GABA-B RECEPTORS AND PARKINSON'S DISEASE

GABA-B 受体与帕金森病

• 批准号: 7958115
• 负责人: Yoland Smith
• 金额: $ 4.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958115
• 关键词: Agonist; Basal Ganglia; Brain; Cells; Computer Retrieval of Information on Scientific Projects Database; Disease; Funding; GABA transporter; GABA-B Receptor; GAT3 transporter; Globus Pallidus; Goals; Grant; Injection of therapeutic agent; Institution; Mediating; Methods; Monkeys; Neurons; Parkinson Disease; Parkinsonian Disorders; Presynaptic Receptors; Primates; Rattus; Receptor Activation; Regulation; Research; Research Personnel; Resources; Role; Slice; Solid; Source; Testing; United States National Institutes of Health; base; gamma-Aminobutyric Acid; new therapeutic target; patch clamp; receptor; receptor function; response; transmission process

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的主要目标是：（1）表征MPTP处理的Parkinsonian猴子中GABAB受体的定位和功能的变化，以及（2）阐明GABA转运蛋白在调节Gabab受体在Globus Pallidus（GP）调节GABAB受体激活中的作用。 在过去的一年中，每周注射MPTP，将两只猴子送给帕金森尼人。然后，我们研究了GPE，局部注射GABA受体激动剂和拮抗剂，GAT-1或GAT-1或GAT-3阻滞剂的单个神经元的活性。 GABA-B激动剂的作用与我们先前在正常猴子中发现的作用相似，也就是说，所有测试的GPE神经元的触发都大幅下降。相比之下，GABA-B受体的阻断引起的可变反应，最明显的发射增加。解释这一意外结果的一种可能方法是，帕金森氏症中GABA-B前受体上调，因此它们的封锁产生了GABA能传播的增加，随后发射的下降。用GAT阻滞剂获得的效果与在正常猴子中观察到的效果不同，即GAT-1和GAT-3阻断剂在正常猴子中产生的细胞发射一致降低，而GPE细胞在GAT-1的发射速率通常没有影响GAT-1后GPE细胞的发射速率，而GAT-3 Transporter Bockporter bockparders bock parkinsonians却没有影响。最后，使用脑切片中的斑块夹记录方法，我们显示了GABA转运蛋白阻断对大鼠GP神经元中GABAB介导的传播的强大影响，这表明非突触GABA溢出在介导GP受体在GP中激活的GABA受体激活的重要性。 总之，这些发现为基底神经节中GABAB受体功能的更深入了解提供了坚实的基础，并有助于将这些受体作为帕金森氏病的新治疗靶点的潜在意义。