Mennerick S, Jevtovic-Todorovic V, Todorovic S M, Shen W, Olney J W, Zorumski C F
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 1998 Dec 1;18(23):9716-26. doi: 10.1523/JNEUROSCI.18-23-09716.1998.
Nitrous oxide (N2O; laughing gas) has been a widely used anesthetic/analgesic since the 19th century, although its cellular mechanism of action is not understood. Here we characterize the effects of N2O on excitatory and inhibitory synaptic transmission in microcultures of rat hippocampal neurons, a preparation in which anesthetic effects on monosynaptic communication can be examined in a setting free of polysynaptic network variables. Eighty percent N2O occludes peak NMDA receptor-mediated (NMDAR) excitatory autaptic currents (EACs) with no effect on the NMDAR EAC decay time course. N2O also mildly depresses AMPA receptor-mediated (AMPAR) EACs. We find that N2O inhibits both NMDA and non-NMDA receptor-mediated responses to exogenous agonist. The postsynaptic blockade of NMDA receptors exhibits slight apparent voltage dependence, whereas the blockade of AMPA receptors is not voltage dependent. Although the degree of ketamine and Mg2+ blockade of NMDA-induced responses is dependent on permeant ion concentration, the degree of N2O blockade is not. We also observe a slight and variable prolongation of GABAA receptor-mediated (GABAR) postsynaptic currents likely caused by previously reported effects of N2O on GABAA receptors. Despite the effects of N2O on both NMDA and non-NMDA ionotropic receptors, glial glutamate transporter currents and metabotropic glutamate receptor-mediated synaptic depression are not affected. Paired-pulse depression, the frequency of spontaneous miniature excitatory synaptic currents, and high-voltage-activated calcium currents are not affected by N2O. Our results suggest that the effects of N2O on synaptic transmission are confined to postsynaptic targets.
自19世纪以来，一氧化二氮（N₂O；笑气）一直是一种广泛使用的麻醉剂/镇痛药，尽管其细胞作用机制尚不清楚。在此，我们描述了N₂O对大鼠海马神经元微培养物中兴奋性和抑制性突触传递的影响，在这种制备中，可以在没有多突触网络变量的环境中检查麻醉剂对单突触通讯的影响。80%的N₂O可阻断峰值N-甲基-D-天冬氨酸受体介导的（NMDAR）兴奋性自突触电流（EACs），而对NMDAR EAC衰减时间进程没有影响。N₂O也会轻度抑制α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体介导的（AMPAR）EACs。我们发现N₂O抑制NMDA和非NMDA受体对外源性激动剂的反应。NMDA受体的突触后阻断表现出轻微的明显电压依赖性，而AMPA受体的阻断则不依赖电压。尽管氯胺酮和Mg²⁺对NMDA诱导反应的阻断程度取决于通透离子浓度，但N₂O的阻断程度并非如此。我们还观察到γ-氨基丁酸A受体介导的（GABAR）突触后电流有轻微且可变的延长，这可能是由先前报道的N₂O对GABAA受体的作用引起的。尽管N₂O对NMDA和非NMDA离子型受体都有影响，但胶质谷氨酸转运体电流和代谢型谷氨酸受体介导的突触抑制不受影响。配对脉冲抑制、自发微小兴奋性突触电流的频率和高压激活钙电流不受N₂O影响。我们的结果表明，N₂O对突触传递的影响仅限于突触后靶点。
