Antidepressants noncompetitively inhibit nicotinic acetylcholine receptor function
Antidepressants noncompetitively inhibit nicotinic acetylcholine receptor function
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DOI：
10.1046/j.1471-4159.1999.0721117.x
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发表时间：
1999-03-01
影响因子：
4.7
通讯作者：
Lukas, RJ
中科院分区：
文献类型：
--
作者：
Fryer, JD;Lukas, RJ
烟碱型乙酰胆碱受体(NAChRs)是神经递质门控离子通道超家族的成员之一，在整个神经系统的化学信号传递中起着关键作用。本研究首次证实舍曲林(左洛复)、帕罗西汀(帕罗西汀)、奈法唑酮(舍拉酮)和文拉法辛(Effexor)对两个人和一只鸡的nAChR亚型的急性功能作用。本研究也证实了氟西汀(Prozac)对nAChR功能的阻断作用。用RB-86(+)外排试验检测TE671/RD细胞中人肌型nAChR、SH-SY5Y神经母细胞瘤细胞中人自主神经nAChR(α3β4α5+/-β2)以及天然nAChR缺失SH-EPI细胞中异源表达的鸡V274T突变体α7-nAChR的功能。每种药物在低到中等微摩尔范围内产生对人肌型和自主神经nAChRs的功能阻断，在中到高微摩尔范围产生对鸡V274T-α7-nAChR的功能阻断。通过增加每种药物测试的每一种nAChR亚型的激动剂浓度，功能阻断是无法克服的，这表明nAChR功能受到非竞争性抑制。这些研究开启了大脑中nAChR亚型可能成为治疗抗抑郁药物的靶点，并可能在临床抑郁症中发挥作用的可能性。
Nicotinic acetylcholine receptors (nAChRs) are diverse members of the neurotransmitter-gated ion channel superfamily and play critical roles in chemical signaling throughout the nervous system. The present study establishes for the first time the acute functional effects of sertraline (Zoloft), paroxetine (Paxil), nefazodone (Serzone), and venlafaxine (Effexor) on two human and one chick nAChR subtype. This study also confirms previous findings of nAChR functional block by fluoxetine (Prozac). Function of human muscle-type nAChR (alpha 1 beta gamma delta) in TE671/RD cells, human autonomic nAChR (alpha 3 beta 4 alpha 5 +/- beta 2) in SH-SY5Y neuroblastoma cells, or chick V274T mutant alpha 7-nAChR heterologously expressed in native nAChR-null SH-EPI epithelial cells was measured using Rb-86(+) efflux assays. Functional blockade of human muscle-type and autonomic nAChRs is produced by each of the drugs in the low to intermediate micromolar range, and functional blockade of chick V274T-alpha 7-nAChR is produced in the intermediate to high micromolar range. Functional blockade is insurmountable by increasing agonist concentrations at each nAChR subtype tested for each of these drugs, suggesting noncompetitive inhibition of nAChR function. These studies open the possibilities that nAChR subtypes in the brain could be targets for therapeutic antidepressants and could play roles in clinical depression.