{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:02:12Z","timestamp":1788786132531,"version":"build-2803163510"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T00:00:00Z","timestamp":1663200000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Recently we identified a deficiency in metabotropic glutamate receptor 2 (mGlu2) function in the corticoaccumbal pathway, as a common pathological mechanism underlying alcohol-seeking and relapse behavior. Based on this mechanism, we hypothesized that mGlu2\/3 agonists and mGlu2 positive allosteric modulators (PAMs) may be effective in reducing relapse-like behavior. Two mGlu2\/3 agonists, LY379268 and LY354740 (a structural analog of LY379268 six-fold more potent in activating mGlu2 over mGluR3), were tested in a well-established rat model of relapse, the alcohol deprivation effect (ADE) with repeated deprivation phases. Since these agonists do not readily discriminate between contributions of mGlu2 and mGluR3, we also tested LY487379, a highly specific PAM that potentiates the effect of glutamate on the mGlu2 with less specificity on other mGlu receptor subtypes. Both LY379268 and LY354740 significantly and dose-dependently reduced the expression of the ADE. No significant changes in water intake, body weight and locomotor activity were observed. Importantly, repeated administration of mGlu2\/3 agonist did not lead to tolerance development. mGlu2 PAM LY487379 treatment significantly reduced expression of the ADE in both male and female rats. Combination treatment of mGlu2\/3 agonist and PAM had similar effect on relapse-like drinking to that seen in mGlu2\/3 agonist treatment alone. Together with other preclinical data showing that PAMs can reduce alcohol-seeking behavior we conclude that mGlu2 PAMs should be considered for clinical trials in alcohol-dependent patients.<\/jats:p>","DOI":"10.3389\/fphar.2022.985954","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T08:00:57Z","timestamp":1663228857000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["mGlu2 mechanism-based interventions to treat alcohol relapse"],"prefix":"10.3389","volume":"13","author":[{"given":"Valentina","family":"Vengeliene","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Spanagel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2932","DOI":"10.1038\/npp.2016.107","article-title":"The mGluR2 positive allosteric modulator, AZD8529, and cue-induced relapse to alcohol seeking in rats.","volume":"41","author":"Augier","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.ejphar.2005.10.051","article-title":"Suppression of alcohol self-administration and cue-induced reinstatement of alcohol seeking by the mGlu2\/3 receptor agonist LY379268 and the mGlu8 receptor agonist (S)-3, 4-DCPG","volume":"528","author":"B\u00e4ckstr\u00f6m","year":"2005","journal-title":"Eur. J. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1016\/j.biopsych.2009.09.016","article-title":"Metabotropic glutamate receptor 5 activity in the nucleus accumbens is required for the maintenance of ethanol self-administration in a rat genetic model of high alcohol intake","volume":"67","author":"Besheer","year":"2010","journal-title":"Biol. Psychiatry"},{"key":"B5","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.tips.2016.01.008","article-title":"Drug tolerance: A known unknown in translational neuroscience","volume":"37","author":"Bespalov","year":"2016","journal-title":"Trends Pharmacol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1007\/s00213-013-3120-y","article-title":"The reinstatement model of drug relapse: Recent neurobiological findings, emerging research topics, and translational research","volume":"229","author":"Bossert","year":"2013","journal-title":"Psychopharmacology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/npp.2013.106","article-title":"The mGlu2\/3 agonist LY379268 induced anti-reinstatement effects in rats exhibiting addiction-like behavior","volume":"38","author":"Cannella","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"5426","DOI":"10.1038\/s41467-021-25620-5","article-title":"Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state","volume":"12","author":"Cao","year":"2021","journal-title":"Nat. Commun."},{"key":"B9","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.biopsych.2017.08.018","article-title":"Effect of novel allosteric modulators of metabotropic glutamate receptors on drug self-administration and relapse: A review of preclinical studies and their clinical implications","volume":"84","author":"Caprioli","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"B10","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1080\/13556210500223132","article-title":"The acute anti-craving effect of acamprosate in alcohol-preferring rats is associated with modulation of the mesolimbic dopamine system","volume":"10","author":"Cowen","year":"2005","journal-title":"Addict. Biol."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/acer.14910","article-title":"Alcohol solution strength preference predicts compulsive-like drinking behavior in rats","author":"Foo","year":"2022","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1111\/j.1369-1600.2010.00262.x","article-title":"Alcohol-seeking behavior is associated with increased glutamate transmission in basolateral amygdala and nucleus accumbens as measured by glutamate-oxidase-coated biosensors","volume":"16","author":"Gass","year":"2011","journal-title":"Addict. Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1038\/sj.npp.1300672","article-title":"Group II and III metabotropic glutamate receptors suppress excitatory synaptic transmission in the dorsolateral bed nucleus of the stria terminalis","volume":"30","author":"Grueter","year":"2005","journal-title":"Neuropsychopharmacology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e12866","DOI":"10.1111\/adb.12866","article-title":"Addiction Research Consortium: Losing and regaining control over drug intake (ReCoDe)-From trajectories to mechanisms and interventions","volume":"25","author":"Heinz","year":"2020","journal-title":"Addict. Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1016\/j.biopsych.2011.07.034","article-title":"Translational magnetic resonance spectroscopy reveals excessive central glutamate levels during alcohol withdrawal in humans and rats","volume":"71","author":"Hermann","year":"2012","journal-title":"Biol. Psychiatry"},{"key":"B16","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1007\/s00213-013-3226-2","article-title":"Glutamatergic targets for new alcohol medications","volume":"229","author":"Holmes","year":"2013","journal-title":"Psychopharmacology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.neuropharm.2005.05.008","article-title":"Analgesic effects of the selective group II (mGlu2\/3) metabotropic glutamate receptor agonists LY379268 and LY389795 in persistent and inflammatory pain models after acute and repeated dosing","volume":"49","author":"Jones","year":"2005","journal-title":"Neuropharmacology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2762","DOI":"10.1038\/npp.2011.174","article-title":"Enhanced sensitivity to attenuation of conditioned reinstatement by the mGluR 2\/3 agonist LY379268 and increased functional activity of mGluR 2\/3 in rats with a history of ethanol dependence","volume":"36","author":"Kufahl","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.coph.2005.09.006","article-title":"Glutamate-based therapeutic approaches: Allosteric modulators of metabotropic glutamate receptors","volume":"6","author":"Marino","year":"2006","journal-title":"Curr. Opin. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2794","DOI":"10.1523\/JNEUROSCI.4062-12.2013","article-title":"Rescue of infralimbic mGluR2 deficit restores control over drug-seeking behavior in alcohol dependence.","volume":"33","author":"Meinhardt","year":"2013","journal-title":"J. Neurosci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"eabh2399","DOI":"10.1126\/sciadv.abh2399","article-title":"Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism","volume":"7","author":"Meinhardt","year":"2021","journal-title":"Sci. Adv."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/adb.12187","article-title":"Postdependent state in rats as a model for medication development in alcoholism","volume":"20","author":"Meinhardt","year":"2015","journal-title":"Addict. Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1124\/jpet.110.170506","article-title":"Effects of a positive allosteric modulator of group II metabotropic glutamate receptors, LY487379, on cognitive flexibility and impulsive-like responding in rats","volume":"335","author":"Nikiforuk","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B25","doi-asserted-by":"publisher","first-page":"4346","DOI":"10.1523\/JNEUROSCI.22-11-04346.2002","article-title":"Role of p\/q-Ca2+ channels in metabotropic glutamate receptor 2\/3-dependent presynaptic long-term depression at nucleus accumbens synapses","volume":"22","author":"Robbe","year":"2002","journal-title":"J. Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.bbr.2006.03.032","article-title":"The metabotropic glutamate 2\/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats","volume":"171","author":"Rodd","year":"2006","journal-title":"Behav. Brain Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1111\/adb.12382","article-title":"Why we should consider sex (and study sex differences) in addiction research","volume":"21","author":"Sanchis-Segura","year":"2016","journal-title":"Addict. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1124\/mol.64.4.798","article-title":"Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2","volume":"64","author":"Schaffhauser","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0028-3908(96)00160-8","article-title":"LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors","volume":"36","author":"Schoepp","year":"1997","journal-title":"Neuropharmacology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1016\/j.biopsych.2010.01.005","article-title":"Effects of the mGlu2\/3 agonist LY379268 and the mGlu5 antagonist MTEP on ethanol seeking and reinforcement are differentially altered in rats with a history of ethanol dependence","volume":"67","author":"Sidhpura","year":"2010","journal-title":"Biol. Psychiatry"},{"key":"B31","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1007\/s00213-013-2974-3","article-title":"Varenicline and cytisine: Two nicotinic acetylcholine receptor ligands reduce ethanol intake in university of Chile bibulous rats","volume":"227","author":"Sotomayor-Z\u00e1rate","year":"2013","journal-title":"Psychopharmacology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"247","DOI":"10.31887\/dcns.2017.19.3\/rspanagel","article-title":"Animal models of addiction","volume":"19","author":"Spanagel","year":"2017","journal-title":"Dialogues Clin. Neurosci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"869511","DOI":"10.3389\/fnbeh.2022.869511","article-title":"Ten points to improve reproducibility and translation of animal research","volume":"16","author":"Spanagel","year":"2022","journal-title":"Front. Behav. Neurosci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/0014-2999(96)00174-4","article-title":"Acamprosate and alcohol: I. Effects on alcohol intake following alcohol deprivation in the rat","volume":"305","author":"Spanagel","year":"1996","journal-title":"Eur. J. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1111\/adb.12109","article-title":"A systems medicine research approach for studying alcohol addiction","volume":"18","author":"Spanagel","year":"2013","journal-title":"Addict. Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1093\/alcalc\/34.2.231","article-title":"Long-term alcohol self-administration with repeated alcohol deprivation phases: An animal model of alcoholism?","volume":"34","author":"Spanagel","year":"1999","journal-title":"Alcohol Alcohol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1007\/7854_2012_205","article-title":"New pharmacological treatment strategies for relapse prevention","volume":"13","author":"Spanagel","year":"2013","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1111\/j.1369-1600.2009.00177.x","article-title":"Compulsive alcohol drinking in rodents","volume":"14","author":"Vengeliene","year":"2009","journal-title":"Addict. Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1016\/j.biopsych.2010.05.029","article-title":"Glycine transporter-1 blockade leads to persistently reduced relapse-like alcohol drinking in rats","volume":"68","author":"Vengeliene","year":"2010","journal-title":"Biol. Psychiatry"},{"key":"B41","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.alcohol.2014.03.002","article-title":"The alcohol deprivation effect model for studying relapse behavior: A comparison between rats and mice","volume":"48","author":"Vengeliene","year":"2014","journal-title":"Alcohol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1038\/npp.2015.225","article-title":"The calpain inhibitor A-705253 attenuates alcohol-seeking and relapse with low side-effect profile","volume":"41","author":"Vengeliene","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1124\/jpet.117.244822","article-title":"Targeting Glycine reuptake in alcohol seeking and relapse","volume":"365","author":"Vengeliene","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B44","doi-asserted-by":"publisher","first-page":"416864","DOI":"10.1155\/2012\/416864","article-title":"Mechanisms underlying tolerance after long-term benzodiazepine use: A future for subtype-selective GABA(A) receptor modulators?","volume":"2012","author":"Vinkers","year":"2012","journal-title":"Adv. Pharmacol. Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"9967","DOI":"10.1523\/JNEUROSCI.2384-06.2006","article-title":"Activation of group II metabotropic glutamate receptors attenuates both stress and cue-induced ethanol-seeking and modulates c-fos expression in the hippocampus and amygdala","volume":"26","author":"Zhao","year":"2006","journal-title":"J. Neurosci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"16963","DOI":"10.1073\/pnas.1309839110","article-title":"Loss of metabotropic glutamate receptor 2 escalates alcohol consumption","volume":"110","author":"Zhou","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.985954\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T08:01:01Z","timestamp":1663228861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.985954\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,15]]},"references-count":43,"alternative-id":["10.3389\/fphar.2022.985954"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.985954","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,15]]},"article-number":"985954"}}