Sonner James M, Werner David F, Elsen Frank P, Xing Yilei, Liao Mark, Harris R Adron, Harrison Neil L, Fanselow Michael S, Eger Edmond I, Homanics Gregg E
Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94143-0464, USA.
Anesthesiology. 2007 Jan;106(1):107-13. doi: 10.1097/00000542-200701000-00019.
Enhancement of the function of gamma-aminobutyric acid type A receptors containing the alpha1 subunit may underlie a portion of inhaled anesthetic action. To test this, the authors created gene knock-in mice harboring mutations that render the receptors insensitive to isoflurane while preserving sensitivity to halothane.
The authors recorded miniature inhibitory synaptic currents in hippocampal neurons from hippocampal slices from knock-in and wild-type mice. They also determined the minimum alveolar concentration (MAC), and the concentration at which 50% of animals lost their righting reflexes and which suppressed pavlovian fear conditioning to tone and context in both genotypes.
Miniature inhibitory postsynaptic currents decayed more rapidly in interneurons and CA1 pyramidal cells from the knock-in mice compared with wild-type animals. Isoflurane (0.5-1 MAC) prolonged the decay phase of miniature inhibitory postsynaptic currents in neurons of the wild-type mice, but this effect was significantly reduced in neurons from knock-in mice. Halothane (1 MAC) slowed the decay of miniature inhibitory postsynaptic current in both genotypes. The homozygous knock-in mice were more resistant than wild-type controls to loss of righting reflexes induced by isoflurane and enflurane, but not to halothane. The MAC for isoflurane, desflurane, and halothane did not differ between knock-in and wild-type mice. The knock-in mice and wild-type mice did not differ in their sensitivity to isoflurane for fear conditioning.
gamma-Aminobutyric acid type A receptors containing the alpha1 subunit participate in the inhibition of the righting reflexes by isoflurane and enflurane. They are not, however, involved in the amnestic effect of isoflurane or immobilizing actions of inhaled agents.
含有α1亚基的γ-氨基丁酸A型受体功能增强可能是吸入麻醉药部分作用的基础。为验证这一点，作者构建了基因敲入小鼠，其携带的突变使受体对异氟烷不敏感，而对氟烷仍保持敏感。
作者记录了敲入小鼠和野生型小鼠海马切片中海马神经元的微小抑制性突触电流。他们还测定了最低肺泡有效浓度（MAC），以及50%的动物失去翻正反射且抑制两种基因型对音调及环境的巴甫洛夫恐惧条件反射时的浓度。
与野生型动物相比，敲入小鼠中间神经元和CA1锥体细胞的微小抑制性突触后电流衰减更快。异氟烷（0.5 - 1 MAC）可延长野生型小鼠神经元微小抑制性突触后电流的衰减期，但在敲入小鼠的神经元中这种作用显著减弱。氟烷（1 MAC）可减慢两种基因型小鼠微小抑制性突触后电流的衰减。纯合敲入小鼠比野生型对照对异氟烷和恩氟烷诱导的翻正反射丧失更具抵抗力，但对氟烷不敏感。敲入小鼠和野生型小鼠对异氟烷、地氟烷和氟烷的MAC无差异。敲入小鼠和野生型小鼠对异氟烷恐惧条件反射的敏感性无差异。
含有α1亚基的γ-氨基丁酸A型受体参与异氟烷和恩氟烷对翻正反射的抑制作用。然而，它们不参与异氟烷的遗忘效应或吸入药物的制动作用。
