Westphalen R I, Gomez R S, Hemmings H C
Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10021, USA.
Br J Anaesth. 2009 Mar;102(3):355-60. doi: 10.1093/bja/aen387. Epub 2009 Feb 2.
Inhaled anaesthetics (IAs) produce multiple dose-dependent behavioural effects including amnesia, hypnosis, and immobility in response to painful stimuli that are mediated by distinct anatomical, cellular, and molecular mechanisms. Amnesia is produced at lower anaesthetic concentrations compared with hypnosis or immobility. Nicotinic acetylcholine receptors (nAChRs) modulate hippocampal neural network correlates of memory and are highly sensitive to IAs. Activation of hippocampal nAChRs stimulates the release of norepinephrine (NE), a neurotransmitter implicated in modulating hippocampal synaptic plasticity. We tested the hypothesis that IAs disrupt hippocampal synaptic mechanisms critical to memory by determining the effects of isoflurane on NE release from hippocampal nerve terminals.
Isolated nerve terminals prepared from adult male Sprague-Dawley rat hippocampus were radiolabelled with [(3)H]NE and either [(14)C]GABA or [(14)C]glutamate and superfused at 37 degrees C. Release evoked by a 2 min pulse of 100 microM nicotine or 5 microM 4-aminopyridine was evaluated in the presence or absence of isoflurane and/or selective antagonists.
Nicotine-evoked NE release from rat hippocampal nerve terminals was nAChR- and Ca(2+)-dependent, involved both alpha7 and non-alpha7 subunit-containing nAChRs, and was partially dependent on voltage-gated Na(+) channel activation based on sensitivities to various antagonists. Isoflurane inhibited nicotine-evoked NE release (IC(50)=0.18 mM) more potently than depolarization-evoked NE release (IC(50)=0.27 mM, P=0.014), consistent with distinct presynaptic mechanisms of IA action.
Inhibition of hippocampal nAChR-dependent NE release by subanaesthetic concentrations of isoflurane supports a role in IA-induced amnesia.
吸入麻醉药（IAs）会产生多种剂量依赖性行为效应，包括失忆、催眠以及对疼痛刺激无反应，这些效应由不同的解剖学、细胞和分子机制介导。与催眠或无反应相比，在较低麻醉浓度下即可产生失忆。烟碱型乙酰胆碱受体（nAChRs）调节海马神经网络与记忆的关联，并且对吸入麻醉药高度敏感。海马nAChRs的激活会刺激去甲肾上腺素（NE）释放，NE是一种与调节海马突触可塑性有关的神经递质。我们通过确定异氟烷对海马神经末梢NE释放的影响，来检验吸入麻醉药通过破坏对记忆至关重要的海马突触机制这一假说。
从成年雄性Sprague-Dawley大鼠海马制备的离体神经末梢用[³H]NE以及[¹⁴C]GABA或[¹⁴C]谷氨酸进行放射性标记，并在37℃下进行灌流。在有或无异氟烷和/或选择性拮抗剂存在的情况下，评估由100μM尼古丁或5μM 4-氨基吡啶的2分钟脉冲诱发的释放。
尼古丁诱发的大鼠海马神经末梢NE释放依赖于nAChR和Ca²⁺，涉及含α7和不含α7亚基的nAChRs，并且基于对各种拮抗剂的敏感性，部分依赖于电压门控Na⁺通道激活。异氟烷抑制尼古丁诱发的NE释放（IC₅₀ = 0.18 mM）比去极化诱发的NE释放（IC₅₀ = 0.27 mM，P = 0.014）更有效，这与吸入麻醉药作用的不同突触前机制一致。
亚麻醉浓度的异氟烷抑制海马nAChR依赖性NE释放，支持其在吸入麻醉药诱导失忆中的作用。
