AMNESTIC/IMMOBILIZING EFFECTS OF INHALED ANESTHETICS

吸入麻醉剂的遗忘/固定作用

• 批准号: 7110198
• 负责人: JAMES Michael SONNER
• 金额: $ 24.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7110198
• 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.

这项建议的重点是遗忘和固定的影响，原型吸入 麻醉剂，异氟烷，与其他麻醉剂的效果进行对比。等 提出对比来揭示吸入麻醉剂作用的机制。的 异氟烷产生其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导致健忘或不动。该项目在该计划中 项目资助（PPG）发现，几个这样的渠道可能不介导不动，但 甘氨酸和NMDA受体和钠通道仍然是合理的靶。没有受体或离子通道已被确定或排除为失忆症的主要介质。 因为许多GABA能药物（例如，苯二氮卓类）和NMDA抑制剂， 深刻的遗忘作用，并且因为吸入麻醉剂对GABAA和NMDA受体具有这些作用，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。使用基因修饰的小鼠和施用GABAA和NMDA受体调节剂的动物提出了对该假设的检验。初步数据表明甘氨酸受体对异氟烷诱导的不动性的作用。这些研究将使用携带甘氨酸受体的敲入小鼠继续进行，这些受体对甘氨酸有正常反应，但不受异氟烷的影响。类似的研究将检查钠通道对异氟烷的遗忘和固定作用的作用。将使用巴甫洛夫恐惧条件反射和MAC（50%受试者对有害刺激产生不动性的最低肺泡麻醉剂浓度）不动性评价震颤。