Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors

Physiol Behav. 2016 Jul 1;161:140-144. doi: 10.1016/j.physbeh.2016.04.013. Epub 2016 Apr 9.


Recent data implicate glucagon-like peptide-1 (GLP-1), a potent anorexigenic peptide released in response to nutrient intake, as a regulator for the reinforcing properties of food, alcohol and psychostimulants. While, both central and peripheral mechanisms mediate effects of GLP-1R signaling on food intake, the extent to which central or peripheral GLP-1R signaling regulates reinforcing properties of drugs of abuse is unknown. Here, we examined amphetamine reinforcement, alcohol intake and hedonic feeding following peripheral administration of EX-4 (a GLP-1 analog) in FLOX and GLP-1R KD(Nestin) (GLP-1R selectively ablated from the central nervous system) mice (n=13/group). First, the effect of EX-4 pretreatment on the expression of amphetamine-induced conditioned place preference (Amp-CPP) was examined in the FLOX and GLP-1R KD(Nestin) mice. Next, alcohol intake (10% v/v) was evaluated in FLOX and GLP-1R KD(Nestin) mice following saline or EX-4 injections. Finally, we assessed the effects of EX-4 pretreatment on hedonic feeding behavior. Results indicate that Amp-CPP was completely blocked in the FLOX mice, but not in the GLP-1R KD(Nestin) mice following EX-4 pretreatment. Ex-4 pretreatment selectively blocked alcohol consumption in the FLOX mice, but was ineffective in altering alcohol intake in the GLP-1R KD(Nestin) mice. Notably, hedonic feeding was partially blocked in the GLP-1R KD(Nestin) mice, whereas it was abolished in the FLOX mice. The present study provides critical insights regarding the nature by which GLP-1 signaling controls reinforced behaviors and underscores the importance of both peripheral and central GLP-1R signaling for the regulation of addictive disorders.

Keywords: Alcohol intake; Amphetamine reinforcement; GLP-1; GLP-1R; Hedonic feeding.

Publication types

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

MeSH terms

  • Alcohol Drinking / drug therapy
  • Amphetamine / pharmacology
  • Animals
  • Behavior, Addictive / drug therapy
  • Behavior, Addictive / genetics*
  • Central Nervous System Stimulants / pharmacology
  • Conditioning, Operant / drug effects
  • Conditioning, Operant / physiology
  • Diet
  • Disease Models, Animal
  • Exenatide
  • Feeding Behavior / drug effects
  • Glucagon-Like Peptide-1 Receptor / deficiency
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nestin / metabolism
  • Peptides / therapeutic use
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Venoms / therapeutic use


  • Central Nervous System Stimulants
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Nestin
  • Peptides
  • Venoms
  • Exenatide
  • Amphetamine