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.

该提案的重点是原型吸入剂的记忆删除和固定效果 麻醉剂异氟烷，将这些效果与其他麻醉剂的效果进行对比。这样的 提出对比以揭示吸入麻醉作用的机制。这 异氟醚产生行为效应的机制尚不清楚。异氟醚对许多离子通道的作用可能会导致失忆或不动。该项目在计划中 资助项目 (PPG) 发现，几个这样的通道可能不会调节不动，但 甘氨酸和 NMDA 受体以及钠通道仍然是合理的目标。尚未发现或排除任何受体或离子通道作为失忆症的主要介质。 因为许多 GABA 能药物（例如苯二氮卓类药物）和 NMDA 抑制剂具有 严重的遗忘效应，并且由于吸入麻醉剂对 GABAA 和 NMDA 受体都有这些影响，因此该提议假设吸入麻醉剂通过改变 GABAA 和/或 NMDA 受体功能来干扰记忆。建议使用转基因小鼠以及给予 GABAA 和 NMDA 受体调节剂的动物来检验这一假设。初步数据表明甘氨酸受体对异氟烷诱导的不动性有一定作用。这些研究将继续使用携带甘氨酸受体的敲入小鼠，这些受体对甘氨酸有正常反应，但异氟烷的作用不会增强。类似的研究将检验钠通道对异氟烷的记忆删除和固定作用的作用。失忆症将使用巴甫洛夫恐惧条件反射进行评估，而不动则通过 MAC 进行评估，即 50% 的受试者对有害刺激做出反应时产生不动的麻醉剂的最低肺泡浓度。