Studies in rodent models and human subjects have demonstrated that α4β2 nAChRs play an important role in nicotine dependence (ND). First, activity of α4β2 nAChRs contributes to nicotine self-administration. Pretreatment with a nicotinic receptor antagonist dihydro-β-erythroidine, which blocks the α4β2 subtype, decreases nicotine self-administration in rats (4). Consistent with this finding, β2 knock-out mice, which lack high-affinity nAChRs, do not maintain self-administration of nicotine (5). Second, α4β2 receptors activate mesolimbic dopamine systems that contribute to the rewarding effects of nicotine. For example, activation of α4β2 receptors in the ventral tegmental area increases extracellular dopamine levels in the nucleus accumbens (6,7), and neither β2 nor α4 knock-out mice exhibit nicotine-elicited increases in dopamine levels (5,8). Third, experiments with gain-of-function α4* nAChR knock-in mice demonstrate that α4* nAChR activation is sufficient for nicotine-induced reward, tolerance, and sensitization (9). Finally, in humans, a partial agonist of α4β2 nAChRs, varenicline, is efficacious for smoking cessation (10).
