Glucagon-like peptide-1 receptor activation in the nucleus accumbens core suppresses feeding by increasing glutamatergic AMPA/kainate signaling

J Neurosci. 2014 May 14;34(20):6985-92. doi: 10.1523/JNEUROSCI.0115-14.2014.


Glucagon-like peptide-1 receptor (GLP-1R) activation in the nucleus accumbens (NAc) core is pharmacologically and physiologically relevant for regulating palatable food intake. Here, we assess whether GLP-1R signaling in the NAc core of rats modulates GABAergic medium spiny neurons (MSNs) through presynaptic-glutamatergic and/or presynaptic-dopaminergic signaling to control feeding. First, ex vivo fast-scan cyclic voltammetry showed that the GLP-1R agonist exendin-4 (Ex-4) does not alter dopamine release in the NAc core. Instead, support for a glutamatergic mechanism was provided by ex vivo electrophysiological analyses showing that Ex-4 activates presynaptic GLP-1Rs in the NAc core to increase the activity of MSNs via a glutamatergic, AMPA/kainate receptor-mediated mechanism, indicated by increased mEPSC frequency and decreased paired pulse ratio in core MSNs. Only a small, direct excitatory effect on MSNs by Ex-4 was observed, suggesting that the contribution of postsynaptic GLP-1R to MSN activity is minimal. The behavioral relevance of the electrophysiological data was confirmed by the finding that intracore injection of the AMPA/kainate receptor antagonist CNQX attenuated the ability of NAc core GLP-1R activation by Ex-4 microinjection to suppress food intake and body weight gain; in contrast, intracore NMDA receptor blockade by AP-5 did not inhibit the energy balance effects of NAc core Ex-4. Together, these data provide evidence for a novel glutamatergic, but not dopaminergic, mechanism by which NAc core GLP-1Rs promote negative energy balance.

Keywords: VTA; diabetes; dopamine; energy balance; mesolimbic; obesity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dopamine / metabolism
  • Eating / drug effects*
  • Eating / physiology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Exenatide
  • Glucagon-Like Peptide-1 Receptor
  • Male
  • Miniature Postsynaptic Potentials / drug effects
  • Miniature Postsynaptic Potentials / physiology
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism
  • Peptides / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, Glucagon / agonists*
  • Receptors, Kainic Acid / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Venoms / pharmacology*


  • Excitatory Amino Acid Antagonists
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Peptides
  • Receptors, AMPA
  • Receptors, Glucagon
  • Receptors, Kainic Acid
  • Venoms
  • Exenatide
  • Dopamine