Habenula cholinergic neurons regulate anxiety during nicotine withdrawal via nicotinic acetylcholine receptors.
Habenula cholinergic neurons regulate anxiety during nicotine withdrawal via nicotinic acetylcholine receptors.
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DOI：
10.1016/j.neuropharm.2016.03.039
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发表时间：
2016-08
影响因子：
4.7
通讯作者：
Tapper AR
中科院分区：
文献类型：
--
作者：
Pang X;Liu L;Ngolab J;Zhao-Shea R;McIntosh JM;Gardner PD;Tapper AR
内侧缰核 (MHb) 中的胆碱能神经元在尼古丁戒断期间调节焦虑，尽管 MHb 内在尼古丁戒断期间诱导情感行为的分子神经适应在很大程度上尚不清楚。 MHb 胆碱能神经元的独特之处在于它们强烈表达神经元烟碱乙酰胆碱受体 (nAChR)，尽管它们作为这些神经元中自身受体的行为作用尚未被描述。为了检验 MHb 胆碱能神经元中的 nAChR 信号传导可以调节焦虑的假设，我们在成年小鼠的 MHb 胆碱能神经元中选择性表达新的“功能获得”nAChR 亚基。表达这些突变型 nAChR 的小鼠表现出焦虑样行为增加，但通过 nAChR 拮抗剂阻断可以缓解这种行为。为了验证尼古丁戒断引起的焦虑可能是由 MHb 烟碱受体信号传导增加介导的假设，我们将 nAChR 亚型选择性拮抗剂注入尼古丁初次接触和戒断小鼠的 MHb 中。虽然拮抗剂对未接触过尼古丁的小鼠影响不大，但阻断 MHb 中的 α4β2 或 α6β2，而不是 α3β4 nAChR，可以减轻尼古丁戒断小鼠的焦虑。与行为结果一致，在也表达 α4 亚基的 MHb 神经元中，含有 α6 亚基的 nAChR 的功能表达增加。总之，这些数据表明，MHb 胆碱能神经元通过含有 α6 亚基的烟碱受体增加信号传导来调节尼古丁戒断引起的焦虑，并指出 MHb 胆碱能神经元中的 nAChR 作为戒烟治疗的分子靶点。
Cholinergic neurons in the medial habenula (MHb) modulate anxiety during nicotine withdrawal although the molecular neuroadaptation(s) within the MHb that induce affective behaviors during nicotine cessation is largely unknown. MHb cholinergic neurons are unique in that they robustly express neuronal nicotinic acetylcholine receptors (nAChRs), although their behavioral role as autoreceptors in these neurons has not been described. To test the hypothesis that nAChR signaling in MHb cholinergic neurons could modulate anxiety, we expressed novel "gain of function" nAChR subunits selectively in MHb cholinergic neurons of adult mice. Mice expressing these mutant nAChRs exhibited increased anxiety-like behavior that was alleviated by blockade with a nAChR antagonist. To test the hypothesis that anxiety induced by nicotine withdrawal may be mediated by increased MHb nicotinic receptor signaling, we infused nAChR subtype selective antagonists into the MHb of nicotine naïve and withdrawn mice. While antagonists had little effect on nicotine naïve mice, blocking α4β2 or α6β2, but not α3β4 nAChRs in the MHb alleviated anxiety in mice undergoing nicotine withdrawal. Consistent with behavioral results, there was increased functional expression of nAChRs containing the α6 subunit in MHb neurons that also expressed the α4 subunit. Together, these data indicate that MHb cholinergic neurons regulate nicotine withdrawal-induced anxiety via increased signaling through nicotinic receptors containing the α6 subunit and point toward nAChRs in MHb cholinergic neurons as molecular targets for smoking cessation therapeutics.