Glucagon-Like Peptide-1 Receptor Activation in the Ventral Tegmental Area Decreases the Reinforcing Efficacy of Cocaine

Neuropsychopharmacology. 2016 Jun;41(7):1917-28. doi: 10.1038/npp.2015.362. Epub 2015 Dec 17.


Cocaine addiction continues to be a significant public health problem for which there are currently no effective FDA-approved treatments. Thus, there is a clear need to identify and develop novel pharmacotherapies for cocaine addiction. Recent evidence indicates that activation of glucagon-like peptide-1 (GLP-1) receptors in the ventral tegmental area (VTA) reduces intake of highly palatable food. As the neural circuits and neurobiological mechanisms underlying drug taking overlap to some degree with those regulating food intake, these findings suggest that activation of central GLP-1 receptors may also attenuate cocaine taking. Here, we show that intra-VTA administration of the GLP-1 receptor agonist exendin-4 (0.05 μg) significantly reduced cocaine, but not sucrose, self-administration in rats. We also demonstrate that cocaine taking is associated with elevated plasma corticosterone levels and that systemic infusion of cocaine activates GLP-1-expressing neurons in the nucleus tractus solitarius (NTS), a hindbrain nucleus that projects monosynaptically to the VTA. To determine the potential mechanisms by which cocaine activates NTS GLP-1-expressing neurons, we microinjected corticosterone (0.5 μg) directly into the hindbrain fourth ventricle. Intraventricular corticosterone attenuated cocaine self-administration and this effect was blocked in animals pretreated with the GLP-1 receptor antagonist exendin-(9-39) (10 μg) in the VTA. Finally, AAV-shRNA-mediated knockdown of VTA GLP-1 receptors was sufficient to augment cocaine self-administration. Taken together, these findings indicate that increased activation of NTS GLP-1-expressing neurons by corticosterone may represent a homeostatic response to cocaine taking, thereby reducing the reinforcing efficacy of cocaine. Therefore, central GLP-1 receptors may represent a novel target for cocaine addiction pharmacotherapies.

MeSH terms

  • Anesthetics, Local / pharmacology
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Cocaine / pharmacology*
  • Conditioning, Operant / drug effects*
  • Corticosterone / blood
  • Corticosterone / pharmacology
  • Exenatide
  • Fourth Ventricle / drug effects
  • Fourth Ventricle / physiology
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Glucagon-Like Peptide-1 Receptor / metabolism*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hypoglycemic Agents / pharmacology
  • Male
  • Neurons / drug effects
  • Neurons / metabolism
  • Peptide Fragments / pharmacology
  • Peptides / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement, Psychology*
  • Self Administration
  • Venoms / pharmacology
  • Ventral Tegmental Area / cytology
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / metabolism


  • Anesthetics, Local
  • Anti-Inflammatory Agents
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Peptide Fragments
  • Peptides
  • RNA, Small Interfering
  • Venoms
  • Green Fluorescent Proteins
  • exendin (9-39)
  • Exenatide
  • Cocaine
  • Corticosterone