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The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors.

Journal article
Authors Suzanne L. Dickson
Rozita H. Shirazi
Caroline Hansson
Filip Bergquist
Hans Nissbrandt
Karolina P Skibicka
Published in The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume 32
Issue 14
Pages 4812-20
ISSN 1529-2401
Publication year 2012
Published at Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Physiology
Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 4812-20
Language en
Links dx.doi.org/10.1523/JNEUROSCI.6326-1...
Keywords Animals, Conditioning, Operant, physiology, Diabetes Mellitus, Experimental, metabolism, psychology, Eating, drug effects, physiology, psychology, Food, Glucagon-Like Peptide 1, administration & dosage, physiology, Infusions, Intraventricular, Limbic System, drug effects, physiology, Lizards, Male, Peptides, administration & dosage, physiology, Rats, Rats, Sprague-Dawley, Receptors, Glucagon, agonists, physiology, Reward, Venoms, administration & dosage
Subject categories Neurosciences

Abstract

The glucagon-like peptide 1 (GLP-1) system is a recently established target for type 2 diabetes treatment. In addition to regulating glucose homeostasis, GLP-1 also reduces food intake. Previous studies demonstrate that the anorexigenic effects of GLP-1 can be mediated through hypothalamic and brainstem circuits which regulate homeostatic feeding. Here, we demonstrate an entirely novel neurobiological mechanism for GLP-1-induced anorexia in rats, involving direct effects of a GLP-1 agonist, Exendin-4 (EX4) on food reward that are exerted at the level of the mesolimbic reward system. We assessed the impact of peripheral, central, and intramesolimbic EX4 on two models of food reward: conditioned place preference (CPP) and progressive ratio operant-conditioning. Food-reward behavior was reduced in the CPP test by EX4, as rats no longer preferred an environment previously paired to chocolate pellets. EX4 also decreased motivated behavior for sucrose in a progressive ratio operant-conditioning paradigm when administered peripherally. We show that this effect is mediated centrally, via GLP-1 receptors (GLP-1Rs). GLP-1Rs are expressed in several key nodes of the mesolimbic reward system; however, their function remains unexplored. Thus we sought to determine the neurobiological substrates underlying the food-reward effect. We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures-ventral tegmental area and nucleus accumbens-without inducing concurrent malaise or locomotor impairment. The current findings, that activation of central GLP-1Rs strikingly suppresses food reward/motivation by interacting with the mesolimbic system, indicate an entirely novel mechanism by which the GLP-1R stimulation affects feeding-oriented behavior.

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