen; Brain; Complement; Complex; Corpus striatum structure; Data; Funding; GABA Transporter 1; GABA transporter; GABA-B Receptor; GAT3 transporter; Globus Pallidus; Grant; In Vitro; Injection of therapeutic agent; Lead; Mediating; Microinjections; Monkeys; National Center for Research Resources; Parkinson Disease; Parkinsonian Disorders; Play; Primates; Principal Investigator; Rattus; Receptor Activation; Regulation; Research; Research Infrastructure; Resources; Role; Site; Slice; Source; Synapses; Time; United States National Institutes of Health; cost; gamma-Aminobutyric Acid; inhibitor/antagonist; nonhuman primate; postsynaptic; presynaptic; research study; reuptake; transmission process

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 在过去的资金期间，努力旨在理解GABA转运蛋白（GAT）在调节正常和帕金森氏症非人类灵长类动物的苍白体复合物中的GABA-B受体激活方面发挥作用。这些实验与大鼠脑切片中的体外电生理研究相辅相成，以进一步了解GAT阻断调节球pallidus的突触前和突触后GABA-B受体的活性的突触机制。从这些研究中可以得出以下结论：（1）帕金森氏和正常猴子在GPE和GPI中GABA-B受体的GABA-BR1亚基的定位相似。然而，与普通猴子相比，与正常猴子相比，由MPTP处理的动物显微注射GPE和GPI的发射减少更大，而GP55555555845A在GPI中降低了GPI降低的parkInian parkInian的注射。 另外，在GPE和GPI中注射baclofen或GPI中的CGP55845A导致帕金森氏动物反弹爆发的尖峰比例显着增加，但在正常猴子中没有显着增加。因此，GPI的GABA受体介导的传播发生了变化，可能会导致帕金森州的破裂活动。 （2）在体外，GAT抑制剂显着延长了衰减时间，但不会影响大鼠GP中纹状体刺激（15-20伏）引起的EIPSC的振幅。这些数据表明，GAT-1和GAT-3代表差异目标位点，GABA再摄取可以通过大鼠GP中GABA能传播的互补调节。