reward pathways, consequently extending the range of nicotine doses that have net stimulatory effects on reward systems. Such a scenario is likely to be most important in the acquisition of the tobacco habit in which experiencing a negative effect of nicotine on reward pathways may decrease the likelihood of repeatedly engaging in smoking behavior64. As such, these findings have important implications for understanding the high incidence of lung cancer and COPD in individuals carrying CHRNA5 risk alleles, suggesting that far higher levels of nicotine can be tolerated in these individuals, likely resulting in greater exposure to carcinogens contained in tobacco smoke. In summary, we have established a new framework for understanding the motivational drives that control nicotine intake. These findings are a key advance in our understanding of brain systems that regulate vulnerability to tobacco addiction, and reveal the importance of a5* nAChRs as targets for the development of novel smoking cessation therapeutics.
