The food intake-suppressive effects of glucagon-like peptide-1 receptor signaling in the ventral tegmental area are mediated by AMPA/kainate receptors

Am J Physiol Endocrinol Metab. 2013 Dec 1;305(11):E1367-74. doi: 10.1152/ajpendo.00413.2013. Epub 2013 Oct 8.


Glucagon-like peptide-1 receptor (GLP-1R) activation in the ventral tegmental area (VTA) is physiologically relevant for the control of palatable food intake. Here, we tested whether the food intake-suppressive effects of VTA GLP-1R activation are mediated by glutamatergic signaling within the VTA. Intra-VTA injections of the GLP-1R agonist exendin-4 (Ex-4) reduced palatable high-fat food intake in rats primarily by reducing meal size; these effects were mediated in part via glutamatergic AMPA/kainate but not NMDA receptor signaling. Additional behavioral data indicated that GLP-1R expressed specifically within the VTA can partially mediate the intake- and body weight-suppressive effects of systemically administered Ex-4, offering the intriguing possibility that this receptor population may be clinically relevant for food intake control. Intra-VTA Ex-4 rapidly increased tyrosine hydroxylase levels within the VTA, suggesting that GLP-1R activation modulates VTA dopaminergic signaling. Further evidence for this hypothesis was provided by electrophysiological data showing that Ex-4 increased the frequency of AMPA-mediated currents and reduced the paired/pulse ratio in VTA dopamine neurons. Together, these data provide novel mechanisms by which GLP-1R agonists in the mesolimbic reward system control for palatable food intake.

Keywords: 2-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid; diabetes; dopamine; glucagon-like peptide-1; glutamate; obesity; reward.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Appetite Depressants / pharmacology
  • Appetite Regulation / drug effects*
  • Diet, High-Fat
  • Feeding Behavior / drug effects
  • Feeding Behavior / physiology
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Like Peptide-1 Receptor
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / physiology*
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / physiology
  • Receptors, Kainic Acid / physiology*
  • Reward
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / metabolism


  • Appetite Depressants
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Receptors, AMPA
  • Receptors, Glucagon
  • Receptors, Kainic Acid
  • Glucagon-Like Peptide 1