The glucagon-like peptide-1 system is modulated by acute and chronic alcohol exposure: Findings from human laboratory experiments and a post-mortem brain study
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Growing evidence suggests that the glucagon‐like peptide‐1 (GLP‐1) system modulates alcohol seeking and consumption, and GLP‐1 analogues may represent novel pharmacotherapies for alcohol use disorder (AUD). Accordingly, it is important to understand the potential effects of alcohol on the endogenous GLP‐1 system. In a series of secondary analyses of previous human laboratory experiments, we first examined the effects of alcohol administration, with different doses and routes of administration, on peripheral active GLP‐1 concentrations in heavy‐drinking individuals with AUD enrolled in placebo‐controlled pharmacological studies (only placebo conditions were analysed here). Alcohol administration resulted in a significant reduction of GLP‐1 levels across the four experiments (oral alcohol, variable dose: F3,28 = 6.52, p = 0.002; oral alcohol, fixed dose: F7,75.94 = 5.08, p < 0.001; intravenous alcohol, variable dose: F4,37.03 = 20.72, p < 0.001; intravenous alcohol, fixed dose: F4,13.92 = 10.44, p < 0.001). Next, central expression of the GLP‐1 receptor (GLP‐1R) in post‐mortem brain tissues (amygdala, ventral tegmental area, nucleus accumbens, hippocampus and prefrontal cortex) was compared between individuals with AUD and controls. Fold change of GLP‐1R mRNA in the hippocampus was significantly higher in individuals with AUD, compared to controls (F1,21 = 6.80, p = 0.01). A trend‐level effect with the same direction was also found in the prefrontal cortex (F1,20 = 3.07, p = 0.09). Exploratory analyses showed that GLP‐1R gene expression levels were correlated with behavioural measures of alcohol drinking (hippocampus) and cigarette smoking (hippocampus and prefrontal cortex). Collectively, these data provide novel information on the crosstalk between alcohol and GLP‐1 in a clinically relevant sample. Further studies are needed to understand the underlying mechanisms of this link.
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In post-mortem brain tissues, individuals with AUD exhibited significantly higher expression of GLP-1R in the hippocampus compared to controls.
“Individuals with AUD exhibited a significantly higher expression of GLP-1R in the hippocampus.”
From A Narrative Review of Current and Emerging Trends in the Treatment of Alcohol Use Disorder (2024) · cites this paper as [98]
Exploratory analyses revealed correlations between GLP-1R gene expression levels and behavioral measures of alcohol consumption.
“Exploratory analyses revealed correlations between GLP-1R gene expression levels and behavioral measures of alcohol consumption”
From A Narrative Review of Current and Emerging Trends in the Treatment of Alcohol Use Disorder (2024) · cites this paper as [98]
These findings are translationally relevant and overall consistent with recent human evidence suggesting a role of the GLP-1 system in alcohol drinking and AUD.
“These are translationally relevant findings and overall consistent with recent human evidence that suggest a role of the GLP-1 system in alcohol drinking and AUD, as indicated by alcohol administration studies (115, 116), postmortem brain analyses (115), and neuroimaging-genetic investigations (116, 117).”
From The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission (2023) · cites this paper as [115]
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Chuong, V., Farokhnia, M., Khom, S., Pince, C. L., Elvig, S. K., Vlkolinsky, R., Marchette, R. C. N., Koob, G. F., Roberto, M., Vendruscolo, L. F., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.170671 · Cited by 214 · see citing works
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- Authors
- Farokhnia, M., Browning, B. D., Crozier, M. E., Sun, H., Akhlaghi, F., & Leggio, L.
- Affiliations
- National Institutes of Health (US)
- University of Rhode Island (US)
- Corresponding author
- Farokhnia, Mehdi
- Leggio, Lorenzo
- Venue
- Addiction Biology
- Publisher
- Wiley
- Published
- 2022-07-19
- Volume
- 27
- Issue
- 5
- Pages
- e13211-e13211
- ISSN
- 1355-6215 (ISSN-L)
- 1369-1600
- PMC
- PMC12258501
- OpenAlex
- W4286213429
- Cited by
- 46
- References
- 58
- Citations by year
- 2026: 9 · 2025: 23 · 2024: 8 · 2023: 5 · 2022: 1
- FWCI
- 6.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Addiction Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Journal of Media Literacy Education (submittedVersion, cc-by)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (ZIA‐AA000218)
- National Institute on Drug Abuse (ZIA‐DA000635)
- Topics
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- glucagon-like peptide-1, GLP-1 receptor, alcoholism, alcohol exposure, hippocampus, prefrontal cortex, alcohol seeking, cigarette smoking, GLP-1 analogues, pharmacotherapy
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Ethanol, Alcoholism, Brain, Humans, Peptides, Glucagon-Like Peptide 1
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