PLoS ONE：研究人员发现尼古丁减轻吸烟者焦虑的机制

近日，一项临床前数据表明一个特定烟碱受体的失活可能是一种有效的策略来帮助烟民戒烟，同时又不会让戒烟者感到焦虑，相关研究由弗吉尼亚联邦大学研究人员领导完成。

这些发现可能有一天帮助研究人员开发出新的疗法帮助吸烟者戒烟。烟民吸烟的原因有很多，但许多报告认为吸烟可以缓解焦虑，尽管吸烟会健康危害。

在这项发表在PLoS ONE杂志上的研究论文中，研究人员发现低剂量的尼古丁可以发挥烟碱受体阻滞剂类似的影响，都可以在动物模型中降低焦虑样行为。他们发现，一个特定的烟碱受体失活，可以减轻焦虑，该受体主要结合尼古丁的β2亚基。

药理学和毒理学系博士Darlene Brunzell说：这项研究表明，尼古丁可通过灭活，而不是激活高亲和力的烟碱受体。尼古丁的作用像一把钥匙，打开（激活）大脑中尼古丁受体。研究结果表明低剂量的尼古丁可能会阻断调节焦虑行为的特定受体亚型。

Brunzell和他的同事们正在进行研究希望确定哪些脑区域调节尼古丁的抗焦虑作用。从治疗角度来看，确定是否阻断β2亚型烟碱受体可以解除吸烟者焦虑将是非常重要的。

doi:10.1371/journal.pone.0048665
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Low Dose Nicotine and Antagonism of β2 Subunit Containing Nicotinic Acetylcholine Receptors Have Similar Effects on Affective Behavior in Mice

Shawn M. Anderson, Darlene H. Brunzell

Nicotine leads to both activation and desensitization (inactivation) of nicotinic acetylcholine receptors (nAChRs). This study tested the hypothesis that nicotine and a selective antagonist of β2*nAChRs would have similar effects on affective behavior. Adult C57BL/6J male mice were tested in a conditioned emotional response (CER) assay which evaluates the ability of an aversive stimulus to inhibit goal-directed behavior. Mice lever-pressed for a saccharin reinforcer according to a variable schedule of reinforcement during sessions in which two presentations of a compound light/tone conditioned stimulus (CS) co-terminated with a 0.1 or 0.3 mA, 0.5 s footshock unconditioned stimulus (US). During testing in the absence of the US, mice received doses of i.p. nicotine (0, 0.0032, 0.01, 0.032, 0.1 mg/kg) or a selective β2 subunit containing nAChR (β2*nAChR) antagonist dihydro-beta-erythroidine (0, 0.1, 0.3, 1.0, 3.0 mg/kg DHβE). There was a dose-dependent effect of nicotine revealing that only low doses (0.01, 0.032 mg/kg) increased CER suppression ratios (SR) in these mice. DHβE also dose-dependently increased SR at the 3 mg/kg dose. In ethological measures of fear?/anxiety-like behavior, these doses of nicotine and DHβE significantly reduced digging behavior in a marble burying task and 0.3 mg/kg DHβE promoted open-arm activity in the elevated plus maze. Doses of nicotine and DHβE that altered affective behavior had no effect on locomotor activity. Similar to previous reports with anxiolytic drugs, low dose nicotine and DHβE reversed SR in a CER assay, decreased digging in a marble burying assay and increased open arm activity in the elevated plus maze. This study provides evidence that inactivation of β2*nAChRs reduces fear-like and anxiety-like behavior in rodents and suggests that smokers may be motivated to smoke in part to desensitize their β2*nAChRs. These data further identify β2*nAChR antagonism as a potential therapeutic strategy for relief of negative affect and anxiety.