Laboratory of Genetic Neuropharmacology, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts, USA.
Anesthesiology. 2013 Mar;118(3):562-76. doi: 10.1097/ALN.0b013e3182800d76.
γ-aminobutyric acid A (GABAA) receptors mediate the actions of several intravenous general anesthetics. However, the contribution of α3-containing GABAA receptors to the action of these drugs is unknown.
The authors compared anesthetic endpoints (hypnosis, immobility, hypothermia) in response to various intravenous anesthetics in mice lacking the α3 subunit of the GABAA receptor (α3 knockout) and in wild-type mice. Furthermore, the authors generated and analyzed conditional mutant mice expressing the GABAA receptor α3 subunit exclusively in noradrenergic neurons.
α3 knockout mice displayed decreased hypnotic and hypothermic responses to etomidate and midazolam, but an increased response to pentobarbital. The hypnotic response to ketamine was unaltered, whereas the hypothermic response was increased. In contrast, the hypnotic but not the hypothermic response to medetomidine was increased. The combination of ketamine/xylazine displayed increased hypnotic, immobilizing, and hypothermic effects in α3 knockout mice. Mice expressing the α3 subunit exclusively in noradrenergic neurons were generated to assess whether the lack of α3 subunits on noradrenergic neurons may be responsible for this effect. In these mice, the increases of the hypnotic and immobilizing actions induced by ketamine/xylazine were largely absent, whereas the increase in the hypothermic action was still present.
α3-containing GABAA receptors bidirectionally regulate essential anesthetic actions: they mediate anesthetic actions of etomidate and midazolam, known to selectively act at GABAA receptors, and they negatively constrain anesthetic actions of compounds with targets partly or exclusively distinct from GABAA receptors such as medetomidine, ketamine, and pentobarbital. Furthermore, our results indicate that α3-containing GABAA receptors on noradrenergic neurons may contribute to this constraint.
γ-氨基丁酸 A（GABAA）受体介导几种静脉全身麻醉药的作用。然而，α3 包含的 GABAA 受体在这些药物作用中的贡献尚不清楚。
作者比较了缺乏 GABAA 受体 α3 亚基（α3 敲除）的小鼠和野生型小鼠对各种静脉麻醉药的麻醉终点（催眠、不动、体温过低）的反应。此外，作者还生成并分析了在去甲肾上腺素能神经元中特异性表达 GABAA 受体 α3 亚基的条件性突变小鼠。
α3 敲除小鼠对依托咪酯和咪达唑仑的催眠和降温反应降低，但对戊巴比妥的反应增加。氯胺酮的催眠反应不变，但降温反应增加。相比之下，美托咪定的催眠但不降温反应增加。氯胺酮/二甲噻嗪的组合在 α3 敲除小鼠中显示出增加的催眠、固定和降温作用。为了评估缺乏去甲肾上腺素能神经元上的 α3 亚基是否可能是这种效应的原因，生成了仅在去甲肾上腺素能神经元中表达 α3 亚基的小鼠。在这些小鼠中，氯胺酮/二甲噻嗪诱导的催眠和固定作用的增加基本上消失，而降温作用的增加仍然存在。
α3 包含的 GABAA 受体双向调节基本的麻醉作用：它们介导依托咪酯和咪达唑仑的麻醉作用，已知这些药物选择性作用于 GABAA 受体，并且它们负向限制了与 GABAA 受体部分或完全不同的化合物的麻醉作用，如美托咪定、氯胺酮和戊巴比妥。此外，我们的结果表明，去甲肾上腺素能神经元上的 α3 包含的 GABAA 受体可能有助于这种限制。
