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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Obesity Agents / therapeutic use*
  • Astrocytes / drug effects
  • Brain / metabolism
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / psychology
  • Conditioning, Operant / drug effects
  • Dose-Response Relationship, Drug
  • Drug-Seeking Behavior / drug effects*
  • Exenatide / administration & dosage
  • Exenatide / pharmacokinetics
  • Exenatide / therapeutic use*
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glucagon-Like Peptide-1 Receptor / metabolism*
  • Male
  • Neurons / drug effects
  • Proglucagon / biosynthesis
  • Proglucagon / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Recurrence
  • Solitary Nucleus / drug effects
  • Solitary Nucleus / metabolism
  • Ventral Tegmental Area / drug effects*


  • Anti-Obesity Agents
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Proglucagon
  • Exenatide