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.
Highlights
High-affinity nicotinic acetylcholine receptor (nAChR) can incorporate additional subunits, including b3, a6, or a5 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 participate in aversive reactions to nicotine and the negative affective state experienced during nicotine withdrawal. nAChRs containing a3 and b4 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 a5 nAChR subunits are expressed
An a6* nAChR-selective antagonist blocked the expression of a nicotine withdrawal-induced conditioned place avoidance (CPA) and withdrawal-associated increases in anxiety-related behavior but did not modify the expression of physical withdrawal signs in mice (Jackson et al, 2009). These findings suggest that the same a6b2b3* nAChR subtype known to regulate the stimulatory effects of nicotine on striatal dopamine release is likely to undergo nicotine-induced adaptations in function and expression during chronic nicotine exposure, which contributes to the development of affective but not physical dependence on nicotine
These findings suggest that adaptive responses in b2*, b3*, and a6* nAChRs in the ventral tegmental area (VTA), leading to alterations in dopamine, corticotropin-releasing factor (CRF), GABA, and glutamate signaling in the accumbens, interpeduncular nucleus (IPn), and other reward and aversion relevant brain sites, drives the expression of affective but not physical components of nicotine withdrawal
Summary
NAChRs 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 a3 and b4 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 a5 nAChR subunits are 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. This article reviews the actions of nicotine in the brain that contribute to tobacco use disorder
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