Belelli Delia, Peden Dianne R, Rosahl Thomas W, Wafford Keith A, Lambert Jeremy J
Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom.
J Neurosci. 2005 Dec 14;25(50):11513-20. doi: 10.1523/JNEUROSCI.2679-05.2005.
Among hypnotic agents that enhance GABAA receptor function, etomidate is unusual because it is selective for beta2/beta3 compared with beta1 subunit-containing GABAA receptors. Mice incorporating an etomidate-insensitive beta2 subunit (beta(2N265S)) revealed that beta2 subunit-containing receptors mediate the enhancement of slow-wave activity (SWA) by etomidate, are required for the sedative, and contribute to the hypnotic actions of this anesthetic. Although the anatomical location of the beta2-containing receptors that mediate these actions is unknown, the thalamus is implicated. We have characterized GABAA receptor-mediated neurotransmission in thalamic nucleus reticularis (nRT) and ventrobasalis complex (VB) neurons of wild-type, beta2(-/-), and beta(2N265S) mice. VB but not nRT neurons exhibit a large GABA-mediated tonic conductance that contributes approximately 80% of the total GABAA receptor-mediated transmission. Consequently, although etomidate enhances inhibition in both neuronal types, the effect of this anesthetic on the tonic conductance of VB neurons is dominant. The GABA-enhancing actions of etomidate in VB but not nRT neurons are greatly suppressed by the beta(2N265S) mutation. The hypnotic THIP (Gaboxadol) induces SWA and at low, clinically relevant concentrations (30 nM to 3 microM) increases the tonic conductance of VB neurons, with no effect on VB or nRT miniature IPSCs (mIPSCs) or on the holding current of nRT neurons. Zolpidem, which has no effect on SWA, prolongs VB mIPSCs but is ineffective on the phasic and tonic conductance of nRT and VB neurons, respectively. Collectively, these findings suggest that enhancement of extrasynaptic inhibition in the thalamus may contribute to the distinct sleep EEG profiles of etomidate and THIP compared with zolpidem.
在增强GABAA受体功能的催眠药物中，依托咪酯不同寻常，因为与含β1亚基的GABAA受体相比，它对β2/β3具有选择性。整合了对依托咪酯不敏感的β2亚基（β(2N265S)）的小鼠显示，含β2亚基的受体介导依托咪酯对慢波活动（SWA）的增强作用，是产生镇静作用所必需的，并且对这种麻醉剂的催眠作用有贡献。尽管介导这些作用的含β2受体的解剖位置尚不清楚，但丘脑与之相关。我们已经对野生型、β2基因敲除型和β(2N265S)小鼠丘脑网状核（nRT）和腹侧基底复合体（VB）神经元中GABAA受体介导的神经传递进行了表征。VB神经元而非nRT神经元表现出较大的GABA介导的强直电导，约占GABAA受体介导的总传递的80%。因此，尽管依托咪酯增强了两种神经元类型的抑制作用，但这种麻醉剂对VB神经元强直电导的影响占主导地位。β(2N265S)突变极大地抑制了依托咪酯在VB神经元而非nRT神经元中增强GABA的作用。催眠药THIP（加波沙朵）可诱导SWA，并且在低的、临床相关浓度（30 nM至3 μM）下增加VB神经元的强直电导，对VB或nRT微小抑制性突触后电流（mIPSCs）或nRT神经元的钳制电流没有影响。对SWA无作用的唑吡坦可延长VB的mIPSCs，但分别对nRT和VB神经元的相位和强直电导无效。总体而言，这些发现表明，与唑吡坦相比，丘脑突触外抑制的增强可能导致依托咪酯和THIP不同的睡眠脑电图特征。
