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发挥的作用。目前对于各种麻醉终点的麻醉增强 GABA 抑制存在很大争议。充分的证据表明，对于几个终点，包括记忆丧失、意识丧失甚至不动，都存在相当大的参与，但其他实验表明很少或根本没有参与。尚不清楚突触受体介导的 GABA 抑制作用还是突触外紧张性受体介导的 GABA 抑制作用在抑制电路水平信号传导中发挥更重要的作用。我们最近发现的对 GABAB 的重要影响，除了对 GABAA 系统的影响有据可查之外，还增加了对越来越多的新麻醉靶点（例如 TREK 和 TASK 钾通道、钙通道、其他递质受体）的相关影响的困惑。 、突触前 SNARE 蛋白和钠通道）。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影响最大（合计超过 60%），但我们新的回路水平分析已经为其他关键作用位点提供了证据。 。将解决三个具体目标：1 - 评估快速和慢速突触以及强直性 GABAA 抑制在 CA1 回路整合中所起的作用，2 - 评估这些形式的抑制对麻醉引起的回路抑制的作用，以及 3 - 评估 GABAB 介导的抑制作用对麻醉剂的作用。来自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。短期内，我们将提供定量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定量数据，据此使用计算方法对麻醉效果进行建模 - 当前模型使用 GABA 系统参与的估计，范围从 20% 到 90%，并且几乎没有证据可以作为这些估计的基础。随着各种抑制形式背后的 GABA 受体亚型逐渐为人所知，我们的结果将有助于将所需和不需要的麻醉效果与这些分子靶标联系起来。 公众健康相关性：全身麻醉剂在现代医学中至关重要，尤其是对于手术而言，但这些药物仍然是临床使用的药物中最危险和最不为人所知的药物之一。我们的研究将解决三类重要麻醉剂的基本作用机制，包括静脉注射异丙酚、巴比妥、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。