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Review
. 2022 Jan;74(1):271-310.
doi: 10.1124/pharmrev.121.000299.

Neurobiological Mechanisms of Nicotine Reward and Aversion

Lauren Wills  1 , Jessica L Ables  1 , Kevin M Braunscheidel  1 , Stephanie P B Caligiuri  1 , Karim S Elayouby  1 , Clementine Fillinger  1 , Masago Ishikawa  1 , Janna K Moen  1 , Paul J Kenny  2
Affiliations
Review

Neurobiological Mechanisms of Nicotine Reward and Aversion

Lauren Wills et al. Pharmacol Rev. 2022 Jan.

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) regulate the rewarding actions of nicotine contained in tobacco that establish and maintain the smoking habit. nAChRs also regulate the aversive properties of nicotine, sensitivity to which decreases tobacco use and protects against tobacco use disorder. These opposing behavioral actions of nicotine reflect nAChR expression in brain reward and aversion circuits. nAChRs containing α4 and β2 subunits are responsible for the high-affinity nicotine binding sites in the brain and are densely expressed by reward-relevant neurons, most notably dopaminergic, GABAergic, and glutamatergic neurons in the ventral tegmental area. High-affinity nAChRs can incorporate additional subunits, including β3, α6, or α5 subunits, with the resulting nAChR subtypes playing discrete and dissociable roles in the stimulatory actions of nicotine on brain dopamine transmission. nAChRs in brain dopamine circuits also participate in aversive reactions to nicotine and the negative affective state experienced during nicotine withdrawal. nAChRs containing α3 and β4 subunits are responsible for the low-affinity nicotine binding sites in the brain and are enriched in brain sites involved in aversion, including the medial habenula, interpeduncular nucleus, and nucleus of the solitary tract, brain sites in which α5 nAChR subunits are also expressed. These aversion-related brain sites regulate nicotine avoidance behaviors, and genetic variation that modifies the function of nAChRs in these sites increases vulnerability to tobacco dependence and smoking-related diseases. Here, we review the molecular, cellular, and circuit-level mechanisms through which nicotine elicits reward and aversion and the adaptations in these processes that drive the development of nicotine dependence. SIGNIFICANCE STATEMENT: Tobacco use disorder in the form of habitual cigarette smoking or regular use of other tobacco-related products is a major cause of death and disease worldwide. This article reviews the actions of nicotine in the brain that contribute to tobacco use disorder.

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Figures

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Graphical abstract
Fig. 1
Fig. 1
Structural organization nicotinic acetylcholine receptors. (A) nAChRs are pentameric ligand-gated cationic channels. nAChR agonists, such as acetylcholine and nicotine, stabilize the receptor in the active confirmation associated with an open transmembrane pore permeable to calcium sodium (Na+), potassium (K+), and (Ca2+) ions. Prolonged stimulation of the receptor by agonists, such as nicotine, can drive the receptor into an inactive “desensitized” state. (B) Major stoichiometries of homopentameric or heteropentameric nAChRs expressed in the mammalian brain. The open white circles indicate that one of the adjacent subunits contained within the adjacent box are often incorporated into that nAChR subtype.
Fig. 2
Fig. 2
nAChR subtypes in brain dopamine systems. (A) Ventral midbrain dopaminergic neurons that project to the dorsal striatum or nucleus accumbens are stimulated by nicotine, resulting in increased dopamine transmission in the striatum. (B) Major stoichiometries of nAChRs predicted to be expressed by dopaminergic and GABAergic neurons in the ventral tegmental area. (C) Major stoichiometries of nAChRs predicted to be expressed by on the terminals of dopaminergic in the dorsal striatum and nucleus accumbens.
Fig. 3
Fig. 3
Dopamine mechanisms of nicotine reward and aversion. Dopamine neurons located in the medial VTA that receive input from the LHb and project to the mPFC regulate aversion-related behaviors. Dopamine neurons located in the lateral VTA that receive input from the PPTg and project to the medial portion of the NAc shell regulate reward-related behaviors. Shown in the insert is the putative nAChR-regulated excitatory and inhibitory input from the medial VTA to the lateral VTA, particularly in posterior (caudal) VTA, that may regulate reward-related responses to nicotine.
Fig. 4
Fig. 4
Organization and nAChR subtypes of the habenula-interpeduncular nucleus circuit. (A) Substance P–expressing neurons in in the dorsal region of the mHb and cholinergic neurons in the ventral mHb corelease glutamate and project to the IPn. The IPn send predominately GABAergic projections to the raphe nuclei, LDTg, and the nucleus incertus (NI). (B) Graphical representation of subregions of the interpeduncular nucleus, including the rostral, dorsolateral (DL), intermediate (I), and central (Cen) nuclei that receive input from cholinergic neurons in the ventral mHb. (C) Major stoichiometries of nAChRs predicted to be expressed presynaptically and postsynaptically in the mHb. (D) Major stoichiometries of nAChRs predicted to be expressed presynaptically and postsynaptically in the mHb in the IPn.
Fig. 5
Fig. 5
Habenula-interpeduncular mechanisms of nicotine aversion. Neurons in dorsal and ventral mHb express genes implicated in nicotine aversion and other aversion-related behavioral states. These genes include the orphan G-protein coupled receptor (GPCR) GPR151, the transcription factor TCF7L2, the phosphatase PP2A, neurokinins and their receptors, GABAB receptors, and NMDA receptors that contain NR3A subunits. The IPn receives inputs from the nTS that release the neuropeptide GLP-1, which facilitates excitatory transmission in the IPn and thereby enhances nicotine aversion. The IPn also receives inputs from VTA neurons that release dopamine and CRF, both of which increase IPn neural activity. Excitatory transmission in the IPn derived from excitatory inputs is regulated by locally released glycine, nitric oxide, and endocannabinoids. The IPn sends an inhibitory projection to the LDTg that inhibits cholinergic projections from the LDTg to the VTA, which results in decreased activity of VTA dopamine neurons. See main text for further details.
Fig. 6
Fig. 6
VTA, habenula, and interpeduncular nucleus contributions to nicotine withdrawal. Neurons in ventral mHb show increased excitability after chronic nicotine treatment, and inhibitors of HCN pacemaker channels can precipitate withdrawal in nicotine-dependent animals. In addition, α4* and α6* nAChR function in the mHb is upregulated in nicotinedependent animals. In the IPn, nicotine withdrawal is associated with increased activity of local GABAergic neurons that express somatostatin, and upregulated expression/function of β4*, α5*, and α2* nAChRs is thought to contribute to the expression of nicotine withdrawal. In the VTA, nicotine withdrawal is associated with decreased activity of dopamine neurons that project to the nucleus accumbens, increased production and release of the stress hormone CRF, and upregulated expression/function of β2*, α6* nAChRs.
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