School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
Jiangsu Province Key Laboratory in Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
Acta Pharmacol Sin. 2020 Jan;41(1):1-9. doi: 10.1038/s41401-019-0299-4. Epub 2019 Sep 25.
Midbrain dopaminergic (DA) neurons are governed by an endogenous cholinergic system, originated in the mesopontine nuclei. Nicotine hijacks nicotinic acetylcholine receptors (nAChRs) and interferes with physiological function of the cholinergic system. In this review, we describe the anatomical organization of the cholinergic system and the key nAChR subtypes mediating cholinergic regulation of DA transmission and nicotine reward and dependence, in an effort to identify potential targets for smoking intervention. Cholinergic modulation of midbrain DA systems relies on topographic organization of mesopontine cholinergic projections, and activation of nAChRs in midbrain DA neurons. Previous studies have revealed that α4, α6, and β2 subunit-containing nAChRs expressed in midbrain DA neurons and their terminals in the striatum regulate firings of midbrain DA neurons and activity-dependent dopamine release in the striatum. These nAChRs undergo modification upon chronic nicotine exposure. Clinical investigation has demonstrated that partial agonists of these receptors elevate the success rate of smoking cessation relative to placebo. However, further investigations are required to refine the drug targets to mitigate unpleasant side-effects.
中脑多巴胺（DA）神经元受起源于脑桥中缝核的内源性胆碱能系统调控。尼古丁劫持烟碱型乙酰胆碱受体（nAChRs）并干扰胆碱能系统的生理功能。在这篇综述中，我们描述了胆碱能系统的解剖组织以及介导 DA 传递和尼古丁奖赏和依赖的胆碱能调节的关键 nAChR 亚型，以确定吸烟干预的潜在靶点。中脑 DA 系统的胆碱能调制依赖于脑桥胆碱能投射的拓扑组织，以及中脑 DA 神经元中 nAChRs 的激活。先前的研究表明，中脑 DA 神经元及其在纹状体中的末梢表达的包含α4、α6 和β2 亚基的 nAChRs 调节中脑 DA 神经元的放电和纹状体中活性依赖的多巴胺释放。这些 nAChRs 在慢性尼古丁暴露后发生修饰。临床研究表明，这些受体的部分激动剂相对于安慰剂提高了戒烟的成功率。然而，需要进一步的研究来细化药物靶点以减轻不愉快的副作用。
