Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

Vincent N Marty, Mehdi Farokhnia, Joseph J Munier, Yatendra Mulpuri, Lorenzo Leggio, Igor Spigelman, Vincent N Marty, Mehdi Farokhnia, Joseph J Munier, Yatendra Mulpuri, Lorenzo Leggio, Igor Spigelman

Abstract

Alcohol use disorder (AUD) is a chronic relapsing condition characterized by compulsive alcohol-seeking behaviors, with serious detrimental health consequences. Despite high prevalence and societal burden, available approved medications to treat AUD are limited in number and efficacy, highlighting a critical need for more and novel pharmacotherapies. Glucagon-like peptide-1 (GLP-1) is a gut hormone and neuropeptide involved in the regulation of food intake and glucose metabolism via GLP-1 receptors (GLP-1Rs). GLP-1 analogs are approved for clinical use for diabetes and obesity. Recently, the GLP-1 system has been shown to play a role in the neurobiology of addictive behaviors, including alcohol seeking and consumption. Here we investigated the effects of different pharmacological manipulations of the GLP-1 system on escalated alcohol intake and preference in male Wistar rats exposed to intermittent access 2-bottle choice of 10% ethanol or water. Administration of AR231453 and APD668, two different agonists of G-protein receptor 119, whose activation increases GLP-1 release from intestinal L-cells, did not affect voluntary ethanol intake. By contrast, injections of either liraglutide or semaglutide, two long-acting GLP-1 analogs, potently decreased ethanol intake. These effects, however, were transient, lasting no longer than 48 h. Semaglutide, but not liraglutide, also reduced ethanol preference on the day of injection. As expected, both analogs induced a reduction in body weight. Co-administration of exendin 9-39, a GLP-1R antagonist, did not prevent liraglutide- or semaglutide-induced effects in this study. Injection of exendin 9-39 alone, or blockade of dipeptidyl peptidase-4, an enzyme responsible for GLP-1 degradation, via injection of sitagliptin, did not affect ethanol intake or preference. Our findings suggest that among medications targeting the GLP-1 system, GLP-1 analogs may represent novel and promising pharmacological tools for AUD treatment.

Keywords: GPR119; alcohol intake; dipeptidyl peptidase-4; glucagon-like peptide-1; liraglutide; rat; semaglutide.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2020 Marty, Farokhnia, Munier, Mulpuri, Leggio and Spigelman.

Figures

FIGURE 1
FIGURE 1
Overall measurements of EtOH intake, EtOH preference, water intake, and body weight during the experiment. (A–D) Dashed lines represent the time of injection of each drug. Vehicle was injected at day 36. AR2314553 (light green circle) was injected at day 43. APD668 (DMSO) (green circle) was injected at day 68. APD668 (PEG) (dark green circle) was injected at day 92. Liraglutide (Lira, light blue circle) was injected at day 108. Semaglutide (Sema, lavender circle) was injected at day 122. Liraglutide + Ex9-39 (Lira + Ex9-39, blue circle) was injected at day 143. Semaglutide + Ex9-39 (Sema + Ex9-39, purple circle) was injected at day 171. Sitagliptin (Sitag, yellow circle) was injected at day 199. (A) Time course of the average EtOH intake (g/kg/day) (n = 12 rats). EtOH intake was measured on Mondays, Wednesdays, and Fridays from day 1 to 206. From day 1 to 29, rats progressively drank higher amounts of EtOH 10% (v/w) until reaching a plateau. (B) Time course of the average EtOH preference (%/day) (n = 12 rats). EtOH preference was calculated as the ratio of EtOH-containing solution over the total fluid consumed in a 24-h drinking session (see section “Materials and Methods”). EtOH preference progressively increased until reaching a plateau. (C) Time course of the average water intake (g/kg/day) (n = 12 rats). Water intake progressively decreased until reaching a plateau. (D) Time course of the average body weight (g) (n = 12 rats). The average body weight was 280 ± 2.96 g at day 1, and progressively increased throughout the experiment to reach an average of 623 ± 22.56 g at day 206.
FIGURE 2
FIGURE 2
Effects of GPR119 agonists [AR231453, APD668 (DMSO), and APD668 (PEG)], compared to vehicle, on EtOH intake, preference, water intake, and body weight. Bars and circles represent the mean and individual data points, respectively. (A–I) Baseline represents the average of 3 presentations prior to vehicle/drug injection. (A–C) No significant treatment × time-point interaction effects on EtOH intake were found (note: the interaction term for APD668 (DMSO) was statistically significant, but due to low power, these results were concluded to be potentially false positive). (D–F) No significant treatment × time-point interaction effects on EtOH preference were found. (G–I) No significant treatment × time-point interaction effects on water intake were found. (J,K) Significant increases in body weight were observed under vehicle and AR231453, as shown by significant increases in body weight measured at 2-day (+ 2d) and 5-day (+ 5d) post-injection compared to the body weight measured on the day of injection (pre-injection). (L,M) No significant changes in body weight were observed under APD668 (DMSO) or APD668 (PEG), as shown by the lack of significant increases in body weight measured at 2-day (+ 2d) and 5-day (+ 5d) post-injection compared to the body weight measured on the day of injection (pre-injection). ***p < 0.001.
FIGURE 3
FIGURE 3
Effects of GLP-1 analogs (liraglutide and semaglutide), compared to vehicle, on EtOH intake, preference, water intake, and body weight. Bars and circles represent the mean and individual data points, respectively. (A–F) Baseline represents the average of 3 presentations prior to vehicle/drug injection. (A) A significant treatment × time-point interaction effect on EtOH intake was found for liraglutide; under liraglutide, EtOH intake at the injection day was lower than baseline and 2-day post-injection (+ 2d). (B) A significant treatment × time-point interaction effect on EtOH intake was found for semaglutide; under semaglutide, EtOH intake at the injection day was lower than baseline and + 2d. (C) A significant treatment × time-point interaction effect on EtOH preference was found for liraglutide; under liraglutide, EtOH preference at + 2d was lower than baseline. (D) A significant treatment × time-point interaction effect on EtOH preference was found for semaglutide; under semaglutide, EtOH preference at the injection day was lower than baseline and + 2d. (E) A significant treatment × time-point interaction effect on water intake was found for liraglutide; under liraglutide, water intake at + 2d was higher than baseline and the injection day. (F) No significant treatment × time-point interaction effect on water intake was found for semaglutide. (G) Significant changes in body weight were observed under liraglutide; body weight at + 2d, + 5d, + 7d, and + 9d was lower than the body weight measured prior injection on injection day (pre-injection). (H) Significant changes in body weight were observed under semaglutide; body weight at + 2d was lower, and at + 12d was higher, than the body weight measured prior injection on injection day (pre-injection). *p < 0.05, **p < 0.01, ***p < 0.001.
FIGURE 4
FIGURE 4
Effects of GLP-1 analogs (liraglutide and semaglutide) co-administered with a GLP-1R antagonist (Ex9-39), compared to vehicle, on EtOH intake, preference, water intake, and body weight. Bars and circles represent the mean and individual data points, respectively. (A–F) Baseline represents the average of 3 presentations prior to vehicle/drug injection. (A) A significant treatment × time-point interaction effect on EtOH intake was found for liraglutide + Ex9-39; under liraglutide + Ex9-39, EtOH intake at the injection day was lower than baseline and 2-day post-injection (+ 2d). (B) A significant treatment × time-point interaction effect on EtOH intake was found for semaglutide + Ex9-39; under semaglutide + Ex9-39, EtOH intake at the injection day was lower than baseline and + 2d, and EtOH intake at + 2d was higher than baseline. (C) A significant treatment × time-point interaction effect on EtOH preference was found for liraglutide + Ex9-39; under liraglutide + Ex9-39, EtOH preference at + 2d was lower than baseline. (D) A significant treatment × time-point interaction effect on EtOH preference was found for semaglutide + Ex9-39; under semaglutide + Ex9-39, EtOH preference at the injection day was lower than baseline and + 2d. (E) A significant treatment × time-point interaction effect on water intake was found for liraglutide + Ex9-39; under liraglutide + Ex9-39, water intake at + 2d was higher than baseline and the injection day. (F) No significant treatment × time-point interaction effect on water intake was found for semaglutide + Ex9-39. (G) Significant changes in body weight were observed under liraglutide + Ex9-39; body weight at + 2d, and + 7d was lower than the body weight measured on injection day (pre-injection). (H) Significant changes in body weight were observed under semaglutide + Ex9-39; body weight at + 2d was lower than the body weight measured on injection day (pre-injection). *p < 0.05, **p < 0.01, ***p < 0.001.
FIGURE 5
FIGURE 5
Effects of a DPP4 inhibitor (sitagliptin), compared to vehicle, on EtOH intake, preference, water intake, and body weight. Bars and circles represent the mean and individual data points, respectively. (A–C) Baseline represents the average of 3 presentations prior to vehicle/drug injection. No significant treatment × time-point interaction effects on EtOH intake, EtOH preference, or water intake were found. (D) No significant changes in body weight were observed.
FIGURE 6
FIGURE 6
Overall measurements of EtOH intake, EtOH preference, water intake, and body weight for the second cohort of rats (n = 12). (A–D) Dashed lines represent the time of injection of vehicle (day 45) and Ex9-39 (day 52). (E–G) Effects of Ex9-39, compared to vehicle, on EtOH intake, preference, water intake; bars and circles represent the mean and individual data points, respectively. Baseline represents the average of 3 presentations prior to vehicle/drug injection. No significant treatment × time-point interaction effects on EtOH intake, EtOH preference, or water intake were found (note: the effect of the interaction term on EtOH intake was statistically significant, but due to low power, these results were concluded to be potentially false positive). (H) Effects of Ex9-39 on body weight. Significant changes in body weight were observed; body weight at + 2d and + 5d was higher than the body weight measured on injection day (pre-injection). *p < 0.05.

References

    1. Agersø H., Jensen L. B., Elbrønd B., Rolan P., Zdravkovic M. (2002). The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 45 195–202. 10.1007/s00125-001-0719-z
    1. Alvarez E., Roncero I., Chowen J. A., Thorens B., Blázquez E. (1996). Expression of the glucagon-like peptide-1 receptor gene in rat brain. J. Neurochem. 66 920–927. 10.1046/j.1471-4159.1996.66030920.x
    1. Andresen M. C., Kunze D. L. (1994). Nucleus tractus solitarius–gateway to neural circulatory control. Annu. Rev. Physiol. 56 93–116. 10.1146/annurev.ph.56.030194.000521
    1. Ast J., Arvaniti A., Fine N. H. F., Nasteska D., Ashford F. B., Stamataki Z., et al. (2020). Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics. Nat. Commun. 11:467. 10.1038/s41467-020-14309-w
    1. Bahirat U. A., Shenoy R. R., Goel R. N., Nemmani K. V. (2017). APD668, a G protein-coupled receptor 119 agonist improves fat tolerance and attenuates fatty liver in high-trans fat diet induced steatohepatitis model in C57BL/6 mice. Eur. J. Pharmacol. 801, 35–45. 10.1016/j.ejphar.2017.02.043
    1. Bornebusch A. B., Fink-Jensen A., Wörtwein G., Seeley R. J., Thomsen M. (2019). Glucagon-like peptide-1 receptor agonist treatment does not reduce abuse-related effects of opioid drugs. eNeuro 6:ENEURO.0443-18.2019.
    1. Buse J. B., Rosenstock J., Sesti G., Schmidt W. E., Montanya E., Brett J. H., et al. (2009). Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 374 39–47. 10.1016/S0140-6736(09)60659-0
    1. Carnicella S., Ron D., Barak S. (2014). Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol 48 243–252. 10.1016/j.alcohol.2014.01.006
    1. Chepurny O. G., Bertinetti D., Diskar M., Leech C. A., Afshari P., Tsalkova T., et al. (2013). Stimulation of proglucagon gene expression by human GPR119 in enteroendocrine L-cell line GLUTag. Mol. Endocrinol. 27 1267–1282. 10.1210/me.2013-1029
    1. Chu Z. L., Carroll C., Alfonso J., Gutierrez V., He H., Lucman A., et al. (2008). A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like Peptide-1 and glucose-dependent insulinotropic Peptide release. Endocrinology 149 2038–2047. 10.1210/en.2007-0966
    1. Chu Z. L., Jones R. M., He H., Carroll C., Gutierrez V., Lucman A., et al. (2007). A role for beta-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology 148 2601–2609. 10.1210/en.2006-1608
    1. Cippitelli A., Damadzic R., Singley E., Thorsell A., Ciccocioppo R., Eskay R. L., et al. (2012). Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats. Pharmacol. Biochem. Behav. 100 522–529. 10.1016/j.pbb.2011.10.016
    1. Cork S. C., Richards J. E., Holt M. K., Gribble F. M., 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. 10.1016/j.molmet.2015.07.008
    1. Deacon C. F., Johnsen A. H., Holst J. J. (1995a). Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J. Clin. Endocrinol. Metab. 80 952–957. 10.1210/jcem.80.3.7883856
    1. Deacon C. F., Nauck M. A., Toft-Nielsen M., Pridal L., Willms B., Holst J. J. (1995b). Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 44 1126–1131. 10.2337/diab.44.9.1126
    1. Diana M., Pistis M., Carboni S., Gessa G. L., Rossetti Z. L. (1993). Profound decrement of mesolimbic dopaminergic neuronal activity during ethanol withdrawal syndrome in rats: electrophysiological and biochemical evidence. Proc. Natl. Acad. Sci. U.S.A. 90 7966–7969. 10.1073/pnas.90.17.7966
    1. Edwards C. M., Todd J. F., Mahmoudi M., Wang Z., Wang R. M., Ghatei M. A., et al. (1999). Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. Diabetes 48 86–93. 10.2337/diabetes.48.1.86
    1. Egecioglu E., Engel J. A., Jerlhag E. (2013a). The glucagon-like peptide 1 analogue, exendin-4, attenuates the rewarding properties of psychostimulant drugs in mice. PLoS One 8:e69010. 10.1371/journal.pone.0069010
    1. Egecioglu E., Steensland P., Fredriksson I., Feltmann K., Engel J. A., Jerlhag E. (2013b). The glucagon-like peptide 1 analogue Exendin-4 attenuates alcohol mediated behaviors in rodents. Psychoneuroendocrinology 38 1259–1270. 10.1016/j.psyneuen.2012.11.009
    1. Eng C., Kramer C. K., Zinman B., Retnakaran R. (2014). Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 384 2228–2234. 10.1016/S0140-6736(14)61335-0
    1. Estall J. L., Drucker D. J. (2006). Glucagon and glucagon-like peptide receptors as drug targets. Curr. Pharm. Des. 12 1731–1750. 10.2174/138161206776873671
    1. Fang Y., Zhang S., Li M., Xiong L., Tu L., Xie S., et al. (2020a). Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR119 agonists. J. Enzyme Inhib. Med. Chem. 35 50–58. 10.1080/14756366.2019.1681988
    1. Fang Y., Zhang S., Wu W., Liu Y., Yang J., Li Y., et al. (2020b). Design and synthesis of tetrahydropyridopyrimidine derivatives as dual GPR119 and DPP-4 modulators. Bioorg. Chem. 94 103390. 10.1016/j.bioorg.2019.103390
    1. Farokhnia M., Browning B. D., Leggio L. (2019a). Prospects for pharmacotherapies to treat alcohol use disorder: an update on recent human studies. Curr. Opin. Psychiatry 32 255–265. 10.1097/YCO.0000000000000519
    1. Farokhnia M., Faulkner M. L., Piacentino D., Lee M. R., Leggio L. (2019b). Ghrelin: from a gut hormone to a potential therapeutic target for alcohol use disorder. Physiol. Behav. 204 49–57. 10.1016/j.physbeh.2019.02.008
    1. Flint A., Raben A., Ersbøll A. K., Holst J. J., Astrup A. (2001). The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int. J. Obes. Relat. Metab. Disord. 25 781–792. 10.1038/sj.ijo.0801627
    1. Fortin S. M., Lipsky R. K., Lhamo R., Chen J., Kim E., Borner T., et al. (2020). GABA neurons in the nucleus tractus solitarius express GLP-1 receptors and mediate anorectic effects of liraglutide in rats. Sci. Transl. Med. 12:eaay8071. 10.1126/scitranslmed.aay8071
    1. Fortin S. M., Roitman M. F. (2017). Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core. Physiol. Behav. 176 17–25. 10.1016/j.physbeh.2017.03.019
    1. Fredriksson R., Höglund P. J., Gloriam D. E., Lagerström M. C., Schiöth H. B. (2003). Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives. FEBS Lett. 554 381–388. 10.1016/s0014-5793(03)01196-7
    1. Fu R., Mei Q., Shiwalkar N., Zuo W., Zhang H., Gregor D., et al. (2020). Anxiety during alcohol withdrawal involves 5-HT2C receptors and M-channels in the lateral habenula. Neuropharmacology 163 107863. 10.1016/j.neuropharm.2019.107863
    1. Gabery S., Salinas C. G., Paulsen S. J., Ahnfelt-Rønne J., Alanentalo T., Baquero A. F., et al. (2020). Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 5:e133429. 10.1172/jci.insight.133429
    1. Gaykema R. P., Newmyer B. A., Ottolini M., Raje V., Warthen D. M., Lambeth P. S., et al. (2017). Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight. J. Clin. Invest. 127 1031–1045. 10.1172/JCI81335
    1. Ghosal S., Packard A. E. B., Mahbod P., Mcklveen J. M., Seeley R. J., Myers B., et al. (2017). Disruption of glucagon-like peptide 1 signaling in sim1 neurons reduces physiological and behavioral reactivity to acute and chronic stress. J. Neurosci. 37 184–193. 10.1523/JNEUROSCI.1104-16.2016
    1. Göke R., Fehmann H. C., Linn T., Schmidt H., Krause M., Eng J., et al. (1993). Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J. Biol. Chem. 268 19650–19655.
    1. Göke R., Larsen P. J., Mikkelsen J. D., Sheikh S. P. (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. 10.1111/j.1460-9568.1995.tb00650.x
    1. Graham D. L., Durai H. H., Trammell T. S., Noble B. L., Mortlock D. P., Galli A., et al. (2020). A novel mouse model of glucagon-like peptide-1 receptor expression: a look at the brain. J. Comp. Neurol. 528 2445–2470. 10.1002/cne.24905
    1. Graham D. L., Erreger K., Galli A., Stanwood G. D. (2013). GLP-1 analog attenuates cocaine reward. Mol. Psychiatry 18 961–962. 10.1038/mp.2012.141
    1. Hall S., Isaacs D., Clements J. N. (2018). Pharmacokinetics and clinical implications of semaglutide: a new glucagon-like peptide (GLP)-1 receptor agonist. Clin. Pharmacokinet. 57 1529–1538. 10.1007/s40262-018-0668-z
    1. Han T., Lee B. M., Park Y. H., Lee D. H., Choi H. H., Lee T., et al. (2018). YH18968, a Novel 1,2,4-triazolone G-protein coupled receptor 119 agonist for the treatment of type 2 diabetes mellitus. Biomol. Ther. 26 201–209. 10.4062/biomolther.2018.011
    1. Hansen K. B., Rosenkilde M. M., Knop F. K., Wellner N., Diep T. A., Rehfeld J. F., et al. (2011). 2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J. Clin. Endocrinol. Metab. 96 E1409–E1417. 10.1210/jc.2011-0647
    1. Harasta A. E., Power J. M., Von Jonquieres G., Karl T., Drucker D. J., Housley G. D., et al. (2015). Septal glucagon-like peptide 1 receptor expression determines suppression of cocaine-induced behavior. Neuropsychopharmacology 40 1969–1978. 10.1038/npp.2015.47
    1. Hassing H. A., Engelstoft M. S., Sichlau R. M., Madsen A. N., Rehfeld J. F., Pedersen J., et al. (2016). Oral 2-oleyl glyceryl ether improves glucose tolerance in mice through the GPR119 receptor. Biofactors 42 665–673. 10.1002/biof.1303
    1. Hayes M. R., De Jonghe B. C., Kanoski S. E. (2010). Role of the glucagon-like-peptide-1 receptor in the control of energy balance. Physiol. Behav. 100 503–510. 10.1016/j.physbeh.2010.02.029
    1. Herman M. A., Contet C., Roberto M. (2016). A functional switch in tonic GABA currents alters the output of central amygdala corticotropin releasing factor receptor-1 neurons following chronic ethanol exposure. J. Neurosci. 36 10729–10741. 10.1523/JNEUROSCI.1267-16.2016
    1. Holt M. K., Richards J. E., Cook D. R., Brierley D. I., Williams D. L., Reimann F., et al. (2019). Preproglucagon neurons in the nucleus of the solitary tract are the main source of brain GLP-1, mediate stress-induced hypophagia, and limit unusually large intakes of food. Diabetes 68 21–33. 10.2337/db18-0729
    1. Hopf F. W. (2020). Recent perspectives on orexin/hypocretin promotion of addiction-related behaviors. Neuropharmacology 168:108013. 10.1016/j.neuropharm.2020.108013
    1. Hothersall J. D., Bussey C. E., Brown A. J., Scott J. S., Dale I., Rawlins P. (2015). Sustained wash-resistant receptor activation responses of GPR119 agonists. Eur. J. Pharmacol. 762 430–442. 10.1016/j.ejphar.2015.06.031
    1. Hunter K., Hölscher C. (2012). Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 13:33. 10.1186/1471-2202-13-33
    1. Jerlhag E. (2018). GLP-1 signaling and alcohol-mediated behaviors; preclinical and clinical evidence. Neuropharmacology 136 343–349. 10.1016/j.neuropharm.2018.01.013
    1. Kang S., Li J., Zuo W., Chen P., Gregor D., Fu R., et al. (2019). Downregulation of M-channels in the lateral habenula mediates hyperalgesia during alcohol withdrawal in rats. Sci. Rep. 9:2714. 10.1038/s41598-018-38393-7
    1. Kanoski S. E., Fortin S. M., Arnold M., Grill H. J., Hayes M. R. (2011). Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. Endocrinology 152 3103–3112. 10.1210/en.2011-0174
    1. Kanoski S. E., Rupprecht L. E., Fortin S. M., De Jonghe B. C., Hayes M. R. (2012). The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide. Neuropharmacology 62 1916–1927. 10.1016/j.neuropharm.2011.12.022
    1. Kapitza C., Nosek L., Jensen L., Hartvig H., Jensen C. B., Flint A. (2015). Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel. J. Clin. Pharmacol. 55 497–504. 10.1002/jcph.443
    1. Kastin A. J., 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. 10.1038/sj.ijo.0802206
    1. Katz L. B., Gambale J. J., Rothenberg P. L., Vanapalli S. R., Vaccaro N., Xi L., et al. (2011). Pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-38431055, a novel GPR119 receptor agonist and potential antidiabetes agent, in healthy male subjects. Clin. Pharmacol. Ther. 90 685–692. 10.1038/clpt.2011.169
    1. Keshavarzian A., Farhadi A., Forsyth C. B., Rangan J., Jakate S., Shaikh M., et al. (2009). Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats. J. Hepatol. 50 538–547. 10.1016/j.jhep.2008.10.028
    1. Kinzig K. P., D’alessio D. A., Herman J. P., Sakai R. R., Vahl T. P., Figueiredo H. F., et al. (2003). CNS glucagon-like peptide-1 receptors mediate endocrine and anxiety responses to interoceptive and psychogenic stressors. J. Neurosci. 23 6163–6170. 10.1523/JNEUROSCI.23-15-06163.2003
    1. Klein J. W. (2016). Pharmacotherapy for substance use disorders. Med. Clin. North Am. 100 891–910. 10.1016/j.mcna.2016.03.011
    1. Knudsen L. B., Lau J. (2019). The discovery and development of liraglutide and semaglutide. Front. Endocrinol. 10:155. 10.3389/fendo.2019.00155
    1. Kolterman O. G., Kim D. D., Shen L., Ruggles J. A., Nielsen L. L., Fineman M. S., et al. (2005). Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am. J. Health Syst. Pharm. 62 173–181. 10.1093/ajhp/62.2.173
    1. Koob G. F. (2015). The dark side of emotion: the addiction perspective. Eur. J. Pharmacol. 753 73–87. 10.1016/j.ejphar.2014.11.044
    1. Koole C., Wootten D., Simms J., Valant C., Sridhar R., Woodman O. L., et al. (2010). Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: implications for drug screening. Mol. Pharmacol. 78 456–465. 10.1124/mol.110.065664
    1. Lan H., Lin H. V., Wang C. F., Wright M. J., Xu S., Kang L., et al. (2012). Agonists at GPR119 mediate secretion of GLP-1 from mouse enteroendocrine cells through glucose-independent pathways. Br. J. Pharmacol. 165 2799–2807. 10.1111/j.1476-5381.2011.01754.x
    1. Larsen P. J., Fledelius C., Knudsen L. B., Tang-Christensen M. (2001). Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats. Diabetes 50 2530–2539. 10.2337/diabetes.50.11.2530
    1. Larsen P. J., Tang-Christensen M., Holst J. J., Orskov C. (1997). Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience 77 257–270. 10.1016/s0306-4522(96)00434-4
    1. Lau J., Bloch P., Schäffer L., Pettersson I., Spetzler J., Kofoed J., et al. (2015). Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J. Med. Chem. 58 7370–7380. 10.1021/acs.jmedchem.5b00726
    1. Li G., Meng B., Yuan B., Huan Y., Zhou T., Jiang Q., et al. (2020). The optimization of xanthine derivatives leading to HBK001 hydrochloride as a potent dual ligand targeting DPP-IV and GPR119. Eur. J. Med. Chem. 188 112017. 10.1016/j.ejmech.2019.112017
    1. Li J., Chen P., Han X., Zuo W., Mei Q., Bian E. Y., et al. (2019). Differences between male and female rats in alcohol drinking, negative affects and neuronal activity after acute and prolonged abstinence. Int. J. Physiol. Pathophysiol. Pharmacol. 11 163–176.
    1. Liang J., Lindemeyer A. K., Suryanarayanan A., Meyer E. M., Marty V. N., Ahmad S. O., et al. (2014a). Plasticity of GABA(A) receptor-mediated neurotransmission in the nucleus accumbens of alcohol-dependent rats. J. Neurophysiol. 112 39–50. 10.1152/jn.00565.2013
    1. Liang J., Marty V. N., Mulpuri Y., Olsen R. W., Spigelman I. (2014b). Selective modulation of GABAergic tonic current by dopamine in the nucleus accumbens of alcohol-dependent rats. J. Neurophysiol. 112 51–60. 10.1152/jn.00564.2013
    1. Liu J., Conde K., Zhang P., Lilascharoen V., Xu Z., Lim B. K., et al. (2017). Enhanced AMPA receptor trafficking mediates the anorexigenic effect of endogenous glucagon-like peptide-1 in the paraventricular hypothalamus. Neuron 96 897–909.e5. 10.1016/j.neuron.2017.09.042
    1. Llewellyn-Smith I. J., Reimann F., Gribble F. M., Trapp S. (2011). Preproglucagon neurons project widely to autonomic control areas in the mouse brain. Neuroscience 180 111–121. 10.1016/j.neuroscience.2011.02.023
    1. Mandøe M. J., Hansen K. B., Hartmann B., Rehfeld J. F., Holst J. J., Hansen H. S. (2015). The 2-monoacylglycerol moiety of dietary fat appears to be responsible for the fat-induced release of GLP-1 in humans. Am. J. Clin. Nutr. 102 548–555. 10.3945/ajcn.115.106799
    1. Marty V., El Hachmane M., Amedee T. (2008). Dual modulation of synaptic transmission in the nucleus tractus solitarius by prostaglandin E2 synthesized downstream of IL-1beta. Eur J. Neurosci. 27 3132–3150. 10.1111/j.1460-9568.2008.06296.x
    1. Marty V. N., Mulpuri Y., Munier J. J., Spigelman I. (2020). Chronic alcohol disrupts hypothalamic responses to stress by modifying CRF and NMDA receptor function. Neuropharmacology 167:107991. 10.1016/j.neuropharm.2020.107991
    1. Marty V. N., Spigelman I. (2012). Long-lasting alterations in membrane properties, k(+) currents, and glutamatergic synaptic currents of nucleus accumbens medium spiny neurons in a rat model of alcohol dependence. Front. Neurosci. 6:86. 10.3389/fnins.2012.00086
    1. Matsumoto K., Yoshitomi T., Ishimoto Y., Tanaka N., Takahashi K., Watanabe A., et al. (2018). DS-8500a, an orally available g protein-coupled receptor 119 agonist, upregulates glucagon-like peptide-1 and enhances glucose-dependent insulin secretion and improves glucose homeostasis in type 2 diabetic rats. J. Pharmacol. Exp. Ther. 367 509–517. 10.1124/jpet.118.250019
    1. McKay N. J., Kanoski S. E., Hayes M. R., Daniels D. (2011). Glucagon-like peptide-1 receptor agonists suppress water intake independent of effects on food intake. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301 R1755–R1764. 10.1152/ajpregu.00472.2011
    1. Melancon B. J., Hopkins C. R., Wood M. R., Emmitte K. A., Niswender C. M., Christopoulos A., et al. (2012). Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J. Med. Chem. 55 1445–1464. 10.1021/jm201139r
    1. 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.
    1. Meyer E. M., Long V., Fanselow M. S., Spigelman I. (2013). Stress increases voluntary alcohol intake, but does not alter established drinking habits in a rat model of posttraumatic stress disorder. Alcohol. Clin. Exp. Res. 37 566–574. 10.1111/acer.12012
    1. Motulsky H. J., Brown R. E. (2006). Detecting outliers when fitting data with nonlinear regression - a new method based on robust nonlinear regression and the false discovery rate. BMC Bioinformatics 7:123. 10.1186/1471-2105-7-123
    1. Novak U., Wilks A., Buell G., Mcewen S. (1987). Identical mRNA for preproglucagon in pancreas and gut. Eur. J. Biochem. 164 553–558. 10.1111/j.1432-1033.1987.tb11162.x
    1. Orskov C., Holst J. J., Nielsen O. V. (1988). Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology 123 2009–2013. 10.1210/endo-123-4-2009
    1. Overton H. A., Babbs A. J., Doel S. M., Fyfe M. C., Gardner L. S., Griffin G., et al. (2006). Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 3 167–175. 10.1016/j.cmet.2006.02.004
    1. Park Y. H., Choi H. H., Lee D. H., Chung S. Y., Yang N. Y., Kim D. H., et al. (2017). YH18421, a novel GPR119 agonist exerts sustained glucose lowering and weight loss in diabetic mouse model. Arch. Pharm. Res. 40 772–782. 10.1007/s12272-017-0925-y
    1. Rehm J., Mathers C., Popova S., Thavorncharoensap M., Teerawattananon Y., Patra J. (2009). Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 373 2223–2233.
    1. Roberto M., Cruz M. T., Gilpin N. W., Sabino V., Schweitzer P., Bajo M., et al. (2010). Corticotropin releasing factor-induced amygdala gamma-aminobutyric Acid release plays a key role in alcohol dependence. Biol. Psychiatry 67 831–839. 10.1016/j.biopsych.2009.11.007
    1. Sandoval D. A., Bagnol D., Woods S. C., D’alessio D. A., Seeley R. J. (2008). Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes 57 2046–2054. 10.2337/db07-1824
    1. Schepp W., Schmidtler J., Riedel T., Dehne K., Schusdziarra V., Holst J. J., et al. (1994). Exendin-4 and exendin-(9-39)NH2: agonist and antagonist, respectively, at the rat parietal cell receptor for glucagon-like peptide-1-(7-36)NH2. Eur. J. Pharmacol. 269 183–191. 10.1016/0922-4106(94)90085-x
    1. Secher A., Jelsing J., Baquero A. F., Hecksher-Sørensen J., Cowley M. A., Dalbøge L. S., et al. (2014). The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J. Clin. Invest. 124 4473–4488. 10.1172/JCI75276
    1. Semple G., Fioravanti B., Pereira G., Calderon I., Uy J., Choi K., et al. (2008). Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119. J. Med. Chem. 51 5172–5175. 10.1021/jm8006867
    1. Semple G., Lehmann J., Wong A., Ren A., Bruce M., Shin Y. J., et al. (2012). Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile. Bioorg. Med. Chem. Lett. 22 1750–1755. 10.1016/j.bmcl.2011.12.092
    1. Semple G., Ren A., Fioravanti B., Pereira G., Calderon I., Choi K., et al. (2011). Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control. Bioorg. Med. Chem. Lett. 21 3134–3141. 10.1016/j.bmcl.2011.03.007
    1. Shirazi R. H., Dickson S. L., Skibicka K. P. (2013). Gut peptide GLP-1 and its analogue, Exendin-4, decrease alcohol intake and reward. PLoS One 8:e61965. 10.1371/journal.pone.0061965
    1. Simms J. A., Steensland P., Medina B., Abernathy K. E., Chandler L. J., Wise R., et al. (2008). Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats. Alcohol. Clin. Exp. Res. 32 1816–1823. 10.1111/j.1530-0277.2008.00753.x
    1. Sirohi S., Schurdak J. D., Seeley R. J., Benoit S. C., Davis J. F. (2016). Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors. Physiol. Behav. 161 140–144. 10.1016/j.physbeh.2016.04.013
    1. Soga T., Ohishi T., Matsui T., Saito T., Matsumoto M., Takasaki J., et al. (2005). Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem. Biophys. Res. Commun. 326 744–751. 10.1016/j.bbrc.2004.11.120
    1. Sørensen G., Reddy I. A., Weikop P., Graham D. L., Stanwood G. D., Wortwein G., et al. (2015). The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice. Physiol. Behav. 149 262–268. 10.1016/j.physbeh.2015.06.013
    1. Spasov A. A., Kosolapov V. A., Babkov D. A., Maika O. Y. (2017). Effect of GRP119 receptor agonist, compound MBX-2982, on activity of human glucokinase. Bull. Exp. Biol. Med. 163 695–698. 10.1007/s10517-017-3881-0
    1. Suchankova P., Yan J., Schwandt M. L., Stangl B. L., Caparelli E. C., Momenan R., et al. (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. 10.1038/tp.2015.68
    1. Terauchi Y., Yamada Y., Watada H., Nakatsuka Y., Shiosakai K., Washio T., et al. (2018). Efficacy and safety of the G protein-coupled receptor 119 agonist DS-8500a in Japanese type 2 diabetes mellitus patients with inadequate glycemic control on sitagliptin: a phase 2 randomized placebo-controlled study. J. Diabetes Investig. 9 1333–1341. 10.1111/jdi.12846
    1. Thorens B., Porret A., Bühler L., Deng S. P., Morel P., Widmann C. (1993). Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes 42 1678–1682. 10.2337/diab.42.11.1678
    1. Thorsell A., Mathé A. A. (2017). Neuropeptide Y in alcohol addiction and affective disorders. Front. Endocrinol. 8:178. 10.3389/fendo.2017.00178
    1. Tuesta L. M., Chen Z., Duncan A., Fowler C. D., Ishikawa M., Lee B. R., et al. (2017). GLP-1 acts on habenular avoidance circuits to control nicotine intake. Nat. Neurosci. 20 708–716. 10.1038/nn.4540
    1. Vallöf D., Kalafateli A. L., Jerlhag E. (2019a). Brain region specific glucagon-like peptide-1 receptors regulate alcohol-induced behaviors in rodents. Psychoneuroendocrinology 103 284–295. 10.1016/j.psyneuen.2019.02.006
    1. Vallöf D., Kalafateli A. L., Jerlhag E. (2020). Long-term treatment with a glucagon-like peptide-1 receptor agonist reduces ethanol intake in male and female rats. Transl. Psychiatry 10 238. 10.1038/s41398-020-00923-1
    1. Vallöf D., Maccioni P., Colombo G., Mandrapa M., Jörnulf J. W., Egecioglu E., et al. (2016). The glucagon-like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents. Addict. Biol. 21 422–437. 10.1111/adb.12295
    1. Vallöf D., Vestlund J., Jerlhag E. (2019b). Glucagon-like peptide-1 receptors within the nucleus of the solitary tract regulate alcohol-mediated behaviors in rodents. Neuropharmacology 149 124–132. 10.1016/j.neuropharm.2019.02.020
    1. Volkow N. D., Wang G. J., Telang F., Fowler J. S., Logan J., Jayne M., et al. (2007). Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J. Neurosci. 27 12700–12706. 10.1523/JNEUROSCI.3371-07.2007
    1. von Holstein-Rathlou S., Gillum M. P. (2019). Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite. J. Physiol. 597 3539–3548. 10.1113/JP277117
    1. Wang Z., Wang R. M., Owji A. A., Smith D. M., Ghatei M. A., Bloom S. R. (1995). Glucagon-like peptide-1 is a physiological incretin in rat. J. Clin. Invest. 95 417–421. 10.1172/JCI117671
    1. Weiss F., Parsons L. H., Schulteis G., Hyytia P., Lorang M. T., Bloom F. E., et al. (1996). Ethanol self-administration restores withdrawal-associated deficiencies in accumbal dopamine and 5-hydroxytryptamine release in dependent rats. J. Neurosci. 16 3474–3485. 10.1523/JNEUROSCI.16-10-03474.1996
    1. Wise R. A. (1975). Maximization of ethanol intake in the rat. Adv. Exp. Med. Biol. 59 279–294. 10.1007/978-1-4757-0632-1_19
    1. Witkiewitz K., Litten R. Z., Leggio L. (2019). Advances in the science and treatment of alcohol use disorder. Sci. Adv. 5:eaax4043. 10.1126/sciadv.aax4043
    1. Yang J. W., Kim H. S., Choi Y. W., Kim Y. M., Kang K. W. (2018). Therapeutic application of GPR119 ligands in metabolic disorders. Diabetes Obes. Metab. 20 257–269. 10.1111/dom.13062
    1. Yoshida S., Ohishi T., Matsui T., Tanaka H., Oshima H., Yonetoku Y., et al. (2010). Novel GPR119 agonist AS1535907 contributes to first-phase insulin secretion in rat perfused pancreas and diabetic db/db mice. Biochem. Biophys. Res. Commun. 402 280–285. 10.1016/j.bbrc.2010.10.015
    1. Zhang Y., Kahng M. W., Elkind J. A., Weir V. R., Hernandez N. S., Stein L. M., et al. (2020). Activation of GLP-1 receptors attenuates oxycodone taking and seeking without compromising the antinociceptive effects of oxycodone in rats. Neuropsychopharmacology 45 451–461. 10.1038/s41386-019-0531-4
    1. Zoccal D. B., Furuya W. I., Bassi M., Colombari D. S., Colombari E. (2014). The nucleus of the solitary tract and the coordination of respiratory and sympathetic activities. Front. Physiol. 5:238. 10.3389/fphys.2014.00238

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