DEFINITION OF INHALED ANESTHETIC SITES OF ACTIONS

吸入麻醉药作用部位的定义

• 批准号: 6344898
• 负责人: EDMOND I EGER
• 金额: $ 13.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6344898
• 关键词: GABA receptor; central nervous system; conditioning; cyclic compound; dosage; drug adverse effect; drug interactions; ethanol; fear; gas chromatography; gene targeting; genetic strain; genetically modified animals; glutamate receptor; glycine receptors; halothane; immobilization of body part; inhalation anesthesia; isoflurane; laboratory mouse; memory disorders; molecular site; neuromuscular disorder; neurotransmitter receptor; nicotinic receptors

Despite the broad use of inhaled anesthetics, their mechanisms of action remain unknown. The present project hypothesizes that specific proteins/receptors mediate two primary effects of inhaled anesthetics: (a) suppression of movement, and (b) production of amnesia. The former will be measured as MAC, the minimum alveolar concentration of anesthetic that eliminates movement in 50% of mice in response to a noxious stimulus. The latter will be measured as the ED50 at which an anesthetic will interfere with learning and memory, as determined in mice using fear conditioning. The project will assess the relative importance of GABAA, glycine, glutamate, and neuronal nicotinic acetylcholine receptors to each of the two actions, focusing on these receptors, because in vitro evidence suggests (but does not prove) their relevance to the actions of inhaled anesthetics. Aim 1 of the project is to establish anesthetic dose-response relationships for MAC and for fear conditioning for a panel of five inhaled compounds having diverse properties. We will use commonly studied mouse strains, including those that provide the genetic background for the mutant mice tested in Aim 3 studies. These investigations examine the hypothesis that a constant potency relationship does not exist for the two anesthetic effects. Aim 2 broadens the panel of inhaled compounds but tests in vivo potency (for immobilization and fear conditioning) only in C57BL/6J mice, a strain that supplies the genetic background for most mice used in Aim 3. Compounds will be selected from those previously shown useful in studies of anesthetic-receptor interactions. This will test the working hypotheses (a) that a constant potency relationship does not exist for anesthetic partial pressures for MAC versus fear conditioning, (b) that two sites separated by 5 carbons mediate the immobilizing effects of anesthetics, and (c) that these two sites may not mediate interference with fear conditioning. Aim 3 will examine anesthetic potency in mutant mice lacking specific receptor subunits (null mutant mice) or bearing altered subunits (transgenic or knock in mice), and will compare these results with those for control (wild-type) mice. These results will test the hypotheses that specific receptors and specific receptor regions mediate the capacity of anesthetics to produce immobility or to interfere with fear conditioning. Finally, the data will provide a test of the relevance of the hypotheses proposed in the in vitro molecular studies of the rest of the Program Project Grant to the production of anesthesia.

尽管吸入麻醉剂的广泛使用，其作用机制仍然未知。本项目假设特定的蛋白质/受体介导吸入麻醉剂的两种主要作用：（a）运动抑制和（B）健忘症的产生。前者将被测量为MAC，即消除50%小鼠对有害刺激的反应的运动的麻醉剂的最小肺泡浓度。后者将被测量为麻醉剂将干扰学习和记忆的ED 50，如使用恐惧条件反射在小鼠中测定的。该项目将评估GABAA、甘氨酸、谷氨酸和神经元烟碱乙酰胆碱受体对这两种作用的相对重要性，重点是这些受体，因为体外证据表明（但不能证明）它们与吸入麻醉剂的作用相关。该项目的目的1是建立MAC和恐惧条件反射的五种具有不同性质的吸入化合物的麻醉剂量-反应关系。我们将使用通常研究的小鼠品系，包括为Aim 3研究中检测的突变小鼠提供遗传背景的小鼠品系。这些研究检查了两种麻醉作用不存在恒定效价关系的假设。目标2拓宽了吸入化合物的范围，但仅在C57 BL/6 J小鼠中测试了体内效力（用于固定和恐惧条件反射），该品系为目标3中使用的大多数小鼠提供了遗传背景。化合物将选自先前显示在麻醉剂-受体相互作用的研究中有用的那些。这将检验以下工作假设：（a）MAC与恐惧条件反射的麻醉剂分压之间不存在恒定的效力关系;（B）由5个碳原子隔开的两个位点介导麻醉剂的固定效应;以及（c）这两个位点可能不介导对恐惧条件反射的干扰。目的3将检查缺乏特异性受体亚单位的突变小鼠（无效突变小鼠）或携带改变的亚单位（转基因或敲入小鼠）的麻醉效力，并将这些结果与对照（野生型）小鼠的结果进行比较。这些结果将检验特定受体和特定受体区域介导麻醉剂产生不动或干扰恐惧条件反射的能力的假设。最后，这些数据将提供一个测试的相关性的假设提出的体外分子研究的其余计划项目赠款的麻醉生产。