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

Date Published: September 25, 2019

Publisher: Springer Singapore

Author(s): Cheng Xiao, Chun-yi Zhou, Jin-hong Jiang, Cui Yin.


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.

Partial Text

Cigarette smoking causes the most preventable diseases worldwide [1]. Nicotine is a bioactive compound in cigarettes that exerts rewarding effects by activating nicotinic acetylcholine receptors (nAChRs) in the central nervous system. Repetitive nicotine intake modifies plasticity in the central nervous system, leading to nicotine dependence [2]. Among the brain regions responsive to nicotine, the midbrain contains dopaminergic (DA) neurons, which have been implicated in a wide range of physiological functions, including reward processing, reinforcement learning, aversion avoidance, and motivation [3, 4]. Therefore, the midbrain is unique in that it is the target of nicotine for the development and maintenance of nicotine dependence.

Midbrain DA neurons are distributed in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc), and they receive dense cholinergic innervation from mesopontine cholinergic nuclei, including the pedunculopontine tegmental nucleus (PPN) and the laterodorsal tegmental nucleus (LDT) [5–8]. Previous studies have revealed that the mesopontine cholinergic innervation of midbrain DA neurons is topographically organized and forms anatomical substrates for the independent regulation of different behaviors by the mesopontine cholinergic system [6, 8, 9].

The stimulation of cholinergic afferents results in multiphasic alterations in neuronal firing in vivo [24–27]. Stimulating PPN neurons with kainate increases the firing rate of DA neurons in the ipsilateral substantia nigra by activating nAChRs [27]. Foster and Blaha applied 35 Hz electrical stimulation to the LDT and PPN every other second for 1 min and recorded triphasic alterations (the first increase, second decrease, and third sustained elevation) in dopamine levels in the nucleus accumbens (NAcc) and the caudate putamen (CPu), indicating that stimulating these cholinergic nuclei modulates midbrain DA neurons [25, 26]. Pharmacological evidence has revealed that these responses are, respectively, mediated by nAChRs in the VTA/SN, mAChRs in the LDT/PPN, and mAChRs in the VTA/SN. Therefore, nAChRs and mAChRs in the VTA/SN mediate the fast and slow excitation of VTA/SN neurons, respectively, following stimulation of the PPN and LDT. It is noteworthy that PPN and LDT cholinergic projections not only regulate midbrain DA neurons but are also modulated by nicotine. In the PPN and LDT, nicotine activates nAChRs in non-cholinergic neurons and indirectly modulates cholinergic neurons [28]. This circuitry contributes to nicotine reinforcement learning because lesions of PPN cholinergic neurons or the inhibition of nAChRs in the PPN reduces nicotine self-administration in rats [29].

Acute exposure to nicotine activates nAChRs, while chronic nicotine exposure modifies nAChRs, conferring various physiological outcomes. Chronic nicotine exposure regimens include continuous nicotine administration [72–74], repeated intermittent exposure [75], self-administration [76], and yoked-nicotine administration [74]. To evaluate the effects of chronic nicotine on nAChRs, the levels of nAChRs were quantified with an epibatidine/nicotine binding assay [74, 75, 77] and by studying the levels of fluorescent protein-tagged nAChR subunits [72, 76]. Under different exposure paradigms, chronic nicotine similarly upregulates nAChRs, but with selectivity for nAChR subtypes, the stoichiometry of nAChRs, cell types, and cell compartments [72, 73, 78, 79].

Nicotine dependence is a chronically relapsing behavioral disorder with typical manifestations of drug addiction, such as compulsive cravings for nicotine, a loss of control to limit nicotine intake, and withdrawal-like symptoms after access to nicotine is prevented [2, 85]. The rewarding and reinforcing effects of nicotine involve midbrain neurons and can be measured with nicotine-conditioned place preference and nicotine self-administration [2, 85]. Withdrawal symptoms after nicotine abstinence are regulated by the extended amygdala and MHb-IPN pathway [85, 86]. Accumulating evidence has shown that different subtypes of nAChRs play distinct roles in the effects of nicotine.