Sonner James M, Cascio Mike, Xing Yilei, Fanselow Michael S, Kralic Jason E, Morrow A Leslie, Korpi Esa R, Hardy Steven, Sloat Brian, Eger Edmond I, Homanics Gregg E
Department of Anesthesiology, University of California, San Francisco, San Francisco, California, USA.
Mol Pharmacol. 2005 Jul;68(1):61-8. doi: 10.1124/mol.104.009936. Epub 2005 Apr 15.
Inhaled anesthetics are believed to produce anesthesia by their actions on ion channels. Because inhaled anesthetics robustly enhance GABA A receptor (GABA(A)-R) responses to GABA, these receptors are considered prime targets of anesthetic action. However, the importance of GABA(A)-Rs and individual GABA(A)-R subunits to specific anesthetic-induced behavioral effects in the intact animal is unknown. We hypothesized that inhaled anesthetics produce amnesia, as assessed by loss of fear conditioning, by acting on the forebrain GABA(A)-Rs that harbor the alpha1 subunit. To test this, we used global knockout mice that completely lack the alpha1 subunit and forebrain-specific, conditional knockout mice that lack the alpha1 subunit only in the hippocampus, cortex, and amygdala. Both knockout mice were 75 to 145% less sensitive to the amnestic effects of the inhaled anesthetic isoflurane. These results indicate that alpha1-containing GABA(A)-Rs in the hippocampus, amygdala, and/or cortex influence the amnestic effects of inhaled anesthetics and may be an important molecular target of the drug isoflurane.
吸入麻醉药被认为通过作用于离子通道产生麻醉作用。由于吸入麻醉药能强烈增强γ-氨基丁酸A受体（GABA(A)-R）对γ-氨基丁酸（GABA）的反应，这些受体被视为麻醉作用的主要靶点。然而，在完整动物中，GABA(A)-Rs及单个GABA(A)-R亚基对特定麻醉诱导行为效应的重要性尚不清楚。我们假设吸入麻醉药通过作用于含有α1亚基的前脑GABA(A)-Rs产生遗忘，这通过恐惧条件反射的丧失来评估。为了验证这一点，我们使用了完全缺乏α1亚基的全身性敲除小鼠以及仅在海马体、皮质和杏仁核中缺乏α1亚基的前脑特异性条件性敲除小鼠。两种敲除小鼠对吸入麻醉药异氟烷的遗忘效应的敏感性均降低了75%至145%。这些结果表明，海马体、杏仁核和/或皮质中含α1的GABA(A)-Rs影响吸入麻醉药的遗忘效应，可能是药物异氟烷的一个重要分子靶点。
