Glucagon-like peptide-1 receptor activation in the nucleus accumbens core suppresses feeding by increasing glutamatergic AMPA/kainate signaling.
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.
Translational Neuroscience Program and ebaase@mail.med.upenn.edu hayesmr@mail.med.upenn.edu.
Elizabeth G
EG
Mietlicki-Baase
Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina, Columbia, South Carolina 29209.
Pavel I
PI
Ortinski
Translational Neuroscience Program and.
David J
DJ
Reiner
Department of Psychology, University of Illinois at Chicago, Chicago, Illinois 60607, and.
Christopher G
CG
Sinon
Department of Psychology, University of Illinois at Chicago, Chicago, Illinois 60607, and.
James E
JE
McCutcheon
Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
R Christopher
RC
Pierce
Department of Psychology, University of Illinois at Chicago, Chicago, Illinois 60607, and.
Mitchell F
MF
Roitman
Translational Neuroscience Program and ebaase@mail.med.upenn.edu hayesmr@mail.med.upenn.edu.
Matthew R
MR
Hayes
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D008297:Male; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018027:Receptors, Glucagon / Q000819:agonists*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014688:Venoms / Q000494:pharmacology*
D004298:Dopamine; D018691:Excitatory Amino Acid Antagonists; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018091:Receptors, AMPA; D018027:Receptors, Glucagon; D018092:Kainic Acid Receptors; D014688:Venoms; C000593835:Glp1r protein, rat
VTA; diabetes; dopamine; energy balance; mesolimbic; obesity