The neuronal nicotinic acetylcholine receptor (nAChR) subunit genes (CHRN genes) are strong candidates because nicotine binds to the nAChRs, activating the receptors and initiating a cascade of downstream neurobiological effects. Many nAChRs are expressed on dopaminergic nerve terminals (Grady et al., 2007), which are believed to be key components of the reward pathway involved in addictive behaviors. Several CHRN genes have been associated with tobacco-related phenotypes, including age of initiation (Schlaepfer et al., 2008b), subjective response to tobacco during early experimentation (Ehringer et al., 2007; Zeiger et al., 2008), cigarettes per day (Berrettini et al., 2008), nicotine dependence (Bierut et al., 2007; Greenbaum et al., 2006; Hoft et al., 2008; Li et al., 2005; Saccone et al., 2007; Weiss et al., 2008), and lung cancer (Amos et al., 2008; Hung et al., 2008; Thorgeirsson et al., 2008). The collection of studies strongly suggests the nAChRs are involved in human smoking behaviors, but it remains unclear how different subunits and different receptor subtypes might contribute to different developmental stages of addiction.
