Wang Dian-Shi, Penna Antonello, Orser Beverley A
From the Department of Physiology (D.-S.W., A.P., B.A.O.) and Anesthesia (B.A.O.), University of Toronto, Toronto, Ontario, Canada; Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (B.A.O); and Department of Anaesthesia, Universidad de Chile, Santiago, Chile (A.P.).
Anesthesiology. 2017 Apr;126(4):666-677. doi: 10.1097/ALN.0000000000001483.
The "dissociative " general anesthetic ketamine is a well-known N-methyl-D-aspartate receptor antagonist. However, whether ketamine, at clinically relevant concentrations, increases the activity of inhibitory γ-aminobutyric acid (GABA) receptor type A (GABAA) receptors in different brain regions remains controversial. Here, the authors studied the effects of ketamine on synaptic and extrasynaptic GABAA receptors in hippocampal neurons. Ketamine modulation of extrasynaptic GABAA receptors in cortical neurons was also examined.
Whole cell currents were recorded from cultured murine neurons. Current evoked by exogenous GABA, miniature inhibitory postsynaptic currents, and currents directly activated by ketamine were studied.
Ketamine did not alter the amplitude, frequency, or kinetics of postsynaptic currents but increased a tonic inhibitory current generated by extrasynaptic GABAA receptors in hippocampal neurons. For example, ketamine (100 µM) increased the tonic current by 33.6 ± 6.5% (mean ± SEM; 95% CI, 18.2 to 48.9; n = 8, P < 0.001). Ketamine shifted the GABA concentration-response curve to the left, but only when GABAA receptors were activated by low concentrations of GABA (n = 6). The selective increase in tonic current was attributed to ketamine increasing the apparent potency of GABA at high-affinity extrasynaptic GABAA receptors. Ketamine also increased a tonic current in cortical neurons (n = 11). Ketamine directly gated the opening of GABAA receptors, but only at high concentrations that are unlikely to occur during clinical use.
Clinically relevant concentrations of ketamine increased the activity of high-affinity extrasynaptic GABAA receptors in the hippocampus and cortex, an effect that likely contributes to ketamine's neurodepressive properties.
“解离性”全身麻醉药氯胺酮是一种广为人知的N-甲基-D-天冬氨酸受体拮抗剂。然而，在临床相关浓度下，氯胺酮是否会增加不同脑区抑制性γ-氨基丁酸（GABA）A型（GABAA）受体的活性仍存在争议。在此，作者研究了氯胺酮对海马神经元突触和突触外GABAA受体的影响。还检测了氯胺酮对皮质神经元突触外GABAA受体的调节作用。
从培养的小鼠神经元记录全细胞电流。研究了外源性GABA诱发的电流、微小抑制性突触后电流以及氯胺酮直接激活的电流。
氯胺酮未改变突触后电流的幅度、频率或动力学，但增加了海马神经元中突触外GABAA受体产生的持续性抑制电流。例如，氯胺酮（100μM）使持续性电流增加了33.6±6.5%（平均值±标准误；95%置信区间，18.2至48.9；n = 8，P < 0.001）。氯胺酮将GABA浓度-反应曲线向左移动，但仅在低浓度GABA激活GABAA受体时出现（n = 6）。持续性电流的选择性增加归因于氯胺酮增加了GABA在高亲和力突触外GABAA受体上的表观效力。氯胺酮也增加了皮质神经元中的持续性电流（n = 11）。氯胺酮直接控制GABAA受体的开放，但仅在临床使用期间不太可能出现的高浓度下。
临床相关浓度的氯胺酮增加了海马和皮质中高亲和力突触外GABAA受体的活性，这一效应可能有助于氯胺酮的神经抑制特性。
