title: Gut peptide GLP-1 and its analogue, Exendin-4, decrease alcohol intake and reward.
abstract: Glucagon-like-peptide-1 (GLP-1) is a gut- and neuro-peptide with an important role in the regulation of food intake and glucose metabolism. Interestingly, GLP-1 receptors (GLP-1R) are expressed in key mesolimbic reward areas (including the ventral tegmental area, VTA), innervated by hindbrain GLP-1 neurons. Recently GLP-1 has emerged as a potential regulator of food reward behavior, an effect driven by the mesolimbic GLP-1Rs. Its role in other reward behaviors remains largely unexplored. Since a considerable overlap has been suggested for circuitry controlling reward behavior derived from food and alcohol we hypothesized that GLP-1 and GLP-1Rs could regulate alcohol intake and alcohol reward. We sought to determine whether GLP-1 or its clinically safe stable analogue, Exendin-4, reduce alcohol intake and reward. To determine the potential role of the endogenous GLP-1 in alcohol intake we evaluated whether GLP-1R antagonist, Exendin 9-39, can increase alcohol intake. Furthermore, we set out to evaluate whether VTA GLP-1R activation is sufficient to reduce alcohol intake. Male Wistar rats injected peripherally with GLP-1 or Exendin-4 reduced their alcohol intake in an intermittent access two bottle free choice drinking model. Importantly, a contribution of endogenously released GLP-1 is highlighted by our observation that blockade of GLP-1 receptors alone resulted in an increased alcohol intake. Furthermore, GLP-1 injection reduced alcohol reward in the alcohol conditioned place preference test in mice. To evaluate the neuroanatomical substrate linking GLP-1 with alcohol intake/reward, we selectively microinjected GLP-1 or Exendin 4 into the VTA. This direct stimulation of the VTA GLP-1 receptors potently reduced alcohol intake. Our findings implicate GLP-1R signaling as a novel modulator of alcohol intake and reward. We show for the first time that VTA GLP-1R stimulation leads to reduced alcohol intake. Considering that GLP-1 analogues are already approved for clinical use, this places the GLP system as an exciting new potential therapeutic target for alcohol use disorders.
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Rozita H
authors.initials: RH
authors.lastname: Shirazi
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Dickson
authors.forename: Karolina P
authors.initials: KP
authors.lastname: Skibicka
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy*; D000818:Animals; D004435:Eating / Q000187:drug effects; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014688:Venoms / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide