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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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）GABA-B受体GABA-BR 1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，减少在GPe和GPi产生的GABA-B受体激动剂巴氯芬微量注射MPTP治疗的动物比在正常的猴子，和注射GABA-B受体拮抗剂CGP 55845 A产生更常见的减少在帕金森病的GPi比在正常的动物放电。 此外，巴氯芬注射GPe和GPi，或CGP 55845 A注射GPi导致帕金森病动物的反弹爆发的尖峰的比例显着增加，但在正常猴子。因此，GABA-B受体介导的传输在GPi中改变，并且可能有助于帕金森病状态中的爆发活动。(2)在体外，GAT抑制剂显著延长了大鼠GP中纹状体刺激（15-20伏）诱导的eIPSC的衰减时间，但不影响振幅。这些数据表明，GAT-1和GAT-3代表不同的目标网站，通过GABA再摄取可能subserve补充调节GABA能传输在大鼠GP。