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

Abstract

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.

Keywords: Nicotine; body weight; food intake; glucagon-like peptide-1; obesity; relapse; tobacco; withdrawal.

Fig. 1

Experimental Timeline. (A) Experiment 1: Rats self-administered nicotine in 2-hour sessions for 19–22 days. Nicotine-taking behavior was then extinguished by replacing the nicotine solution with a saline solution. Reinstatement of nicotine-seeking behavior was then assessed. Rats were pretreated daily with vehicle or liraglutide prior to their last nicotine self-administration session and subsequent extinction and reinstatement sessions. (B) Experiment 2: Rats self-administered nicotine or received yoked saline injections for 22 days during two daily 2-h operant sessions. Rats were pretreated with vehicle or liraglutide prior to the last nicotine self-administration session. Treatments continued daily throughout the subsequent withdrawal period. Rats experienced 10 consecutive days of withdrawal in their home cages.

Fig. 2

Acute liraglutide administration attenuated nicotine self-administration in male and female rats. Total active lever responses (A & C) and nicotine infusions (B & D) were significantly reduced in both male and female rats treated with 25 μg/kg liraglutide versus vehicle-treated controls on their final day of nicotine self-administration. (males: n=9/treatment; females: n=11 vehicle, n=13 liraglutide; * p<0.05,** p<0.01, Bonferroni or un-paired t-test).

Fig. 3

Repeated liraglutide administration during abstinence facilitated extinction of drug taking and attenuated subsequent nicotine-seeking behavior. (A) Repeated liraglutide administration decreased total days required to extinguish nicotine taking in male rats (n=7 vehicle, n=8 liraglutide; *p<0.05, un-paired t-test). (B) Repeated liraglutide administration significantly attenuated active lever responding during reinstatement tests in male rats (*p<0.05, Bonferroni). (C) Repeated liraglutide administration decreased total days required to extinguish nicotine taking in female rats (n=12 vehicle, n=7 liraglutide; *p<0.05, un-paired t-test). (D) epeated liraglutide administration significantly attenuated active lever responding during reinstatement tests in female rats (**p<0.01, Bonferroni).

Fig. 4

Repeated liraglutide administration prevented nicotine withdrawal-induced hyperphagia and body weight gain in male rats. (A) Repeated liraglutide administration attenuated daily HFD intake during nicotine abstinence (n= 8 saline/vehicle, 14 saline/liraglutide, 10 nicotine/vehicle, 13 nicotine/liraglutide; *p<0.05 vs saline/vehicle, ^p<0.05 vs nicotine/vehicle, Tukey’s). (B) Repeated liraglutide administration decreased cumulative HFD intake during nicotine abstinence in both saline- and nicotine-experienced male rats (*p<0.05, **p<0.0001, Tukey’s). (C) Repeated liraglutide administration prevented body weight gain during withdrawal in nicotine-experienced male rats (*p<0.05, Tukey’s). There were no effects of repeated liraglutide on daily water intake (D) and kaolin intake (E) during nicotine withdrawal in male rats.

Fig. 5

Repeated liraglutide administration prevented nicotine withdrawal-induced hyperphagia and body weight gain in female rats. (A) Repeated liraglutide administration attenuated daily HFD intake during nicotine abstinence (n=9 saline/vehicle, 6 saline/liraglutide, 8 nicotine/vehicle, 11 nicotine/liraglutide: *p<0.05 vs saline/ vehicle, ^p<0.05 vs nicotine/vehicle, Tukey’s). (B) Repeated liraglutide administration decreased cumulative HFD intake during nicotine abstinence in nicotine-experienced female rats (*p<0.01, **p<0.0001, Tukey’s). (C) Repeated liraglutide administration prevented body weight gain during withdrawal in nicotine-experienced female rats (*p<0.05, Tukey’s). There were no effects of repeated liraglutide on daily water intake (D) and kaolin intake (E) during nicotine withdrawal in female rats.