Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability

Highlights

• Role for nicotine aversion in controlling tobacco consumption highlighted.

• Genetics to tobacco addiction reviewed.

• Mesoaccumbens dopamine systems in nicotine aversion reviewed.

• Habenulo-interpeduncular system in nicotine aversion reviewed.

• Novel smoking cessation therapeutics that increase nicotine aversion considered.

Abstract

Nicotine stimulates brain reward circuitries, most prominently the mesocorticolimbic dopamine system, and this action plays a 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 identified. 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.

This article is part of a Special Issue entitled ‘NIDA 40th Anniversary Issue’.

Introduction

Nicotine is considered the major reinforcing component of tobacco responsible for addiction in human smokers (Stolerman and Jarvis, 1995), and it has been shown that humans, non-human primates and rodents will volitionally self-administer the drug (Corrigall and Coen, 1989, Goldberg et al., 1981, Harvey et al., 2004, Watkins et al., 1999). Volitionally consumed nicotine is known to stimulate activity in brain reward circuitries (Kenny and Markou, 2006), with this action thought to play a central role in the establishment and maintenance of the tobacco habit in human smokers. It is important to note, however, that instead of hedonic reactions, most smokers report their initial smoking experiences as unpleasant. This reflects the fact that in addition to its rewarding effects, nicotine is also highly noxious. Highlighting this dichotomous nature of nicotine, doses of the drug that support maximal rates of responding in squirrel monkeys also induce marked symptoms of aversion, such as vomiting, when the drug-taking habit is being acquired. Moreover, monkeys work to avoid non-contingent delivery of intravenous nicotine infusions even though they will work equally hard to obtain those same nicotine infusions when they are available for contingent delivery (Goldberg and Spealman, 1982, Goldberg and Spealman, 1983, Goldberg et al., 1981, Goldberg et al., 1983, Spealman and Goldberg, 1982). These aversive reactions to nicotine are important in the context of tobacco dependence, as stronger aversive reactions to nicotine after initial exposure are negatively correlated with the development of habitual tobacco use in first time smokers (Sartor et al., 2010).

Aversive responses to nicotine also appear to play key roles in determining the overall amounts of tobacco smoke consumed and patterns of intake. Indeed, when levels of nicotine contained in tobacco are varied, smokers are far more efficient at titrating their intake downwards when consuming high-nicotine-content tobacco to avoid noxious effects of the drug (Henningfield and Goldberg, 1983a, Henningfield et al., 1986, Russell et al., 1975), than they are at adjusting their intake upward to compensate for reduced nicotine in low-content tobacco (Sutton et al., 1978). Hence, self-regulation of tobacco consumption to avoid noxious effects of nicotine is far better regulated that compensation upwards to avoid a reduction in nicotine intake. Also consistent with a key role for noxious nicotine effects in controlling tobacco consumption, a treatment strategy previously employed to facilitate smoking cessation, but no longer typically used (Hajek and Stead, 2004), is to encourage smokers to inhale tobacco smoke more rapidly and deeply than usual. This results in aversive reactions to nicotine, with this increased nicotine exposure from more rapid consumption resulting in persistent suppression of intake (Norton and Barske, 1977). It is likely, therefore, that tolerance to the unpleasant effects of nicotine, and learning to efficiently control tobacco smoking to avoid these effects, must develop in order for habitual tobacco use to be established (Russell, 1979). As such, it is probable that discrete circuitries in the brain respond to the noxious properties of nicotine and that learning to titrate patterns of tobacco consumption in order to avoid activation of these circuitries plays a key role in the acquisition of smoking behavior. Indeed, the nicotinic acetylcholine receptor antagonist mecamylamine has been shown to block both the rewarding and aversive effects of nicotine, delivered by intravenous infusions to human volunteers (Lundahl et al., 2000), consistent with their being at least two discrete populations of nAChRs with each regulating either rewarding or aversive effects of the drug. Diminished sensitivity of nicotine-related aversion systems in the brain is therefore likely to increase vulnerability to develop habitual smoking. As such, it may be possible to target such circuitries in brain to enhance the noxious properties of nicotine with small molecule drugs, offering a novel treatment strategy to facilitate lower levels of tobacco consumption, and perhaps increased ability to cease tobacco smoking altogether. Nevertheless, until recently relatively little was known about which circuits in the brain regulate nicotine aversion, in sharp contrast to our burgeoning knowledge on mechanisms of nicotine reward. Here, we summarize much of the current knowledge on the mechanisms of nicotine aversion.