The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice
Open accessAbstract
Glucagon-like peptide 1 (GLP-1) analogues are used for the treatment of type 2 diabetes. The ability of the GLP-1 system to decrease food intake in rodents has been well described and parallels results from clinical trials. GLP-1 receptors are expressed in the brain, including within the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Dopaminergic neurons in the VTA project to the NAc, and these neurons play a pivotal role in the rewarding effects of drugs of abuse. Based on the anatomical distribution of GLP-1 receptors in the brain and the well-established effects of GLP-1 on food reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction.
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Although animal studies suggest an interference of GLP-1 receptor agonists with cocaine self-administration, this was not confirmed in a clinical trial with short-term exenatide administration.
“Although animal studies suggest an interference of GLP-1 receptor agonists with cocaine self-administration, 118 this was not confirmed in a clinical trial with short-term exenatide administration.119”
From GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits (2026) · cites this paper as [118]
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References 31 · Cited by 140
- Authors
- Sørensen, G., Reddy, I. A., Weikop, P., Graham, D. L., Stanwood, G. D., Wortwein, G., Galli, A., & Fink-Jensen, A.
- Affiliations
- University of Copenhagen (DK)
- Vanderbilt University Medical Center (US)
- Florida State University (US)
- Venue
- Physiology & Behavior
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 149
- Pages
- 262-268
- ISSN
- 0031-9384 (ISSN-L)
- PMC
- PMC4668599
- OpenAlex
- W560666237
- Cited by
- 140
- References
- 31
- Citations by year
- 2026: 24 · 2025: 17 · 2024: 6 · 2023: 9 · 2022: 13 · 2021: 20 · 2020: 14 · 2019: 14 · 2018: 8 · 2017: 8 · 2016: 6 · 2015: 1
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Physiology & Behavior (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Institutes of Health (DA035588, DA036940, T32 GM07347)
- National Institute of General Medical Sciences
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- exendin-4, GLP-1 receptor agonists, cocaine self-administration, striatum, Fos expression, dopamine D1 receptor, drug addiction, food reward, ventral tegmental area, nucleus accumbens, dopamine homeostasis
- MeSH terms
- Exenatide, Analysis of Variance, Animals, Benzazepines, Cocaine, Corpus Striatum, Dopamine, Dose-Response Relationship, Drug, Exploratory Behavior, Gene Expression Regulation, Hyperkinesis, Hypoglycemic Agents, Male, Motor Activity, Peptides, Self Administration, Time Factors, Venoms, Proto-Oncogene Proteins c-fos, Microdialysis, Dopamine Agonists, Dopamine Uptake Inhibitors, Mice
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