, 2005). Chemically, varenicline is a derivative of the nAChR partial agonist (?)-cytisine; a natural product derived from Cytisus laburnum and other plant species (Coe et al., 2005). In electrophysiological assays using Xenopus oocytes, varenicline partially activates ��4��2* nAChRs when tested alone (~68% of the maximal response elicited by 10 ��M nicotine) (Coe such information et al., 2005) and partially blocks the effects of nicotine (~34% inhibition) (Coe et al., 2005). The partial agonist properties of varenicline have also been confirmed in vivo. For example, varenicline attenuated the stimulatory effects of nicotine on mesoaccumbens dopamine turnover (Coe et al., 2005). However, when varenicline was administered alone, it stimulated midbrain dopamine turnover to a lesser degree than nicotine (Coe et al.

, 2005; Reperant et al., 2010), consistent with a partial agonist activity. In early smoking-cessation studies, cytisine failed to exhibit efficacy (Benndorf, Scharfenberg, Kempe, Wendekamm, & Winkelvoss, 1970; Scharfenberg, Benndorf, & Kempe, 1971), but more recent clinical trials in eastern Europe suggest that cytisine (Tabex) may indeed promote smoking cessation (Etter, 2006). The reduced therapeutic efficacy of cytisine compared with varenicline may be attributed to its poorer absorption and brain penetration properties (Barlow & McLeod, 1969; Reavill, Walther, Stolerman, & Testa, 1990). Similarly, the ��4��2* nAChR partial agonist dianicline (SSR-591,813), developed by Sanofi-Aventis for smoking cessation, is less efficacious than varenicline likely because of its poorer brain penetration properties (Rollema et al.

, 2010). These findings demonstrate the feasibility of rationally designing small-molecule drugs that modulate nAChR signaling and that demonstrate clinical utility for smoking cessation. Thus, a major challenge for future drug development will be to better understand the nAChR subtypes that play a role in tobacco dependence. In this manner, new nAChR-based smoking cessation agents, possessing suitable drug-like physiochemical and brain penetration properties, and also favorable compliance and tolerability profiles, may be developed. Nicotinic Acetylcholine Receptors and the Genetics of Smoking Recent findings from human genome-wide association studies (GWAS) suggest that nAChR subtypes other than ��4��2* (and ��6* or ��7) nAChRs may contribute to tobacco dependence and have provided important insights into novel nAChR subtypes that may regulate smoking behavior and thereby represent important targets for medications development.

Allelic variation in the CHRNA5-CHRNA3-CHRNB4 subunit gene cluster located in Carfilzomib chromosome region 15q25, which encodes the ��5, ��3, ��4 nAChR subunits, respectively, significantly increases risk of tobacco addiction (Berrettini et al., 2008; Bierut et al., 2008; Hung et al., 2008; Lips et al., 2009; Saccone et al., 2007; Thorgeirsson et al., 2008).