Anesthetics discriminate between tonic and phasic gamma-aminobutyric acid receptors on hippocampal CA1 neurons.
Anesthetics discriminate between tonic and phasic gamma-aminobutyric acid receptors on hippocampal CA1 neurons.
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DOI：
10.1213/ane.0b013e3181904571
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发表时间：
2009-02
影响因子：
5.7
通讯作者：
Maclver, M. Bruce
中科院分区：
文献类型：
--
作者：
Bieda, Mark C.;Su, Henry;Maclver, M. Bruce
麻醉是由中枢神经系统（CNS）神经元信号传导抑制产生的，然而，这种抑制的作用机制仍不清楚。最近的研究表明，麻醉剂可以通过增加流经神经元膜上强效γ-氨基丁酸（GABAA）受体门控氯离子通道的电流来增强对中枢神经系统神经元的抑制。增强的强直抑制会导致麻醉药产生的中枢神经系统抑制，但这些受体的麻醉作用在多大程度上会导致中枢神经系统抑制仍有待确定。在本研究中，我们比较和对比了强直性和突触性 GABAA 受体在异氟烷和硫喷妥钠产生的 CNS 神经元功能抑制中的作用。在大鼠海马切片中，全细胞膜片钳记录用于研究麻醉对 CA1 神经元内在兴奋性的影响，群体尖峰记录用于研究对突触诱发放电的影响。选择这些反应是为了测试对 GABA 受体的麻醉作用是否会改变单个神经元放电和/或回路水平突触功能。使用 GABAA 拮抗剂加巴嗪选择性阻断阶段性（突触）GABA 受体，并使用氯离子通道阻断剂印防己毒素阻断强直反应。临床相关且等效浓度的硫喷妥钠和异氟烷可抑制 CA1 神经元突触诱发放电。通过用加巴嗪 (20 μM) 阻断突触 GABAA 受体，可以部分逆转这种抑制。硫喷妥钠诱发的抑郁症可逆转约 60%，但异氟烷诱发的抑郁症仅逆转约 20%。通过添加 100 μM 印防己毒素来阻断强直性 GABAA 受体，可使硫喷妥钠诱导的抑郁反应额外逆转 40%，但异氟烷抑制反应则未见额外逆转。响应于直接直流电流注入，硫喷妥钠抑制了 CA1 神经元放电，并且膜电导增加。这两种效应均可被印防己毒素逆转，但加巴嗪则不能逆转。相比之下，异氟烷既不会抑制电流诱发的放电，也不会改变 CA1 神经元的膜电导。这些结果表明全身麻醉药区分突触和强直 GABAA 受体。对相位和强直受体的作用结合起来抑制硫喷妥钠产生的回路反应，而异氟醚似乎仅对突触 GABA 受体的作用发挥重要作用。与这两种麻醉剂的其他已知作用位点一起，我们的结果支持多位点、特定于麻醉剂的麻醉作用机制。
Anesthesia is produced by a depression of neuronal signaling in the central nervous system (CNS), however, the mechanism(s) of action underlying this depression remain unclear. Recent studies have indicated that anesthetics can enhance inhibition of CNS neurons by increasing current flow through tonic gamma-aminobutyric acid (GABAA) receptor gated chloride channels in their membranes. Enhanced tonic inhibition would contribute to CNS depression produced by anesthetics, but it remains to be determined to what extent anesthetic actions at these receptors contribute to CNS depression. In the present study, we compared and contrasted the involvement of tonic versus synaptic GABAA receptors in the functional depression of CNS neurons produced by isoflurane and thiopental. In rat hippocampal slices, whole cell patch clamp recordings were used to study anesthetic effects on CA1 neuron intrinsic excitability, and population spike recordings were used to investigate effects on synaptically evoked discharge. These responses were chosen to test whether anesthetic effects on GABA receptors alter single neuron discharge and/or circuit level synaptic functioning. Phasic (synaptic) GABA receptors were selectively blocked using the GABAA antagonist gabazine and tonic responses were blocked using the chloride channel blocker picrotoxin. Clinically relevant and equi-effective concentrations of thiopental and isoflurane depressed CA1 neuron synaptically evoked discharge. This depression was partially reversed by blocking synaptic GABAA receptors with gabazine (20 μM). The thiopental-induced depression was reversed by ~ 60 %, but the isoflurane-induced depression was reversed by only ~ 20%. Blocking tonic GABAA receptors with the addition of 100 μM picrotoxin produced an additional 40 % reversal of the thiopental-induced depression, but no additional reversal was seen for isoflurane-depressed responses. In response to direct DC current injection, CA1 neuron discharge was depressed by thiopental and membrane conductance was increased. Both of these effects were reversed by picrotoxin, but not by gabazine. Isoflurane, in contrast, neither depressed current-evoked discharge, nor altered the membrane conductance of CA1 neurons. These results indicate that general anesthetics discriminate between synaptic and tonic GABAA receptors. Effects on both phasic and tonic receptors combined to depress circuit responses produced by thiopental, whereas only effects on synaptic GABA receptors appeared to play an important role for isoflurane. Together with the other known sites of action for these 2 anesthetics, our results support a multi-site, agent-specific mechanism for anesthetic actions.
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