, 2003). The ��Dual Reinforcement�� model of nicotine reinforcement incorporates these two actions of nicotine (Caggiula et al., 2009). There are currently a number of smoking cessation aids on the market, including nicotine replacement therapy (patch, lozenge, etc.), denicotinized selleck compound cigarettes, and sustained-release bupropion (Zyban), but quit success rates are quite low, and relapse is common among these forms of cessation therapy (Cahill, Stead, & Lancaster, 2008; Hughes, Stead, & Lancaster, 2007; Stead, Perera, Bullen, Mant, & Lancaster, 2008). The most recently released smoking cessation aid, varenicline (Chantix), is the most effective smoking cessation pharmacotherapy to date. For example, varenicline reduced craving and symptoms of withdrawal significantly more than bupropion in a clinical trial (Gonzales et al.

, 2006) and was more effective than nicotine replacement therapy during a cessation period (Aubin et al., 2008). Those in this study who did not remain abstinent but continued to take varenicline reported decreased pleasure in smoking compared with those who did not remain abstinent but continued to receive nicotine replacement therapy. Additionally, the abuse liability of varenicline is very low, with the highest therapeutic dose (3 mg) being similar to the abuse liability of placebo (McColl et al., 2008). Data suggest that the therapeutic efficacy of varenicline is due to its ability to substitute for and/or block the effects of nicotine on brain reward systems (Rollema, Coe, et al., 2007).

These effects depend on partial agonism of ��4��2 nicotinic acetylcholine receptors (nAChRs) in midbrain reward systems (Foulds, 2006; Mihalak, Carroll, & Luetje, 2006; Rollema, Coe, et al., 2007). Thus, low to moderate doses of varenicline mimic the action of nicotine at nAChRs, while higher doses inhibit the effects of nicotine. A recent study investigated this hypothesis by looking at brain stimulation reward (BSR) threshold in rats (Spiller et al., 2009). Both nicotine (0.25 and 0.5 mg/kg) and low doses of varenicline (0.03, 0.1, and 0.3 mg/kg) reduced BSR threshold, while higher varenicline doses (3.0 mg/kg) increased BSR thresholds. Combining nicotine (0.25 and 0.5 mg/kg) with varenicline (0.3 and 1.0 mg/kg) reduced BSR thresholds relative to nicotine alone. Mecamylamine, an antagonist at non-��7 nAChRs, and dihydro-��-erythroidine, an antagonist at ��4 nAChRs, blocked the enhancement of BSR seen with 1.

0 mg/kg varenicline, but this effect was not blocked Cilengitide by methyllycaconitine, an antagonist at ��7 nAChRs. The authors concluded that reward function (i.e., BSR threshold) is enhanced when varenicline is given in isolation at lower doses and decreased when varenicline is given at higher doses in combination with nicotine. The results from this study also demonstrated that at 1.0 mg/kg varenicline, the decrease in BSR threshold is mediated through ��4-containing nAChRs and not ��7 nAChRs.