title: The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors.
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.
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Dickson
authors.forename: Rozita H
authors.initials: RH
authors.lastname: Shirazi
authors.forename: Caroline
authors.initials: C
authors.lastname: Hansson
authors.forename: Filip
authors.initials: F
authors.lastname: Bergquist
authors.forename: Hans
authors.initials: H
authors.lastname: Nissbrandt
authors.forename: Karolina P
authors.initials: KP
authors.lastname: Skibicka
mesh_terms: D000818:Animals; D003216:Conditioning, Operant / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000523:psychology; D004435:Eating / Q000187:drug effects / Q000502:physiology / Q000523:psychology; D000077270:Exenatide; D005502:Food; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D057967:Infusions, Intraventricular; D008032:Limbic System / Q000187:drug effects / Q000502:physiology*; D008116:Lizards; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists / Q000502:physiology*; D012201:Reward; D014688:Venoms / Q000008:administration & dosage
chemical_list: C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide