Almeida L E, Pereira E F, Alkondon M, Fawcett W P, Randall W R, Albuquerque E X
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, MD 21201, Baltimore, USA.
Neuropharmacology. 2000 Oct;39(13):2740-55. doi: 10.1016/s0028-3908(00)00157-x.
This study was designed to investigate whether naltrexone, an opioid antagonist that has been evaluated clinically as a co-adjuvant in smoking cessation programs, affects function and expression of neuronal nicotinic receptors (nAChRs). Whole-cell current recordings from rat hippocampal neurons in culture and in slices demonstrated that alpha7 nAChRs can be inhibited non-competitively by naltrexone (IC(50) approximately 25 microM). The voltage dependence of the effect suggested that naltrexone acts as an open-channel blocker of alpha7 nAChRs. Naltrexone also inhibited activation of alpha4beta2 nAChRs in hippocampal neurons; however its IC(50) was higher ( approximately 141 microM). At a concentration as high as 300 microM (which is sufficient to block by 100% and 70% the activity of alpha7 and alpha4beta2 nAChRs, respectively), naltrexone had no effect on kainate and AMPA receptors, blocked by no more than 20% the activity of NMDA and glycine receptors, and reduced by 35% the activity of GABA(A) receptors. A 3-day exposure of cultured hippocampal neurons to naltrexone (30 microM) or nicotine (10 microM, a concentration that fully desensitized alpha7 nAChRs) resulted in a 2-fold increase in the average amplitude of alpha7 nAChR-subserved currents. Naltrexone did not augment the maximal up-regulation of alpha7 nAChRs induced by nicotine, indicating that both drugs act via a common mechanism. In addition to increasing alpha7 nAChRs-mediated responses per neuron, nicotine increased the number of neurons expressing functional non-alpha7 nAChRs (probably alpha4beta2 nAChRs); this effect was blocked by naltrexone (0.3 and 30 microM). Therefore, naltrexone may affect dependence on cigarette smoking by differentially altering function and expression of alpha7 and alpha4beta2 nAChRs in the central nervous system.
本研究旨在调查纳曲酮（一种已在戒烟项目中作为辅助药物进行临床评估的阿片类拮抗剂）是否会影响神经元烟碱型受体（nAChRs）的功能和表达。来自培养的大鼠海马神经元以及脑片的全细胞电流记录表明，α7 nAChRs可被纳曲酮非竞争性抑制（半数抑制浓度[IC(50)]约为25微摩尔）。该效应的电压依赖性表明纳曲酮作为α7 nAChRs的开放通道阻滞剂发挥作用。纳曲酮还抑制海马神经元中α4β2 nAChRs的激活；然而其IC(50)更高（约为141微摩尔）。在高达300微摩尔的浓度下（该浓度足以分别100%和70%阻断α7和α4β2 nAChRs的活性），纳曲酮对海人藻酸受体和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体无影响，对N-甲基-D-天冬氨酸（NMDA）受体和甘氨酸受体的活性阻断不超过20%，并使γ-氨基丁酸A型（GABA(A)）受体的活性降低35%。将培养的海马神经元暴露于纳曲酮（3微摩尔）或尼古丁（10微摩尔，该浓度可使α7 nAChRs完全脱敏）3天，导致α7 nAChR介导的电流平均幅度增加2倍。纳曲酮并未增强尼古丁诱导的α7 nAChRs的最大上调，表明两种药物通过共同机制发挥作用。除了增加每个神经元中α7 nAChR介导的反应外，尼古丁还增加了表达功能性非α7 nAChRs（可能是α4β2 nAChRs）的神经元数量；该效应被纳曲酮（0.3和3微摩尔）阻断。因此，纳曲酮可能通过差异性改变中枢神经系统中α7和α4β2 nAChRs的功能和表达来影响对吸烟的依赖。
