Impact of Genetic Variability in Nicotinic Acetylcholine Receptors on Nicotine Addiction and Smoking Cessation Treatment

Abstract

Nicotine dependence (ND) is one of the world's leading causes of preventable death. Nicotine addiction and other forms of drug addiction continue to be significant public health problems in the world. Evidence for a genetic influence on smoking behaviour and ND has prompted a search for susceptibility genes. Evidence has recently accumulated that single nucleotide polymorphisms (SNPs) in the genetic region encoding the nicotinic acetylcholine receptor (nAChR) subunits α6, α5, α3, and β4 are associated with smoking and ND. Brain nAChR are a heterogeneous family of ion channels expressed in the various parts of the brain. A number of studies suggest that brain nAChR are critical targets for the development of pharmacotherapy for nicotine and other drug addictions. In this review, we will discuss the nAChR subtypes, their function in response to endogenous brain transmitters, and how their functions are regulated in the presence of nicotine. Additionally, we will provide an overview of the three major pharmacotherapies for smoking cessation (which have demonstrated efficacy) such as: nicotine replacement therapy (NRT), bupropion, and varenicline. An appreciation of the complexity of nAChR and their regulation will be necessary for the development of nAChR modulators as potential pharmacotherapy for drug addiction. Prevention strategies should be tailored to carriers of SNPs located on chromosome 15q and that are strongly associated with nicotine dependence and risk of lung cancer.

α6β2 subunit containing nicotinic acetylcholine receptors exert opposing actions on rapid dopamine signaling in the nucleus accumbens of rats with high-versus low-response to novelty

“…Moreover, we postulate that HR animals display augmentation of reward-related dopamine signaling (Flagel et al,2011) through differences in nAChR function in both the cell body (Fagen et al,2007) and terminal regions (current study) of the mesolimbic dopamine system. Indeed, smoking cessation treatments that target nAChRs have been shown to engender wide individual variability in treatment outcomes (Russo et al,2011). These data may inform personalization of pharmacotherapeutic interventions, perhaps based on measures of sensation seeking, and could also lead to novel therapeutic approaches to learning deficits in other neuropsychiatric disorders.…”

Patterns of Nicotinic Receptor Antagonism: Nicotine Discrimination Studies

“…Drug discrimination assays have been used in attempts to isolate the receptor that is most relevant to nicotine's interoceptive effects, and several lines of evidence indicate that these are also mediated through the ␣4␤2 subtype of the nAChR (for review, see Smith and Stolerman, 2009). Nevertheless, genetic studies in particular have implicated other nicotinic receptor subtypes, such as the ␣3, ␣5, ␣6, and ␤4 subunits, in the abuse liability of nicotine (Improgo et al, 2010;Sherva et al, 2010;Russo et al, 2011).…”

Nicotinic receptor gene variants interact with attention deficient hyperactive disorder symptoms to predict smoking trajectories from early adolescence to adulthood

“…The observed interaction effect helps to reveal that not all individuals who were high in ADHD symptoms also reported problems with smoking. Researchers have suggested that certain aspects of neurocognitive functioning, such as sustained attention (Greenbaum & Lerer, 2009; Rigbi et al, 2008; Russo et al, 2011; Ware et al, 2011; Winterer et al, 2010; Zhang et al, 2010), could be a potential mechanism for both smoking vulnerability and components of the ADHD phenotype. Also, variation in subunits of the nAChRs, including rs13280604, plays a role in dopamine modulation which may affect ADHD symptoms and reinforce cigarette usage (Zeiger et al, 2008).…”

“…Variants of nicotinic-acetylcholine receptor (nAChR) complex genes have been widely studied as predictors of a range of smoking outcomes (Greenbaum & Lerer, 2009; Russo et al, 2011; Ware, van den Bree, & Munafo, 2011; Winterer et al, 2010; Zhang, Kranzler, Poling, & Gelernter, 2010). Eleven different nAChR subunit-encoding genes have been identified, including the CHRNB3 and CHRNA6 genes, both of which are located at chromosome 8p11.2.…”