Alkondon M, Pereira E F, Almeida L E, Randall W R, Albuquerque E X
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Neuropharmacology. 2000 Oct;39(13):2726-39. doi: 10.1016/s0028-3908(00)00156-8.
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 alpha4beta2 nAChRs, the two major brain subtypes, natively expressed in CA1 interneurons of rat hippocampal slices. Only at concentrations > or =5 microM did nicotine (applied for 6-60 s) elicit action potentials or measurable whole-cell currents (EC(50)=158 microM) in stratum radiatum interneurons that express alpha7 nAChRs. Continuous exposure for 10-15 min of the neurons to nicotine (0.5-2.5 microM) inhibited alpha7 nAChR-mediated currents (IC(50)=640 nM) evoked by choline (10 mM). Nicotine (> or =0.125 microM) applied to the neurons for 1-5 min induced slowly desensitizing whole-cell currents (EC(50)=3.2 microM) in stratum lacunosum moleculare interneurons; this effect was mediated by alpha4beta2 nAChRs. Also via activation of alpha4beta2 nAChRs, nicotine (0.125-0.5 microM) 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 microM) resulted in desensitization of alpha4beta2 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 alpha4beta2 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.
吸烟的行为效应归因于尼古丁与脑烟碱型乙酰胆碱受体（nAChRs）的相互作用。然而，吸烟者体内尼古丁水平（50 - 500 nM）影响发育中和成熟大脑中nAChR功能的机制仍不清楚。因此，本研究的目的是确定尼古丁对α7和α4β2 nAChRs这两种主要脑亚型的浓度和时间依赖性效应，这两种亚型在大鼠海马切片CA1中间神经元中天然表达。仅在浓度≥5 μM时，尼古丁（施加6 - 60秒）才会在表达α7 nAChRs的辐射层中间神经元中引发动作电位或可测量的全细胞电流（EC50 = 158 μM）。将神经元持续暴露于尼古丁（0.5 - 2.5 μM）10 - 15分钟会抑制胆碱（10 mM）诱发的α7 nAChR介导的电流（IC50 = 640 nM）。尼古丁（≥0.125 μM）施加于神经元1 - 5分钟会在分子层空泡状中间神经元中诱导缓慢脱敏的全细胞电流（EC50 = 3.2 μM）；这种效应由α4β2 nAChRs介导。同样通过激活α4β2 nAChRs，尼古丁（0.125 - 0.5 μM）增加了辐射层中间神经元中GABA能突触后电流（PSCs）的频率和幅度。然而，将神经元暴露于尼古丁（0.25 - 0.5 μM）10 - 15分钟会导致α4β2 nAChRs脱敏。有人提出，急性摄入后纳摩尔浓度的尼古丁通过涉及激活α4β2 nAChRs和α7 nAChRs脱敏的去抑制机制抑制对锥体细胞的抑制性输入，而慢性摄入后会通过脱敏导致两种受体亚型上调。这些发现对吸烟者体内尼古丁的作用有直接影响。
