Medications that target the noradrenergic system are important therapeutics for depression and anxiety disorders. More recently, clinical studies have shown that the α2-noradrenergic receptor (α2AR) agonist guanfacine can decrease stress-induced smoking relapse during acute abstinence, suggesting that targeting the noradrenergic system may aid in smoking cessation through effects on stress pathways in the brain. Acetylcholine (ACh), like the nicotine in tobacco, acts at nicotinic acetylcholine receptors (nAChRs) to regulate behaviors related to anxiety and depression. We therefore investigated interactions between guanfacine and ACh signaling in tests of anxiolytic and antidepressant efficacy in female and male C57BL/6J mice, focusing on the amygdala as a potential site of noradrenergic/cholinergic interaction. The antidepressant-like effects of guanfacine were blocked by shRNA-mediated knockdown of α2AR in amygdala. Knockdown of the high-affinity β2 nAChR subunit in amygdala also prevented antidepressant-like effects of guanfacine, suggesting that these behavioral effects require ACh signaling through β2-containing nAChRs in this brain area. Ablation of NE terminals prevented the anxiolytic- and antidepressant-like effects of the nicotinic partial agonist cytisine, whereas administration of the cholinesterase antagonist physostigmine induced a depression-like phenotype that was not altered by knocking down α2AR in the amygdala. These studies suggest that ACh and NE have opposing actions on behaviors related to anxiety and depression and that cholinergic signaling through β2-containing nAChRs and noradrenergic signaling through α2a receptors in neurons of the amygdala are critical for regulation of these behaviors.

中文翻译：

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杏仁核中去甲肾上腺素能和胆碱能信号之间的相互作用调节小鼠的焦虑和抑郁相关行为。

靶向去甲肾上腺素能系统的药物是治疗抑郁症和焦虑症的重要疗法。最近，临床研究表明，α2-去甲肾上腺素能受体（α2AR）激动剂胍法辛可以减少急性戒断期间压力诱发的吸烟复发，这表明靶向去甲肾上腺素能系统可以通过影响大脑中的应激途径来帮助戒烟。乙酰胆碱（ACh）像烟草中的尼古丁一样，作用于烟碱乙酰胆碱受体（nAChR），以调节与焦虑和抑郁相关的行为。因此，我们在雌性和雄性C57BL / 6J小鼠的抗焦虑和抗抑郁功效测试中研究了胍法辛和ACh信号之间的相互作用，重点是杏仁核作为去甲肾上腺素/胆碱能相互作用的潜在位点。shRNA介导的杏仁核中α2AR的敲低阻断了胍法辛的抗抑郁样作用。杏仁核中高亲和力β2nAChR亚基的敲低也阻止了胍法辛的抗抑郁样作用，表明这些行为作用需要该脑区域中通过含β2的nAChRs进行ACh信号传导。NE末端的消融阻止了烟碱型部分激动剂胱氨酸的抗焦虑和抗抑郁样作用，而胆碱酯酶拮抗剂毒扁豆碱的给药则诱导了抑郁样表型，但不能通过敲低杏仁核中的α2AR而改变。