Attenuation of nicotine taking and seeking in rats by the stoichiometry-selective alpha4beta2 nicotinic acetylcholine receptor positive allosteric modulator NS9283.
Attenuation of nicotine taking and seeking in rats by the stoichiometry-selective alpha4beta2 nicotinic acetylcholine receptor positive allosteric modulator NS9283.
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化学计量选择性 α4β2 烟碱乙酰胆碱受体正变构调节剂 NS9283 减弱大鼠体内尼古丁的摄取和寻找。
DOI：
10.1007/s00213-016-4475-7
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发表时间：
2017
影响因子：
3.4
通讯作者：
Schmidt,HeathD
中科院分区：
文献类型：
--
作者：
Maurer,JohnJ;Sandager-Nielsen,Karin;Schmidt,HeathD
尼古丁的奖赏和强化作用在很大程度上是通过激活神经元α4β2* 烟碱乙酰胆碱受体（nAChR）产生的，nAChR是由不同化学计量的α4和β2亚基组成的五聚体蛋白复合物。目的NS9283是一类化学计量选择性正变构调节剂（positive allosteric modulators，PAMs），可选择性结合α4β2 nAChRs（3（α4）2（β2）nAChRs）。本实验旨在确定NS 9283对尼古丁自我给药和尼古丁寻求行为（吸烟复吸的动物模型）的恢复的影响。蔗糖自我管理和恢复的平行研究进行了单独的大鼠队列，以确定是否NS 9283的影响推广到其他reinforced behaviors.ResultsAcute和重复管理的NS 9283剂量依赖性减少尼古丁自我管理和恢复在雄性Sprague道利大鼠。这些作用是更特异性的，因为没有观察到NS 9283对蔗糖自我施用和恢复的作用。NS 9283也未能替代尼古丁支持自我给药行为，这表明在测试的剂量下，单独的NS 9283没有增强作用。这些结果提供了令人信服的证据，即化学计量选择性的3（α4）2（β2）nAChR PAM减弱了大鼠的尼古丁摄入和寻求，并表明靶向3（α4）2（β2）nAChRs可能代表预防吸烟复发的有希望的治疗策略。
RationaleThe rewarding and reinforcing effects of nicotine are produced, in large part, by activation of neuronal α4β2* nicotinic acetylcholine receptors (nAChRs), pentameric protein complexes comprised of different stoichiometries of α4 and β2 subunits. However, little is known about the functional role of distinct subtypes of α4β2* nAChRs in nicotine addiction.ObjectivesNS9283 represents a new class of stoichiometry-selective positive allosteric modulators (PAMs) that selectively bind to α4β2 nAChRs containing three α4 and two β2 subunits (3(α4)2(β2) nAChRs). The present experiments were designed to determine the effects of NS9283 on nicotine self-administration and the reinstatement of nicotine-seeking behavior, an animal model of smoking relapse. Parallel studies of sucrose self-administration and reinstatement were conducted in separate cohorts of rats to determine if the effects of NS9283 generalized to other reinforced behaviors.ResultsAcute and repeated administration of NS9283 dose-dependently reduced nicotine self-administration and reinstatement in male Sprague Dawley rats. These effects were reinforcer specific as no effects of NS9283 on sucrose self-administration and reinstatement were noted. NS9283 also failed to substitute for nicotine in supporting self-administration behavior suggesting that, at the doses tested, NS9283 alone is not reinforcing.ConclusionTaken together, these results provide compelling evidence that stoichiometry-selective PAMs of 3(α4)2(β2) nAChRs attenuate nicotine taking and seeking in rats and suggest that targeting 3(α4)2(β2) nAChRs may represent a promising therapeutic strategy for preventing smoking relapse.