Rau Vinuta, Iyer Sangeetha V, Oh Irene, Chandra Dev, Harrison Neil, Eger Edmond I, Fanselow Michael S, Homanics Gregg E, Sonner James M
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California 94143-0464, USA.
Anesth Analg. 2009 Dec;109(6):1816-22. doi: 10.1213/ANE.0b013e3181bf6ae6.
General anesthesia produces multiple end points including immobility, hypnosis, sedation, and amnesia. Tonic inhibition via gamma-aminobutyric acid type A receptors (GABA(A)-Rs) may play a role in mediating behavioral end points that are suppressed by low concentrations of anesthetics (e.g., hypnosis and amnesia). GABA(A)-Rs containing the alpha4 subunit are highly concentrated in the hippocampus and thalamus, and when combined with delta subunits they mediate tonic inhibition, which is sensitive to low concentrations of isoflurane.
In this study, we used a GABA(A) alpha4 receptor knockout mouse line to evaluate the contribution of alpha4-containing GABA(A)-Rs to the effects of immobility, hypnosis, and amnesia produced by isoflurane. Knockout mice and their wild-type counterparts were assessed on 3 behavioral tests: conditional fear (to assess amnesia), loss of righting reflex (to assess hypnosis), and the minimum alveolar concentration of inhaled anesthetic necessary to produce immobility in response to noxious stimulation in 50% of subjects (to assess immobility).
Genetic inactivation of the alpha4 subunit reduced the amnestic effect of isoflurane, minimally affected loss of righting reflex, and had no effect on immobility.
These results lend support to the hypothesis that different sites of action mediate different anesthetic end points and suggest that alpha4-containing GABA(A)-Rs are important mediators of the amnestic effect of isoflurane on hippocampal-dependent declarative memory.
全身麻醉会产生多种终点效应，包括不动、催眠、镇静和失忆。通过A型γ-氨基丁酸受体（GABA(A)-Rs）介导的强直性抑制可能在介导低浓度麻醉药所抑制的行为终点效应（如催眠和失忆）中发挥作用。含有α4亚基的GABA(A)-Rs在海马体和丘脑高度富集，当与δ亚基结合时，它们介导对低浓度异氟烷敏感的强直性抑制。
在本研究中，我们使用GABA(A)α4受体敲除小鼠品系来评估含α4的GABA(A)-Rs对异氟烷产生的不动、催眠和失忆效应的作用。在三项行为测试中对敲除小鼠及其野生型对照进行评估：条件性恐惧（以评估失忆）、翻正反射消失（以评估催眠）以及在50%的受试对象中产生对有害刺激无反应的不动状态所需的吸入麻醉药的最低肺泡浓度（以评估不动）。
α4亚基的基因失活降低了异氟烷的失忆效应，对翻正反射消失影响极小，对不动状态无影响。
这些结果支持了不同作用位点介导不同麻醉终点效应的假说，并表明含α4的GABA(A)-Rs是异氟烷对海马体依赖性陈述性记忆失忆效应的重要介导因子。
