Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability

Abstract

Nicotine stimulates brain reward circuitries, most prominently the mesocorticolimbic dopamine system, and this action is considered critical in establishing and maintaining the tobacco smoking habit. Compounds that attenuate nicotine reward are considered promising therapeutic candidates for tobacco dependence, but many of these agents have other actions that limit their potential utility. Nicotine is also highly noxious, particularly at higher doses, and aversive reactions to nicotine after initial exposure can decrease the likelihood of developing a tobacco habit in many first time smokers. Nevertheless, relatively little is known about the mechanisms of nicotine aversion. The purpose of this review is to present recent new insights into the neurobiological mechanisms that regulate avoidance of nicotine. First, the role of the mesocorticolimbic system, so often associated with nicotine reward, in regulating nicotine aversion is highlighted. Second, genetic variation that modifies noxious responses to nicotine and thereby influences vulnerability to tobacco dependence, in particular variation in the CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster, will be discussed. Third, the role of the habenular complex in nicotine aversion, primarily medial habenular projections to the interpeduncular nucleus (IPN) but also lateral habenular projections to rostromedial tegmental nucleus (RMTg) and ventral tegmental area (VTA) are reviewed. Forth, brain circuits that are enriched in nAChRs, but whose role in nicotine avoidance has not yet been assessed, will be proposed. Finally, the feasibility of developing novel therapeutic agents for tobacco dependence that act not by blocking nicotine reward but by enhancing nicotine avoidance will be considered.

Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo–Interpeduncular Pathway in Nicotine Reinforcement in Mice

“…The role of β4* nAChRs has been investigated in certain nicotine-mediated behaviors, including nicotine-elicited seizures (Salas et al, 2004), aversion (Frahm et al, 2013;Slimak et al, 2014), anxiety (Salas et al, 2003), and withdrawal (Salas et al, 2004;Zhao-Shea et al, 2013), supporting the involvement of this subunit in regulating the aversive properties of nicotine (Fowler and Kenny, 2014). However, recent findings provide evidence for their role in the habenulo-interpeduncular pathway in nicotine reinforcement.…”

Unorthodox Acetylcholine Binding Sites Formed by α5 and β3 Accessory Subunits in α4β2* Nicotinic Acetylcholine Receptors

“…(␣4␤2) 2 ␣5 and (␣4␤2) 2 ␤3 nAChRs are found in the brain, as are (␣6␤2)(␣4␤2)␤3 nAChRs (3, 16 -20). ␣5 and ␤3 subunits have been implicated in nicotine addiction and are likely to be involved in many diseases associated with nAChRs (21)(22)(23)(24)(25)(26)). An ␣5 D398N and some ␤3 polymorphisms are associated with susceptibility to smoking (26,27).…”

Individual Variations in the Mechanisms of Nicotine Seeking: A Key for Research on Nicotine Dependence

“…For instance, a single-nucleotide polymorphism of the CHRNA5 gene has been associated with heavy smoking, which appears to be caused by a lowered sensitivity to the aversive effects of nicotine (Fowler and Kenny, 2014). In smokers who carry this CHRNA5 risk allele, compared with noncarriers, nicotine seeking through PF is increased, namely through withdrawal avoidance, whereas susceptibility to NPF, in particular cue-induced craving (Janes et al, 2012), is decreased.…”