SNPs in the CHRNA5/A3/B4 region have been related to several different nicotine and other substance use behaviors (genetic studies reviewed below, see also Greenbaum and Lerer 2009). These genes encode for α5, α3, β4 subunits which contribute to neuronal acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channels composed of five subunits, which may combine in a variety of configurations and are specifically expressed in different brain regions. Different combinations of subunits lead to differences in receptor pharmacology. For example, α4β2* receptors (* indicates some other receptor subunit) are most widely expressed in the brain, show high nicotine affinity, and slow desensitization (Gotti et al. 2009). In brief, nicotine directly binds to nAChRs, which initiates a receptor activation-desensitization cycle. Activation of nAChRs has been shown to activate dopamine release, establishing their role in the dopaminergic reward system (Schlaepfer et al. 2008). Alcohol is thought to moderate the function of nAChRs, which might explain at least partially the comorbidity of nicotine and alcohol dependence (Chatterjee 2010). Receptors containing the α5, α3, β4 subunits are expressed in limited regions of the brain (Gotti et al. 2009), but recent studies have provided strong evidence for their role in mediating drug responses.
