Liraglutide attenuates nicotine self-administration as well as nicotine seeking and hyperphagia during withdrawal in male and female rats.

RATIONALE: Nicotine cessation is associated with increased consumption of highly palatable foods and body weight gain in most smokers. Concerns about body weight gain are a major barrier to maintaining long-term smoking abstinence, and current treatments for nicotine use disorder (NUD) delay, but do not prevent, body weight gain during abstinence. Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and are FDA-approved for treating obesity. However, the effects of GLP-1R agonist monotherapy on nicotine seeking and withdrawal-induced hyperphagia are unknown. OBJECTIVES: We screened the efficacy of the long-lasting GLP-1R agonist liraglutide to reduce nicotine-mediated behaviors including voluntary nicotine taking, as well as nicotine seeking and hyperphagia during withdrawal. METHODS: Male and female rats self-administered intravenous nicotine (0.03 mg/kg/inf) for ~21 days. Daily liraglutide administration (25 µg/kg, i.p.) started on the last self-administration day and continued throughout the extinction and reinstatement phases of the experiment. Once nicotine taking was extinguished, the reinstatement of nicotine-seeking behavior was assessed after an acute priming injection of nicotine (0.2 mg/kg, s.c.) and re-exposure to conditioned light cues. Using a novel model of nicotine withdrawal-induced hyperphagia, intake of a high fat diet (HFD) was measured during home cage abstinence in male and female rats with a history of nicotine self-administration. RESULTS: Liraglutide attenuated nicotine self-administration and reinstatement in male and female rats. Repeated liraglutide attenuated withdrawal-induced hyperphagia and body weight gain in male and female rats at a dose that was not associated with malaise-like effects. CONCLUSIONS: These findings support further studies investigating the translational potential of GLP-1R agonists to treat NUD.

Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers.

Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg(-1) per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg(-1) galantamine and 3.0 mg kg(-1) donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects.

APOE ɛ4, an Alzheimer's disease susceptibility allele, and smoking cessation.

Possessing an apolipoprotein E (APOE) ɛ4 allele, advanced age and smoking are risk factors for Alzheimer's disease and cognitive decline. Deficits in cognitive function also increase risk for smoking relapse. Data from 917 adult smokers of European ancestry were pooled across three randomized trials of smoking cessation. We examined whether smokers who carry at least one ɛ4 allele (n=252) have more difficulty quitting smoking compared with noncarriers (n=665), and whether age moderated this association. The genotype by age interaction was significant for 7-day point-prevalence abstinence rates (P=0.04) and time to 7-day failure (P=0.03). Among smokers over age 60, ɛ4 carriers were less likely to quit (odds ratio=0.27, P=0.018) and relapsed more quickly (hazard ratio=3.38, P=0.001) compared with noncarriers. The genotype association with relapse was nonsignificant among younger smokers. An increased understanding of the underlying pathophysiological mechanisms of this association could facilitate the development of targeted therapies for smokers with increased risk for cognitive decline.

The effects of extended pre-quit varenicline treatment on smoking behavior and short-term abstinence: a randomized clinical trial.

Preclinical research and learning theory suggest that a longer duration of varenicline treatment prior to the target quit date (TQD) would reduce smoking rates before cessation and improve abstinence outcomes. A double-blind randomized controlled trial tested this hypothesis in 60 smokers randomized to either an Extended run-in group (4 weeks of pre-TQD varenicline) or a Standard run-in group (3 weeks of placebo, 1 week of pre-TQD varenicline); all the participants received 11 weeks of post-TQD varenicline and brief counseling. During the pre-quit run-in, the reduction in smoking rates was greater in the Extended run-in group than in the Standard run-in group (42% vs. 24%, P < 0.01), and this effect was greater in women than in men (57% vs. 26%, P = 0.001). The rate of continuous abstinence during the final 4 weeks of treatment was higher among women in the Extended group compared to women in the Standard run-in group (67% vs. 35%). Although these data suggest that extension of varenicline treatment reduces smoking during the pre-quit period and may further enhance cessation rates, confirmatory evidence is needed from phase III clinical trials.