The increases in behavior observed here under both schedules of reinforcement support the interpretation that varenicline increases the reinforcing efficacy of the VS. One limitation of these studies is the use of nicotine-na?ve rats as opposed Nintedanib to rats that are chronically exposed to nicotine. Prior research suggests that repeated exposure to nicotine leads to neuronal adaptations, including desensitization and upregulation of nAChRs (Quick & Lester, 2002). It is also believed that chronic nicotine administration engenders tolerance to most of the drug��s pharmacological effects (Benowitz, 2008). Varenicline is a pharmacotherapy that is targeted toward a population that is chronically exposed to nicotine and was designed to aid smoking cessation for this group.

It is therefore important to utilize a similar paradigm in an animal model, that is, a model that incorporates the neuroadaptations that occur with chronic nicotine exposure. Another possible future direction to take includes utilizing an animal��s, self-administration paradigm. To date, a limited number of studies have been conducted looking at varenicline self-administration (Rollema, Chambers, et al., 2007 and Paterson et al., 2010). These studies found that animals will self-administer varenicline but did not dissociate whether this effect was due to the primary reinforcing and/or reinforcement-enhancing effects of varenicline. Future studies should isolate the primary reinforcing effects from reinforcement enhancement in order to address the extent to which primary reinforcement is playing a role in varenicline self-administration.

Despite the known adverse health outcomes of smoking, prevalence remains high (Centers for Disease Control and Prevention 2009). As stated above, previous research suggests this may be, in part, due to the reinforcement-enhancing properties of nicotine. Our data demonstrate that varenicline independently mimics these properties as well as antagonizes them when nicotine is concurrently present. Thus, the efficacy of varenicline may be related to reinforcement enhancement in that varenicline can partially replace some of the reinforcement-enhancing effects of nicotine when a person refrains from smoking as well as hinder these effects when a person does smoke. It is crucial to better understand the mechanisms underlying these properties of nicotine and the role of smoking cessation pharmacotherapies in replacing or reducing these effects.

This approach may lead to ways to improve current smoking cessation aids, such as varenicline, and/or develop novel pharmacotherapies. Funding This work was supported by the National Institutes of Health (DA-10464 and DA-24801); and varenicline Anacetrapib was generously donated by Pfizer, Inc. Declaration of Interests None declared.