Anesthetic actions on GABA(A) fast, slow, tonic and GABA(B) receptors

描述(由申请人提供)：我们研究的长期目标是确定不同形式的GABA介导的抑制在麻醉中所起的作用。目前，关于不同麻醉终点的麻醉剂增强的GABA抑制作用存在很大争议。良好的证据表明，在几个终点，包括记忆丧失、意识丧失，甚至是静止不动，都有相当大的参与，但其他实验表明，参与很少或根本没有参与。目前也不清楚是突触受体还是突触外紧张性受体介导的GABA抑制在抑制电路水平的信号中起着更重要的作用。我们最近发现的对GABAB的重要影响，除了对GABAA系统的影响外，还增加了对越来越多的新麻醉剂靶点(如Trek和TASK钾通道、钙通道、其他递质受体、突触前SNARE蛋白和钠通道)的相关影响的困惑。我们将把这项研究的重点放在GABAA和GABAB介导的抑制上，因为从我们的初步研究来看，这两种物质似乎对抑郁的贡献最大(当联合使用时超过60%)，但我们新的电路水平分析已经为其他关键作用部位提供了证据。三个具体目标将被解决：1-评估快、慢突触以及强直的GABAA抑制在CA1环路整合中的作用，2-评估这些形式的抑制在麻醉剂诱导的环路抑制中所起的作用，以及3-评估GABAB介导的抑制在麻醉剂中所起的作用。来自这些目标的信息对于设计更安全、更有效的麻醉药来说是必不可少的，这些麻醉药选择性地针对最相关的GABA受体。在短期内，我们将提供量化评估来解决当前的争议，并评估GABAB对三类全身麻醉药的新贡献。我们的结果将提供可用的最佳量化数据，用于使用计算方法模拟麻醉效果--当前的模型使用的是对GABA系统参与程度的估计，范围从~20%到90%，几乎没有证据来基于这些估计。随着各种形式抑制的GABA受体亚型变得已知，我们的结果将有助于将所需和不想要的麻醉效果与这些分子靶点联系起来。

DESCRIPTION (provided by applicant): The long term goal of our research is to define the role played in anesthesia by various forms of GABA-mediated inhibition. There is great controversy at present regarding anesthetic-enhanced GABA inhibition for various anesthetic end-points. Good evidence points to considerable involvement, for several end-points, including loss of recall, loss of consciousness and even immobility, but other experiments have suggested little or no involvement. Nor is it clear whether GABA inhibition mediated by synaptic receptors or extrasynaptic tonic receptors play the more important role in depressing circuit level signaling. Our recent discovery of important effects on GABAB, in addition to well documented effects on GABAA systems, have added to the confusion about relevant effects for a growing array of new anesthetic target sites (e.g TREK and TASK potassium channels, calcium channels, other transmitter receptors, presynaptic SNARE proteins, and sodium channels). We will focus this study on GABAA and GABAB mediated inhibition, because these appear to contribute most to depression (over 60% when combined) from our preliminary studies, but our new circuit level analysis has already provided evidence for other key sites of action as well. Three specific aims will be addressed: 1 - to assess the role that fast and slow synaptic as well as tonic GABAA inhibition plays in CA1 circuit integration, 2 - to assess the roles these forms of inhibition play for anesthetic- induced circuit depression, and 3 - to assess the role GABAB mediated inhibition plays for anesthetics. Information from these aims is essential for designing safer and more effective anesthetics that selectively target the most relevant GABA receptors. In the immediate-term, we will contribute quantitative assessments to resolve current controversies, and assess new GABAB contributions for three classes of general anesthetics. Our results will provide the best quantitative data available upon which to model anesthetic effects using computational approaches - current models use estimates of the involvement of GABA systems that range from ~ 20 to 90 %, and there is little evidence upon which to base these estimates. As the GABA receptor subtypes underlying various forms of inhibition become known, our results will help link desired and unwanted anesthetic effects to these molecular targets.