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.
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Acknowledgements
The authors would like to thank Sana Zeb, Kael Ragnini, and Victoria Chinaka for their technical contributions to this project.
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The authors declare no other competing financial interests.
Funding
This work was supported by the following grants from the National Institutes of Health (NIH): R01 DA037897 and R21 DA045792 (H.D.S.), R01 DK105155 (H.D.S. and M.R.H.), R01 CA206058 (J.A.-M.), and training grant T32 DA028874 and fellowship F31 DA058451 (R.J.H.). R.L.A. was supported in part by an investigator-initiated grant from Novo Nordisk.
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R.J.H. acquired and analyzed the data and drafted the manuscript. H.D.S. was responsible for the study concept and design, supervised the acquisition of the data and helped draft the manuscript. M.R.H., J. A.-M., and R.L.A. were also responsible for the study concept and design. All authors reviewed content and approved the final version for publication.
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Herman, R., Hayes, M., Audrain-McGovern, J. et al. Liraglutide attenuates nicotine self-administration as well as nicotine seeking and hyperphagia during withdrawal in male and female rats. Psychopharmacology 240, 1373–1386 (2023). https://doi.org/10.1007/s00213-023-06376-w
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DOI: https://doi.org/10.1007/s00213-023-06376-w