Daily Liraglutide for Nicotine Dependence

Tobacco use and obesity are the two leading causes of preventable deaths. A growing literature indicates that common neurobiological substrates mediate drug addiction and obesity. Therefore, it is not surprising that during smoking abstinence, highly palatable food may serve as a substitute reinforcer ultimately leading to increased body weight gain. Importantly, post-cessation weight gain (PCWG) can deter a quit attempt, precipitate smoking relapse, and contribute to health issues related to excess body weight. The majority of weight gain occurs within 3-6 months of quitting smoking and many individuals maintain this increased weight 5 to 20 years post-cessation. Although there is substantial variability in the amount of weight gained, individuals who successfully quit smoking gain an average of 4.2 kg, with estimates ranging from 2.5 kg to 8.6 kg, at 6-month follow-up. Weight gain after smoking cessation contributes to increased risk of obesity, type II diabetes mellitus and hypertension (18), as well as reducing the improvement in lung function conferred by smoking cessation. Moreover, overweight or obese smokers comprise 70% of treatment-seeking smokers, gain the most weight, and are the least accepting of PCWG. Thus, post-cessation weight gain is a significant clinical problem. Unfortunately, current pharmacological interventions to reduce post-cessation weight gain are not very effective. While weight gain is often cited as a primary reason for smoking relapse, there is a significant gap in our understanding of the biobehavioral mechanisms linking smoking cessation and overeating. Recent evidence indicates that glucagon-like peptide-1 (GLP-1) regulates the rewarding effects of nicotine. These effects are mediated, in part, by reduced dopamine signaling in the nucleus accumbens, a key brain region known to regulate the reinforcing effects of both drugs of abuse and palatable foods. Indeed, activation of GLP-1 receptors in the ventral tegmental area (VTA), a brain region that sends dopaminergic projections to the nucleus accumbens, reduces both drug intake and consumption of palatable food. Based on the ability of GLP-1 receptor agonists to reduce drug and food intake, it is plausible that targeting GLP-1 receptor signaling may be an effective strategy toward reducing withdrawal-induced weight gain in abstinent smokers. Investigators have recently developed a novel animal model of nicotine withdrawal-induced hyperphagia and body weight gain in order to gain an improved understanding of the molecular and behavioral mechanisms underlying increased food intake and body weight gain during nicotine withdrawal. The pilot data provide strong empirical rationale for the proposed study by establishing an animal model of withdrawal-induced hyperphagia and body weight gain following voluntary nicotine self-administration. This withdrawal phenotype was evident only in rats given ad libitum access to a highly palatable diet during withdrawal as parallel studies using a normal chow diet did not produce hyperphagia or changes in body weight during nicotine withdrawal (data not shown). Collectively,these results are consistent with human laboratory studies indicating that nicotine withdrawal is associated with increased consumption of highly palatable foods and body weight. The translational implications of studying this behavioral phenotype are clear and significant and include: 1) informing clinical approaches to treating weight gain during smoking abstinence, 2) identifying potential biomarkers associated with nicotine addiction, and 3) addressing two significant public health concerns. GLP-1 receptor ligands are currently FDA-approved for the treatment of type II diabetes mellitus and obesity. Re-purposing an existing FDA-approved treatment that has been "de-risked" (i.e., previously shown to be safe) in numerous clinical trials removes a key barrier for drug development and reduces the resources required to bring new drugs to market. The promising preclinical data, combined with evidence that GLP-1 receptor agonists are effective treatments for obesity, suggest that GLP-1 receptor ligands could be re-purposed for attenuating nicotine withdrawal-induced bodyweight gain, thereby improving smoking cessation rates. Specifically, this study will examine the effects of the GLP-1 receptor agonist liraglutide on smoking behavior as well as food intake and body weight gain during abstinence.