Nicotine at concentrations found in cigarette smokers activates and desensitizes nicotinic acetylcholine receptors in CA1 interneurons of rat hippocampus
Nicotine at concentrations found in cigarette smokers activates and desensitizes nicotinic acetylcholine receptors in CA1 interneurons of rat hippocampus
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DOI：
10.1016/s0028-3908(00)00156-8
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发表时间：
2000-01-01
影响因子：
4.7
通讯作者：
Albuquerque, EX
中科院分区：
文献类型：
--
作者：
Alkondon, M;Pereira, EFR;Albuquerque, EX
吸烟对行为的影响归因于尼古丁与大脑烟碱型乙酰胆碱受体(NAChRs)的相互作用。然而，nAChR在发育和成熟的大脑中的功能受到吸烟者尼古丁水平(50-500 NM)影响的机制尚不清楚。因此，本研究的目的是确定尼古丁对脑中两个主要亚型α7和α4β2 nAChRs的浓度和时间依赖效应，这两种亚型在大鼠海马片CA1中间神经元中自然表达。只有在大于或等于5um的浓度下，尼古丁(应用于6-60 S)才能在表达α7 nAChRs的放射层中间神经元上诱发动作电位或可测量的全细胞电流(EC_(50)=158um)。尼古丁(0.5-2.5um)连续暴露10-15min可抑制胆碱(10 MM)诱发的α7nAChR介导的电流(IC50=640 nM)。尼古丁(大于或等于0.125微米)作用于神经元1-5分钟，可引起陷窝分子间层神经元缓慢脱敏的全细胞电流(EC_(50)=3.2微米)，这种效应是由α4β2 nAChRs介导的。尼古丁(0.125~0.5um)也可通过激活α4β2nAChRs，增加辐射层中间神经元GABA能突触后电流(PSCs)的频率和幅度。然而，暴露于尼古丁(0.25-0.5微米)10-15分钟可导致α4β2 nAChRs的脱敏。提示纳摩尔浓度的尼古丁在急性摄入后通过α4β2 nAChRs激活和α7 nAChRs脱敏的去抑制机制抑制锥体细胞的抑制性输入，而在慢性摄入后通过脱敏导致两种受体亚型的上调。这些发现对吸烟者体内尼古丁的行为有直接的影响。(C)2000爱思唯尔科学有限公司。保留所有权利。
Behavioral effects of cigarette smoking are attributed to the interactions of nicotine with brain nicotinic acetylcholine receptors (nAChRs). However, the mechanisms by which nAChR function in developing and mature brain is affected by a smoker's level of nicotine (50-500 nM) remain unclear. Thus, the objective of this study was to determine the concentration- and time-dependent effects of nicotine on alpha7 and alpha4 beta2 nAChRs, the two major brain subtypes, natively expressed in CA1 interneurons of rat hippocampal slices. Only at concentrations greater than or equal to5 muM did nicotine (applied for 6-60 s) elicit action potentials or measurable whole-cell currents (EC50=158 muM) in stratum radiatum interneurons that express alpha7 nAChRs. Continuous exposure for 10-15 min of the neurons to nicotine (0.5-2.5 muM) inhibited alpha7 nAChR-mediated currents (IC50=640 nM) evoked by choline (10 mM). Nicotine (greater than or equal to0.125 muM) applied to the neurons for 1-5 min induced slowly desensitizing whole-cell currents (EC50=3.2 muM) in stratum lacunosum moleculare interneurons; this effect was mediated by alpha4 beta2 nAChRs. Also via activation of alpha4 beta2 nAChRs, nicotine (0.125-0.5 muM) increased the frequency and amplitude of GABAergic postsynaptic currents (PSCs) in stratum radiatum interneurons. However, exposure of the neurons for 10-15 min to nicotine (0.25-0.5 muM) resulted in desensitization of alpha4 beta2 nAChRs. It is suggested that nanomolar concentrations of nicotine after acute intake suppress inhibitory inputs to pyramidal cells through a disinhibitory mechanism involving activation of alpha4 beta2 nAChRs and desensitization of alpha7 nAChRs, and after chronic intake leads to up-regulation of both receptor subtypes via desensitization. These findings have direct implications to the actions of nicotine in cigarette smokers. (C) 2000 Elsevier Science Ltd. All rights reserved.