Neuroimaging and preclinical studies showing that nicotinic receptors (nAChR) may play a role in mood control has increased interest in targeting the cholinergic system for treatment of major depressive disorder. Indeed, modulation of nAChRs in the basolateral amygdala (BLA) are sufficient to produce an anti-immobility effect in the mouse tail suspension test. However, how α7 nAChR modulation impacts BLA neuronal activity in vivo as well as the downstream mechanisms involved in its mood-related effects are not understood. In this work, we used the unpredictable chronic mild stress (CMS) model to investigate the mechanisms underlying the antidepressant-like effect of an α7 nAChR full agonist on BLA-induced changes in dopaminergic neurotransmission. Male adult Sprague-Dawley rats were exposed to four weeks of CMS. Behavioral and electrophysiological experiments were performed within one week following stress. CMS exposure increased rats' immobility time in the forced swimming test, decreased the number of spontaneously active dopamine neurons in the ventral tegmental area and increased the firing rate of putative projection neurons in the BLA. Stress-induced behavioral and electrophysiological changes were reversed by a single systemic administration of PNU282987. In summary, our findings corroborate previous descriptions of a potential rapid antidepressant effect for the α7 nAChR full agonist. This effect appears to involve a mechanism distinct from those of classic antidepressants: normalization of BLA hyperactivity and, consequently, of DA hypofunction. These observations corroborate the role of α7 nAChR as a potential target for novel antidepressant drug development.

中文翻译：

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α7 烟碱受体完全激动剂逆转暴露于慢性轻度应激的大鼠基底外侧杏仁核过度活跃和多巴胺能神经元活动减弱

神经影像学和临床前研究表明，烟碱受体 (nAChR) 可能在情绪控制中发挥作用，这增加了针对胆碱能系统治疗重度抑郁症的兴趣。事实上，基底外侧杏仁核 (BLA) 中 nAChR 的调制足以在小鼠悬尾试验中产生抗不动效应。然而，α7 nAChR 调节如何影响体内 BLA 神经元活动以及涉及其情绪相关效应的下游机制尚不清楚。在这项工作中，我们使用不可预测的慢性轻度应激 (CMS) 模型来研究 α7 nAChR 完全激动剂对 BLA 诱导的多巴胺能神经传递变化的抗抑郁样作用的潜在机制。雄性成年 Sprague-Dawley 大鼠暴露于 4 周的 CMS。应激后一周内进行行为和电生理实验。CMS 暴露增加了大鼠在强迫游泳试验中的不动时间，减少了腹侧被盖区自发活跃的多巴胺神经元的数量，并增加了 BLA 中推定的投射神经元的放电率。单次全身给药 PNU282987 可逆转应激引起的行为和电生理变化。总之，我们的发现证实了之前关于 α7 nAChR 全激动剂的潜在快速抗抑郁作用的描述。这种作用似乎涉及与经典抗抑郁药不同的机制：BLA 过度活跃的正常化，因此，DA 功能减退。