AMNESTIC/IMMOBILIZING EFFECTS OF INHALED ANESTHETICS

吸入麻醉剂的遗忘/固定作用

• 批准号: 6807225
• 负责人: JAMES Michael SONNER
• 金额: $ 23.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6807225
• 关键词: GABA receptor; NMDA receptors; anesthetics; body movement; conditioning; drug receptors; gene mutation; gene targeting; genetically modified animals; glycine receptors; inhalation anesthesia; isoflurane; laboratory mouse; membrane channels; memory; memory disorders; microinjections; neuropharmacology; pharmacokinetics; protein structure; protein structure function; psychopharmacology; sodium channel

This proposal focuses on the amnestic and immobilizing effects of a prototypic inhaled anesthetic, isoflurane, contrasting those effects with the effects of other anesthetics. Such contrasts are proposed to reveal the mechanisms underlying inhaled anesthetic actions. The mechanism by which isoflurane produces its behavioral effects is unknown. Isoflurane's actions on many ion channels could plausibly produce amnesia or immobility. This project in the Program Project Grant (PPG) found that several such channels probably do not mediate immobility but that glycine and NMDA receptors and sodium channels remain reasonable targets. No receptors or ion channels have either been identified or excluded as primary mediators of amnesia. Because many GABAergic drugs (e.g., benzodiazepines) and NMDA inhibitors have profound amnestic effects, and because inhaled anesthetics share these effects on GABAA and NMDA receptors, this proposal hypothesizes that inhaled anesthetics interferes with memory by altering GABAA and/or NMDA receptor function. A test of this hypothesis is proposed using genetically modified mice, and animals administered GABAA and NMDA receptor modulators. Preliminary data suggest a role for glycine receptors to isoflurane-induced immobility. These investigations will be continued using knockin mice harboring glycine receptors that respond normally to glycine but are not enhanced in effect by isoflurane. Similar studies will examine the role of sodium channels to the amnestic and immobilizing effect of isoflurane. Amnesia will be evaluated using Pavlovian fear conditioning, and immobility by MAC, the minimum alveolar concentration of anesthetic producing immobility in response to a noxious stimulus in 50% of subjects.

本提案的重点是遗忘和固定效果的原型吸入