Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

Abstract

Tobacco smoking is a leading preventable cause of death in the United States and produces a major health and economic burden. Although the majority of smokers want to quit, few are successful. These data highlight the need for additional research into the neurobiology of tobacco dependence. Addiction to nicotine, the main psychoactive component of tobacco, is influenced by multiple factors that include individual differences in genetic makeup. Twin studies have demonstrated that genetic factors can influence vulnerability to nicotine addiction, and subsequent research has identified genes that may alter sensitivity to nicotine. In humans, genome-wide and candidate gene association studies have demonstrated that genes encoding nicotinic acetylcholine receptor (nAChR) proteins are associated with multiple smoking phenotypes. Similarly, research in mice has provided evidence that naturally occurring variability in nAChR genes is associated with changes in nicotine sensitivity. Furthermore, the use of genetic knockout mice has allowed researchers to determine the nAChR genes that mediate the effects of nicotine, whereas research with knockin mice has demonstrated that changes to nAChR genes can dramatically alter nicotine sensitivity. This review will examine the genetic factors that alter susceptibility to nicotine addiction, with an emphasis on the genes that encode nAChR proteins.

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…131,132 Recently, several review papers have addressed physiological and behavioral phenotypes relevant to ND of nAChR gene manipulation in mice. 77,131,133 In this short section and the companion table (Table 4), we will briefly highlight some of the findings most relevant to the current discussion but not describe them in detail.…”

“…77,131 a7-KO studies have failed to support a role for this subunit in sensitivity to the behavioral effects of nicotine. a7À/À nicotinenaive mice do not display different IV self-administration of nicotine (model of acute reinforcement) than WT, 145 and a7-KO mice did not show weakened responses to nicotine in a drug discrimination experiment nor difference from WT in sensitivity to the locomotor depressant effects of nicotine.…”

Review of alternative practices to cigarette smoking and nicotine replacement therapy: how safe are they?

“…Race and female genotypes have thus been reported to influence the effectiveness of nicotine S Afr Fam Pract 2011 patches and other NRT. 3,61 While NRT was found to be more effective than a placebo among non-white heavy smokers (as compared to whites), highly dependent nonwhite smokers, who smoke within 30 minutes of awakening have high salivary cotinine levels and smoke mentholated cigarettes, tend to find it difficult to quit regardless of the number of cigarettes smoked per day. 61 This suggests that assessing the degree of nicotine addiction and the type of cigarette, smoked may be important considerations when providing cessation treatments to non-white smokers.…”

“…However, nicotine in tobacco is very addictive, such that while most smokers want to quit and will make several attempts to quit smoking, only a few will succeed in the long term. 2,3 The desire to avoid the adverse health effects of cigarette smoking has led to search and advocacy for alternative substances perceived to be less harmful than cigarette smoking. The ideal alternative to cigarette smoking should be safe to use, effectively provide nicotine, prevent the occurrence of withdrawal symptoms and reduce the risk of harm to users and those around them.…”

Nicotinic Acetylcholine Receptor α7 and β4 Subunits Contribute to Nicotine-Induced Apoptosis in Periodontal Ligament Stem Cells

“…Nicotinic acetylcholine receptors (nAChRs) belong to the super family of ligand-gated ion channels and are multi-subunit proteins of neuromuscular and neuronal origins (Picciotto et al, 2001). A functional nAChR consists of five subunits which may differ (certain combinations of α1-9 and β1-4, γ, δ, and ε subunits) or be identical (α7-9) subunits and diverse subunit composition of nAChRs exhibit very different pharmacological and functional properties in various systems (Portugal and Gould, 2008). Recent studies have demonstrated that nicotinic receptors are expressed in undifferentiated and differentiating non-neuronal cells including embryonic stem cells, immune cells, oral epithelium and periodontal tissues (Chernyavsky et al, 2005;Resende et al, 2008;Wang et al, 2010;Wessler and Kirkpatrick, 2008), suggesting that although nAChRs primarily function as ligand-gated ion channels across synapses, they also influence other cellular activities such as cell to cell communication, sur-vival, and apoptosis in various non-neuronal tissues (Gotti and Clementi, 2004).…”