Review Article

Neural circuits and nicotinic acetylcholine receptors mediate the cholinergic regulation of midbrain dopaminergic neurons and nicotine dependence

Authors: Cheng Xiao1,2, Chun-yi Zhou1,2, Jin-hong Jiang1,2, Cui Yin1,2
1 School of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China
2 Jiangsu Province Key Laboratory in Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China
Correspondence to: Cheng Xiao:, Chun-yi Zhou:,
DOI: 10.1038/s41401-019-0299-4
Received: 27 May 2019
Accepted: 6 August 2019
Advance online: 25 September 2019


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.
Keywords: midbrain DA neurons; mesopontine; cholinergic neurons; nicotinic acetylcholine receptors; neural circuits; nicotine reward and dependence; smoking intervention

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