Tobacco dependence is a complex genetic trait, with greater than 50% of the risk of developing dependence attributable to genetic factors (Li et al, 2003). Nicotine, the major psychoactive component in tobacco smoke responsible for dependence, functions in the brain through neuronal nicotinic acetylcholine receptors (nAChRs). A major breakthrough in understanding the genetics of tobacco dependence was the finding that allelic variation in the CHRNA3-CHRNA5-CHRNB4 gene cluster, which encodes the α3, α5, and β4 nAChR subunits, respectively, increases vulnerability to tobacco dependence and smoking-associated diseases (Bierut et al, 2008; Thorgeirsson et al, 2008). In particular, a polymorphism in CHRNA5 (rs16969968) that results in an aspartic acid to asparagine substitution at amino-acid reside 398 (D398N) more than doubles the risk of tobacco dependence in those carrying two copies of the risk allele. Little was known about how nAChRs-containing α5, α3, and/or β4 subunits may contribute to tobacco dependence. However, recent findings suggest that nAChRs containing these subunits play a key role in regulating nicotine reinforcement.

The α3, α5, and β4 nAChR subunits are densely expressed in the medial habenula (MHb) and its major site of projection, the interpeduncular nucleus (IPN) (Salas et al, 2009). Our laboratory has recently shown that mice with null mutation in the α5 nAChR subunit gene intravenously self-administer significantly greater quantities of nicotine than their wild-type counterparts, particularly when higher unit doses of the drug are available for consumption (Fowler et al, 2011). This enhanced intake in the mutant mice was ameliorated by virus-mediated re-expression of α5 nAChR subunits in the MHb–IPN tract. In addition, we found that IPN neurons were insensitive to nicotine in the mutant mice, reflected in greatly diminished induction of Fos immunoreactivity in response to nicotine injections. Moreover, lidocaine-induced inactivation of the MHb or IPN increased nicotine self-administration in rats, particularly at higher units doses of the drug. Finally, virus-mediated knockdown of α5 nAChR subunits in the MHb–IPN tract did not alter the reward-enhancing properties of lower nicotine doses, but greatly attenuated the reward-inhibiting (ie, aversive) effects of higher nicotine doses in rats (Fowler et al, 2011). In keeping with these findings, overexpression of β4 nAChR subunits in the MHb–IPN tract enhanced aversion to nicotine and reduced consumption of the drug in mice (Frahm et al, 2011). Moreover, virus-mediated expression in the MHb of a major risk allele of the α5 subunit gene (D398N allele), which decreases the function of α5-containing nAChRs incorporating this risk allele and increases vulnerability to tobacco dependence in humans, reduced aversion to nicotine and enhanced nicotine intake in the β4 subunit-overexpressing mice (Frahm et al, 2011). Hence, nAChRs-containing α5 and/or β4 subunits regulate the activation of the MHb–IPN tract in response to nicotine, which signals aversion to the drug. Deficient nAChR signaling in the MHb–IPN tract, which likely occurs in humans carrying risk alleles in the CHRNA3-CHRNA5-CHRNB4 gene cluster, reduces nicotine aversion and results in greater consumption of the drug. As such, these finding reveal fundamental new insights into the mechanisms of nicotine reinforcement and the neurocircuitry of tobacco dependence.

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