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Neuropsychopharmacology. 2018 Sep;43(10):2000-2008. doi: 10.1038/s41386-018-0010-3. Epub 2018 Feb 14.

Glucagon-like peptide-1 receptor activation in the ventral tegmental area attenuates cocaine seeking in rats.

Author information

1
Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
2
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
3
Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA.
4
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. hschmidt@nursing.upenn.edu.
5
Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA. hschmidt@nursing.upenn.edu.

Abstract

Novel molecular targets are needed to develop new medications for the treatment of cocaine addiction. Here we investigated a role for glucagon-like peptide-1 (GLP-1) receptors in the reinstatement of cocaine-seeking behavior, an animal model of relapse. We showed that peripheral administration of the GLP-1 receptor agonist exendin-4 dose dependently reduced cocaine seeking in rats at doses that did not affect ad libitum food intake, meal patterns or body weight. We also demonstrated that systemic exendin-4 penetrated the brain where it putatively bound receptors on both neurons and astrocytes in the ventral tegmental area (VTA). The effects of systemic exendin-4 on cocaine reinstatement were attenuated in rats pretreated with intra-VTA infusions of the GLP-1 receptor antagonist exendin-(9-39), indicating that the suppressive effects of systemic exendin-4 on cocaine seeking were due, in part, to activation of GLP-1 receptors in the VTA. Consistent with these effects, infusions of exendin-4 directly into the VTA reduced cocaine seeking. Finally, extinction following cocaine self-administration was associated with decreased preproglucagon mRNA expression in the caudal brainstem. Thus, our study demonstrated a novel role for GLP-1 receptors in the reinstatement of cocaine-seeking behavior and identified behaviorally relevant doses of a GLP-1 receptor agonist that selectively reduced cocaine seeking and did not produce adverse effects.

PMID:
29497166
PMCID:
PMC6098066
[Available on 2019-09-01]
DOI:
10.1038/s41386-018-0010-3

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