title: The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence.
abstract: The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.
authors.affiliation: 1] Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA [2] Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Suchankova
authors.affiliation: 1] Section on Human Psychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA [2] Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yan
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Schwandt
authors.affiliation: Section on Human Psychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Stangl
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Caparelli
authors.affiliation: Section on Brain Electrophysiology and Imaging, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Momenan
authors.affiliation: Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Jerlhag
authors.affiliation: Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: J A
authors.initials: JA
authors.lastname: Engel
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Hodgkinson
authors.affiliation: Division of Neuroscience and Behavior, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Egli
authors.affiliation: Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Lopez
authors.affiliation: 1] Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston, SC, USA [2] Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA [3] Ralph H Johnson VA Medical Center, Charleston, SC, USA.
authors.forename: H C
authors.initials: HC
authors.lastname: Becker
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Goldman
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Heilig
authors.affiliation: Section on Human Psychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: V A
authors.initials: VA
authors.lastname: Ramchandani
authors.affiliation: 1] Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA [2] Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA [3] Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Leggio
mesh_terms: D000328:Adult; D000428:Alcohol Drinking; D000437:Alcoholism / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D000483:Alleles; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000503:physiopathology; D016022:Case-Control Studies; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D059907:Functional Neuroimaging; D056726:Genetic Association Studies; D005838:Genotype; D005917:Globus Pallidus / Q000503:physiopathology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009483:Neuropsychological Tests; D010455:Peptides / Q000494:pharmacology; D012646:Self Administration; D055815:Young Adult; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: C553564:AC3174; D002492:Central Nervous System Depressants; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D000431:Ethanol; D000097789:Glucagon-Like Peptide-1 Receptor Agonists