Abstract
Background
Preclinical studies in rodents have demonstrated inhibitory effects of glucagon-like peptide-1 (GLP-1) receptor stimulation on alcohol consumption. The effects of GLP-1 receptor stimulation on alcohol intake in primates have not been investigated.
Methods
We performed placebo-controlled studies on the effects of the GLP-1 receptor agonists exenatide and liraglutide on alcohol consumption in alcohol-preferring male African vervet monkeys. Monkeys selected for voluntary alcohol drinking were observed for at least 10 days of baseline drinking and allocated to drug or vehicle (n = 11–12 per group) balanced with respect to alcohol intake. Monkeys had access to alcohol 4 h/day. In a first study, monkeys were treated with exenatide 0.04 mg/kg or vehicle once weekly for 5 weeks to obtain steady-state plasma levels. In a second study, monkeys were treated daily with liraglutide (increasing dosing, 10 to 50 μg/kg/day) or vehicle over 2 weeks. In both studies, access to alcohol was suspended during drug up-titration. Then, alcohol was again made available 4 h/day and treatment was continued for 2 weeks, during which alcohol intake was recorded. Observation of alcohol intake was continued for a week of drug washout.
Results
Liraglutide and to a lesser extent exenatide significantly reduced alcohol consumption without causing any signs of emesis and with no effect on water intake as compared to vehicle.
Conclusions
The present study demonstrates for the first time that GLP-1 receptor agonists can reduce voluntary alcohol drinking in non-human primates. The data substantiate the potential usefulness of GLP-1 receptor agonists in the treatment of alcohol use disorder.
Similar content being viewed by others
Change history
25 November 2019
After publication of this paper, the authors determined an error in Fig. 4. Below is the correct Fig. 4.
References
(WHO) World Health Organization (2014) Global status report on alcohol and health 2014. WHO Library Cataloguing-in-Publication Data 2014 ed.
Akbar M, Egli M, Cho YE, Song BJ, Noronha A (2018) Medications for alcohol use disorders: an overview. Pharmacol Ther 185:64–85
Alhadeff AL, Rupprecht LE, Hayes MR (2012) GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake. Endocrinology 153:647–658
Antonsen KK, Kruse MK, Brunchmann AS, le Dous N, Jensen ME, Miskowiak KW, Fisher PM, Thomsen GK, Rindom H, Fahmy TP, Vollstädt-Klein S, Benveniste H, Volkow ND, Becker U, Ekstrøm C, Knudsen GM, Vilsbøll T, Fink-Jensen A (2018) Does glucagon-like peptide-1 (GLP-1) receptor stimulation reduce alcohol intake in patients with alcohol dependence? Study protocol of a randomized, double-blinded, placebo-controlled clinical trial. BMJ Open 8:e019562. https://doi.org/10.1136/bmjopen-2017-019562.
Buse JB, Garber A, Rosenstock J, Schmidt WE, Brett JH, Videbaek N, Holst J, Nauck M (2011) Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the liraglutide effect and action in diabetes (LEAD) trials. J Clin Endocrinol Metab 96:1695–1702
CDC Centers for Disease Control and Prevention (2016) Fact Sheets - alcohol use and your health. Available at: http://www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm. Accessed September 25, 2017
Connor JP, Haber PS, Hall WD (2016) Alcohol use disorders. Lancet 387:988–998
Cork SC, Richards JE, Holt MK, Gribble FM, Reimann F, Trapp S (2015) Distribution and characterisation of glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab 4:718–731
Del Re AC, Maisel N, Blodgett J, Finney J (2013) The declining efficacy of naltrexone pharmacotherapy for alcohol use disorders over time: a multivariate meta-analysis. Alcohol Clin Exp Res 37:1064–1068
Dickson SL, Shirazi RH, Hansson C, Bergquist F, Nissbrandt H, Skibicka KP (2012) The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors. J Neurosci 32:4812–4820
Egecioglu E, Steensland P, Fredriksson I, Feltmann K, Engel JA, Jerlhag E (2013) The glucagon-like peptide 1 analogue exendin-4 attenuates alcohol mediated behaviors in rodents. Psychoneuroendocrinology 38:1259–1270
Ervin FR, Palmour RM, Young SN, Guzman-Flores C, Juarez J (1990) Voluntary consumption of beverage alcohol by vervet monkeys: population screening, descriptive behavior and biochemical measures. Pharmacol Biochem Behav 36:367–373
Faul F, Erdfelder E, Lang AG, Buchner A (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39:175–191
Fineman M, Flanagan S, Taylor K, Aisporna M, Shen LZ, Mace KF, Walsh B, Diamant M, Cirincione B, Kothare P, Li WI, MacConell L (2011) Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing. Clin Pharmacokinet 50:65–74
Fineman MS, Mace KF, Diamant M, Darsow T, Cirincione BB, Booker Porter TK, Kinninger LA, Trautmann ME (2012) Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment. Diabetes Obes Metab 14:546–554
Fiorentino TV, Owston M, Abrahamian G, La Rosa S, Marando A, Perego C, Di Cairano ES, Finzi G, Capella C, Sessa F, Casiraghi F, Paez A, Adivi A, Davalli A, Fiorina P, Guardado Mendoza R, Comuzzie AG, Sharp M, DeFronzo RA, Halff G, Dick EJ, Folli F (2015) Chronic continuous exenatide infusion does not cause pancreatic inflammation and ductal hyperplasia in non-human primates. Am J Pathol 185:139–150
Göke R, Larsen PJ, Mikkelsen JD, Sheikh SP (1995) Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites. Eur J Neurosci 7:2294–2300
Gotfredsen CF, Molck AM, Thorup I, Nyborg NC, Salanti Z, Knudsen LB, Larsen MO (2014) The human GLP-1 analogs liraglutide and semaglutide: absence of histopathological effects on the pancreas in nonhuman primates. Diabetes 63:2486–2497
Heppner KM, Kirigiti M, Secher A, Paulsen SJ, Buckingham R, Pyke C, Knudsen LB, Vrang N, Grove KL (2015) Expression and distribution of glucagon-like peptide-1 receptor mRNA, protein and binding in the male nonhuman primate (Macaca mulatta) brain. Endocrinology 156:255–267
Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87:1409–1439
Holtyn AF, Kaminski BJ, Weerts EM (2017) Baclofen and naltrexone effects on alcohol self-administration: comparison of treatment initiated during abstinence or ongoing alcohol access in baboons. Drug Alcohol Depend 179:47–54
Hunter K, Holscher C (2012) Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 13:33
Jacobsen LV, Flint A, Olsen AK, Ingwersen SH (2016) Liraglutide in type 2 diabetes mellitus: clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 55:657–672
Jerlhag E (2018) GLP-1 signaling and alcohol-mediated behaviors; preclinical and clinical evidence. Neuropharmacology 136:343–349
Juarez J, Guzman-Flores C, Ervin FR, Palmour RM (1993) Voluntary alcohol consumption in vervet monkeys: individual, sex, and age differences. Pharmacol Biochem Behav 46:985–988
Kalra S, Kalra B, Sharma A (2011) Change in alcohol consumption following liraglutide initiation: a real life experience. American Diabetes Association Annual Meeting 2011 Poster 1029
Kastin AJ, Akerstrom V (2003) Entry of exendin-4 into brain is rapid but may be limited at high doses. Int J Obes Relat Metab Disord 27:313–318
Kim BJ, Zhou J, Martin B, Carlson OD, Maudsley S, Greig NH, Mattson MP, Ladenheim EE, Wustner J, Turner A, Sadeghi H, Egan JM (2010) Transferrin fusion technology: a novel approach to prolonging biological half-life of insulinotropic peptides. J Pharmacol Exp Ther 334:682–692
Laramee P, Kusel J, Leonard S, Aubin HJ, Francois C, Daeppen JB (2013) The economic burden of alcohol dependence in Europe. Alcohol Alcohol 48:259–269
Lonborg J, Vejlstrup N, Kelbaek H, Botker HE, Kim WY, Mathiasen AB, Jorgensen E, Helqvist S, Saunamaki K, Clemmensen P, Holmvang L, Thuesen L, Krusell LR, Jensen JS, Kober L, Treiman M, Holst JJ, Engstrom T (2012) Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 33:1491–1499
McKay NJ, Galante DL, Daniels D (2014) Endogenous glucagon-like peptide-1 reduces drinking behavior and is differentially engaged by water and food intakes in rats. J Neurosci 34:16417–16423
Merchenthaler I, Lane M, Shughrue P (1999) Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J Comp Neurol 403:261–280
Naglich AC, Lin A, Wakhlu S, Adinoff BH (2017) Systematic review of combined pharmacotherapy for the treatment of alcohol use disorder in patients without comorbid conditions. CNS Drugs 31:665–674
Nyborg NC, Molck AM, Madsen LW, Knudsen LB (2012) The human GLP-1 analog liraglutide and the pancreas: evidence for the absence of structural pancreatic changes in three species. Diabetes 61:1243–1249
Palmour RM, Ervin FR, Baker GB, Young SN (1998) An amino acid mixture deficient in phenylalanine and tyrosine reduces cerebrospinal fluid catecholamine metabolites and alcohol consumption in vervet monkeys. Psychopharmacology 136:1–7
Renner S, Blutke A, Streckel E, Wanke R, Wolf E (2016) Incretin actions and consequences of incretin-based therapies: lessons from complementary animal models. J Pathol 238:345–358
Secher A, Jelsing J, Baquero AF, Hecksher-Sorensen J, Cowley MA, Dalboge LS, Hansen G, Grove KL, Pyke C, Raun K, Schaffer L, Tang-Christensen M, Verma S, Witgen BM, Vrang N, Bjerre Knudsen L (2014) The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest 124:4473–4488
Shirazi RH, Dickson SL, Skibicka KP (2013) Gut peptide GLP-1 and its analogue, exendin-4, decrease alcohol intake and reward. PLoS One 8:e61965
Sirohi S, Schurdak JD, Seeley RJ, Benoit SC, Davis JF (2016) Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors. Physiol Behav 161:140–144
Sorensen G, Caine SB, Thomsen M (2016) Effects of the GLP-1 agonist exendin-4 on intravenous ethanol self-administration in mice. Alcohol Clin Exp Res 40:2247–2252
Suchankova P, Yan J, Schwandt ML, Stangl BL, Caparelli EC, Momenan R, Jerlhag E, Engel JA, Hodgkinson CA, Egli M, Lopez MF, Becker HC, Goldman D, Heilig M, Ramchandani VA, Leggio L (2015) 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. Transl Psychiatry 5:e583
Syed YY, McCormack PL (2015) Exenatide extended-release: an updated review of its use in type 2 diabetes mellitus. Drugs 75:1141–1152
Tang-Christensen M, Larsen PJ, Goke R, Fink-Jensen A, Jessop DS, Moller M, Sheikh SP (1996) Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats. Am J Phys 271:R848–R856
ten Kulve JS, van Bloemendaal L, Balesar R, RG IJ, Swaab DF, Diamant M, la Fleur SE, Alkemade A (2016) Decreased hypothalamic glucagon-like peptide-1 receptor expression in type 2 diabetes patients. J Clin Endocrinol Metab 101:2122–2129
Thomsen M, Dencker D, Wortwein G, Weikop P, Egecioglu E, Jerlhag E, Fink-Jensen A, Molander A (2017) The glucagon-like peptide 1 receptor agonist exendin-4 decreases relapse-like drinking in socially housed mice. Pharmacol Biochem Behav 160:14–20
Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JP, Smith DM, Ghatei MA, Herbert J, Bloom SR (1996) A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379:69–72
Vallöf D, Maccioni P, Colombo G, Mandrapa M, Jornulf JW, Egecioglu E, Engel JA, Jerlhag E (2016) The glucagon-like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents. Addict Biol 21:422–437
Yardley MM, Ray LA (2017) Medications development for the treatment of alcohol use disorder: insights into the predictive value of animal and human laboratory models. Addict Biol 22:581–615
Acknowledgements
We thank Professor Roberta Palmour, Department of Psychiatry, McGill University, Montreal, Canada, and Behavioral Science Foundation, Saint Kitts, Eastern Caribbean for the help with planning the experiment and interpreting the results. We thank Dr. Lotte Bjerre Knudsen, Novo Nordisk A/S for the help in choosing the liraglutide dosing regimen. We also thank veterinarian Amy Beierschmitt, Behavioral Science Foundation, Saint Kitts, Eastern Caribbean, for the technical and animal care assistance.
Funding
Studies were funded by Psychiatric Center Copenhagen (AFJ). MT was supported by the Psychiatric Center Copenhagen research foundation and by grant R01AA025071 from the National Institutes of Health while preparing the manuscript. The sponsors played no role in study design, data interpretation, or decision to publish.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics statement
The project was reviewed and approved by the BSF Institutional Animal Care and Use Committee (BSF IACUC), operating under the auspices of the Canadian Council on Animal Care (Canadian Council on Animal Care Good Animal Practice registration A5028) and all of the procedures used in the study were covered by standard operating procedures approved by the BSF IACUC. The approval numbers are BSF 1505 for the exenatide study and BSF 1701 for the liraglutide study
Rights and permissions
About this article
Cite this article
Thomsen, M., Holst, J.J., Molander, A. et al. Effects of glucagon-like peptide 1 analogs on alcohol intake in alcohol-preferring vervet monkeys. Psychopharmacology 236, 603–611 (2019). https://doi.org/10.1007/s00213-018-5089-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-018-5089-z