Serotonin neurons in the median raphe nucleus bidirectionally regulate somatic signs of nicotine withdrawal in mice
Serotonin neurons in the median raphe nucleus bidirectionally regulate somatic signs of nicotine withdrawal in mice
复制标题
中缝核中的血清素神经元双向调节小鼠尼古丁戒断的躯体症状
DOI：
10.1016/j.bbrc.2021.05.052
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发表时间：
2021
影响因子：
3.1
通讯作者：
Yoshioka Mitsuhiro
中科院分区：
文献类型：
--
作者：
Nishitani Naoya;Ohmura Yu;Kobayashi Keita;Murashita Taichi;Yoshida Takayuki;Yoshioka Mitsuhiro
对于长期吸烟者，戒烟期间的尼古丁戒断症状可能导致复吸。在啮齿动物模型中，长期接触尼古丁会引起身体依赖性，而烟碱乙酰胆碱受体（nAChR）的急性拮抗作用会立即引发戒断症状。尽管中枢血清素能系统在尼古丁戒断中发挥着重要作用，但调节这些症状的确切血清素能中缝核仍然未知。我们使用仅在中枢血清素能神经元中表达古视紫红质 TP009 或通道视紫红质-2[C128S] 的转基因小鼠来选择性地操纵每个中缝核中的血清素能神经元。长期摄入尼古丁后，急性注射美加明（一种非特异性 nAChR 拮抗剂）会引发尼古丁戒断症状。躯体体征被用来衡量尼古丁戒断症状。与对照组小鼠相比，急性美加明给药显着增加了尼古丁摄入小鼠上睑下垂的发生率。中缝核（MRN）中的血清素能神经元的光遗传学抑制，而不是中缝背核（DRN）中的血清素能神经元，模仿了美加明沉淀尼古丁戒断期间观察到的症状，甚至在急性美加明注射后未接触过尼古丁的小鼠中也是如此。 MRN 中血清素能神经元的光遗传学激活几乎消除了饮用尼古丁小鼠的上睑下垂的发生。 MRN 中的血清素能神经元（而非 DRN 中的血清素能神经元）对于躯体症状（尼古丁戒断症状）的发生是必要的，并且这些神经元的激活可能作为预防尼古丁戒断的躯体表现的潜在治疗策略。
In chronic smokers, nicotine withdrawal symptoms during tobacco cessation can lead to smoking relapse. In rodent models, chronic exposure to nicotine elicited physical dependence, whereas acute antagonism of nicotinic acetylcholine receptors (nAChRs) immediately precipitated withdrawal symptoms. Although the central serotonergic system plays an important role in nicotine withdrawal, the exact serotonergic raphe nuclei regulating these symptoms remain unknown. We used transgenic mice expressing archaerhodopsinTP009 or channelrhodopsin-2[C128S] exclusively in the central serotonergic neurons to selectively manipulate serotonergic neurons in each raphe nucleus. Nicotine withdrawal symptoms were precipitated by an acute injection of mecamylamine, a nonspecific nAChR antagonist, following chronic nicotine consumption. Somatic signs were used as measures of nicotine withdrawal symptoms. Acute mecamylamine administration significantly increased ptosis occurrence in nicotine-drinking mice compared with that in control-drinking mice. Optogenetic inhibition of the serotonergic neurons in the median raphe nucleus (MRN), but not of those in the dorsal raphe nucleus (DRN), mimicked the symptoms observed during mecamylamine-precipitated nicotine withdrawal even in nicotine-naïve mice following the administration of acute mecamylamine injection. Optogenetic activation of the serotonergic neurons in the MRN nearly abolished the occurrence of ptosis in nicotine-drinking mice. The serotonergic neurons in the MRN, but not those in the DRN, are necessary for the occurrence of somatic signs, a nicotine withdrawal symptom, and the activation of these neurons may act as a potential therapeutic strategy for preventing the somatic manifestations of nicotine withdrawal.