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

对 GABA(A) 快、慢、强直和 GABA(B) 受体的麻醉作用

• 批准号: 8186361
• 负责人: M. Bruce MacIver
• 金额: $ 27.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8186361
• 关键词: Address; Agonist; Anesthesia procedures; Anesthetics; Barbiturates; Behavioral; Behavioral inhibition; Brain region; Calcium Channel; Complement; Confusion; Data; Depressed mood; Drug Design; Drug usage; Frequencies; GABA Receptor; GABA-B Receptor; General anesthetic drugs; Goals; Individual; Intravenous; Isoflurane; Learning; Link; Measures; Mediating; Memory; Mental Depression; Modeling; Modern Medicine; Molecular Target; Neocortex; Nervous system structure; Operative Surgical Procedures; Pain; Pattern; Pentobarbital; Pharmaceutical Preparations; Physiological; Play; Potassium Channel; Presynaptic Receptors; Propofol; Reflex action; Research; Role; SNAP receptor; Signal Transduction; Site; Spinal Cord; Synapses; Synaptic Receptors; System; Testing; Therapeutic; Therapeutic Effect; Time; Unconscious State; Ventilatory Depression; Work; barbituric acid salt; base; design; gamma-Aminobutyric Acid; in vivo; receptor; research study; response; sodium channel proteins; synaptic inhibition

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. PUBLIC HEALTH RELEVANCE: General anesthetics are essential in modern medicine, especially for surgery, but these drugs remain among the most dangerous and poorly understood among clinically used drugs. Our research will address fundamental mechanisms of action for three important classes of anesthetics, including the intravenous agent propofol, the barbiturate pentobarbital, and volatile anesthetic isoflurane - to provide a scientific basis for safer drug design.

描述（由申请人提供）：我们研究的长期目标是确定各种形式的GABA介导的抑制在麻醉中所起的作用。目前关于麻醉增强GABA抑制对各种麻醉终点的影响存在很大争议。好的证据表明，对于几个终点，包括记忆丧失、意识丧失甚至不动，参与程度相当高，但其他实验表明参与程度很低或根本没有参与。也不清楚是突触受体介导的GABA抑制还是突触外紧张性受体介导的GABA抑制在抑制回路水平信号传导中发挥更重要的作用。我们最近发现对GABAB的重要作用，以及对GABAA系统的有据可查的作用，增加了对越来越多的新麻醉靶点（例如TREK和ASK钾通道、钙通道、其他递质受体、突触前SNARE蛋白和钠通道）的相关作用的混淆。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，这些似乎对抑郁症的贡献最大（结合起来超过60%），但我们新的回路水平分析已经为其他关键作用部位提供了证据。将讨论三个具体目标：1 -评估快速和慢速突触以及强直性GABAA抑制在CA 1回路整合中的作用，2 -评估这些形式的抑制对麻醉剂诱导的回路抑制的作用，3 -评估GABAB介导的抑制对麻醉剂的作用。这些目标的信息对于设计更安全，更有效的选择性靶向最相关的GABA受体的麻醉剂至关重要。在短期内，我们将提供定量评估，以解决目前的争议，并评估新的GABAB的贡献三类全身麻醉药。我们的研究结果将提供可用的最佳定量数据，用于使用计算方法模拟麻醉效果-目前的模型使用GABA系统参与的估计值，范围从20%到90%，并且几乎没有证据支持这些估计。由于GABA受体亚型潜在的各种形式的抑制变得众所周知，我们的研究结果将有助于链接所需的和不需要的麻醉效果，这些分子靶点。 公共卫生关系：全身麻醉药在现代医学中是必不可少的，特别是对于外科手术，但这些药物仍然是临床使用的药物中最危险和知之甚少的药物。我们的研究将解决三种重要麻醉剂的基本作用机制，包括静脉麻醉剂丙泊酚，巴比妥酸盐戊巴比妥和挥发性麻醉剂异氟烷-为更安全的药物设计提供科学依据。