The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission

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Abstract

Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.

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Once-Weekly Semaglutide in Adults with Overweight or Obesity

John P.H. Wilding, Rachel L. Batterham, Salvatore Calanna … (2021)

Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

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Glucagon-like peptide-1 receptor is involved in learning and neuroprotection.

Matthew J. During, Lei Cao, David S Zuzga … (2003)

Glucagon-like peptide-1 (GLP-1) is a gut peptide that, together with its receptor, GLP-1R, is expressed in the brain. Here we show that intracerebroventricular (i.c.v.) GLP-1 and [Ser(2)]exendin(1-9) (HSEGTFTSD; homologous to a conserved domain in the glucagon/GLP-1 family) enhance associative and spatial learning through GLP-1R. [Ser(2)]exendin(1-9), but not GLP-1, is also active when administered peripherally. GLP-1R-deficient mice have a phenotype characterized by a learning deficit that is restored after hippocampal Glp1r gene transfer. In addition, rats overexpressing GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells. Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents.

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The Discovery and Development of Liraglutide and Semaglutide

Lotte Knudsen, Jesper Lau (2019)

The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in people with type 2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor agonists (GLP-1RAs) followed. Our article charts the discovery and development of the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs. Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Significant weight loss, through an effect to reduce energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease (NASH) and its use in an oral formulation for the treatment of T2D. In summary, rational design has led to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH.

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Author and article information

Contributors

Vicky Chuong:

ORCID: http://orcid.org/0000-0002-1996-8164

Mehdi Farokhnia:

ORCID: http://orcid.org/0000-0003-0902-4212

Sophia Khom:

ORCID: http://orcid.org/0000-0003-3567-8973

Claire L. Pince

Sophie K. Elvig:

ORCID: http://orcid.org/0000-0002-1049-1523

Roman Vlkolinsky:

ORCID: http://orcid.org/0000-0002-9786-0407

Renata C.N. Marchette:

ORCID: http://orcid.org/0000-0001-5040-7966

George F. Koob

Marisa Roberto:

ORCID: http://orcid.org/0000-0003-0729-3961

Leandro F. Vendruscolo:

ORCID: http://orcid.org/0000-0002-8829-8627

Lorenzo Leggio:

ORCID: http://orcid.org/0000-0001-7284-8754

Journal

Journal ID (nlm-ta): JCI Insight

Journal ID (iso-abbrev): JCI Insight

Journal ID (publisher-id): JCI Insight

Title: JCI Insight

Publisher: American Society for Clinical Investigation

ISSN (Electronic): 2379-3708

Publication date (Electronic, pub): 22 June 2023

Publication date (Electronic, collection): 22 June 2023

Publication date PMC-release: 22 June 2023

Volume: 8

Issue: 12

Electronic Location Identifier: e170671

Affiliations

[1 ]Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program (NIDA IRP) and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research (NIAAA DICBR), NIH, Baltimore and Bethesda, Maryland, USA.

[2 ]Neurobiology of Addiction Section, NIDA IRP, NIH, Baltimore, Maryland, USA.

[3 ]Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.

[4 ]Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria.

[5 ]Stress and Addiction Neuroscience Unit, NIDA IRP and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, Maryland, USA.

Author notes

Address correspondence to: Lorenzo Leggio or Leandro F. Vendruscolo, Biomedical Research Center, 251 Bayview Blvd, Suite 200, Room 04A515, Baltimore, Maryland 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@ 123456nih.gov (LL); Email: leandro.vendruscolo@ 123456nih.gov (LFV).

Authorship note: VC, MF, and SK contributed equally to this work and share first authorship. MR, LFV, and LL jointly supervised this work and share senior authorship.

Author information

Vicky Chuong http://orcid.org/0000-0002-1996-8164

Mehdi Farokhnia http://orcid.org/0000-0003-0902-4212

Sophia Khom http://orcid.org/0000-0003-3567-8973

Sophie K. Elvig http://orcid.org/0000-0002-1049-1523

Roman Vlkolinsky http://orcid.org/0000-0002-9786-0407

Renata C.N. Marchette http://orcid.org/0000-0001-5040-7966

Marisa Roberto http://orcid.org/0000-0003-0729-3961

Leandro F. Vendruscolo http://orcid.org/0000-0002-8829-8627

Lorenzo Leggio http://orcid.org/0000-0001-7284-8754

Article

Publisher ID: 170671

DOI: 10.1172/jci.insight.170671

PMC ID: 10371247

PubMed ID: 37192005

SO-VID: 6b2de72d-7c1c-431f-a0d2-006639649643

License:

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 20 March 2023

Date accepted : 10 May 2023

Funding

Funded by: NIH

Award ID: ZIA-DA-000635,ZIA-DA000602,ZIA-DA000644,AA029841,P60 AA006420,AA027700

This work was supported by the NIH intramural funding ZIA-DA-000635 (Joint NIDA/NIAAA Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section – PI: LL), ZIA-DA000602 (NIDA Neurobiology of Addiction Section – PI: GFK), ZIA-DA000644 (Stress & Addiction Neuroscience Unit – PI: LVF), NIH/NIAAA extramural funding AA029841, P60 AA006420, AA027700 (PI: MR), and a fellowship from the Center on Compulsive Behaviors funded by the NIH Deputy Director for Intramural Research Innovation Award (MF and RCNM). This work was also supported by a Pathways Research Award® funded by the Alkermes Pathways Research Awards Program® (PI: MF), which did not have any role in the study design, execution, or interpretation of the results. The content of this article is solely the responsibility of the authors and does not necessarily represent the official view of the funding agencies.

The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission

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Hogrefe Psychology

Most cited references 126

Once-Weekly Semaglutide in Adults with Overweight or Obesity

Glucagon-like peptide-1 receptor is involved in learning and neuroprotection.

The Discovery and Development of Liraglutide and Semaglutide

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