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.

The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial.

To determine whether the functional mu-opioid receptor (OPRM1) Asn40Asp variant predicts the comparative efficacy of different forms of NRT, we conducted a clinical trial of transdermal nicotine (TN) vs nicotine nasal spray (NS) in 320 smokers of European ancestry. Smokers carrying the OPRM1 Asp40 variant (n=82) were significantly more likely than those homozygous for the Asn40 variant (n=238) to be abstinent at the end of treatment, and reported less mood disturbance and weight gain. The genotype effect on treatment outcome was most pronounced among smokers receiving TN, particularly during the 21 mg dose phase. Smokers who carry the OPRM1 Asp40 variant are likely to have a favorable response to TN and may benefit from extended therapy with the 21 mg dose.