{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:51:54Z","timestamp":1791492714935,"version":"4.3.4"},"reference-count":45,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T00:00:00Z","timestamp":1654128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"the German Research Foundation (DFG)","doi-asserted-by":"publisher","award":["FL 729\/2-1"],"award-info":[{"award-number":["FL 729\/2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Chronic psychosocial stress participates prominently in the etiology of various psychiatric conditions and comorbid somatic pathologies; however, suitable pharmacotherapy of these disorders is still of high medical need. During the last few decades, research on mGlu receptors advanced remarkably and much attention was given to the mGlu7 subtype. Here, genetic mGlu7 ablation, short-term pharmacological mGlu7 blockade, as well as siRNA-mediated knockdown of mGlu7 were shown to result in an acute anti-stress, antidepressant- and anxiolytic-like phenotype in mice. Moreover, we recently revealed a prominent stress-protective effect of genetic mGlu7 ablation also with respect to chronic psychosocial stress. In addition, we are able to demonstrate in the present study that the chronic pharmacological blockade of mGlu7 interferes with various chronic stress-induced alterations. For this, we used the chronic subordinate colony housing (CSC), a mouse model of chronic male subordination, in combination with chronic treatment with the mGlu7-selective orthosteric-like antagonist XAP044 (7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one). Interestingly, XAP044 dose-dependently ameliorates hypothalamic\u2013pituitary\u2013adrenal axis dysfunctions, thymus atrophy, as well as the CSC-induced increase in innate anxiety. Taken together, our findings provide further evidence for the role of mGlu7 in chronic psychosocial stress-induced alterations and suggests the pharmacological blockade of mGlu7 as a promising therapeutic approach for the treatment of chronic stress-related pathologies in men.<\/jats:p>","DOI":"10.3390\/cells11111817","type":"journal-article","created":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T04:46:23Z","timestamp":1654145183000},"page":"1817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Karolyne A. R.","family":"Estrela","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Senninger","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine","family":"Arndt","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Kabas","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdinand","family":"Schmid","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2014-8419","authenticated-orcid":false,"given":"Larissa","family":"Dillmann","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Auer","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Stepfer","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Flor","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Uschold-Schmidt","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/nrendo.2009.106","article-title":"Stress and disorders of the stress system","volume":"5","author":"Chrousos","year":"2009","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/nrn2639","article-title":"Effects of stress throughout the lifespan on the brain, behaviour and cognition","volume":"10","author":"Lupien","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fpsyt.2015.00018","article-title":"Chronic subordinate colony housing paradigm: A mouse model to characterize the consequences of insufficient glucocorticoid signaling","volume":"6","author":"Langgartner","year":"2015","journal-title":"Front. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"514","DOI":"10.2174\/1570159X13666150515234920","article-title":"The Emerging Role of Metabotropic Glutamate Receptors in the Pathophysiology of Chronic Stress-Related Disorders","volume":"14","author":"Peterlik","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0163-7258(03)00038-X","article-title":"Evolution, structure, and activation mechanism of family 3\/C G-protein-coupled receptors","volume":"98","author":"Pin","year":"2003","journal-title":"Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1146\/annurev.pharmtox.011008.145533","article-title":"Metabotropic glutamate receptors: Physiology, pharmacology, and disease","volume":"50","author":"Niswender","year":"2010","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/(SICI)1096-9861(19980413)393:3<332::AID-CNE6>3.0.CO;2-2","article-title":"Immunohistochemical localization of metabotropic glutamate receptors, mGluR7a and mGluR7b, in the central nervous system of the adult rat and mouse: A light and electron microscopic study","volume":"393","author":"Kinoshita","year":"1998","journal-title":"J. Comp. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1002\/(SICI)1096-9861(19991213)415:2<266::AID-CNE9>3.0.CO;2-7","article-title":"Localization of metabotropic glutamate receptor 7 mRNA and mGluR7a protein in the rat basal ganglia","volume":"415","author":"Kosinski","year":"1999","journal-title":"J. Comp. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1111\/j.1528-1167.2011.03082.x","article-title":"Metabotropic glutamate receptors in the thalamocortical network: Strategic targets for the treatment of absence epilepsy","volume":"52","author":"Ngomba","year":"2011","journal-title":"Epilepsia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1124\/pr.110.004036","article-title":"Exciting times beyond the brain: Metabotropic glutamate receptors in peripheral and non-neural tissues","volume":"63","author":"Flor","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.bmcl.2009.11.070","article-title":"Isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists","volume":"20","author":"Nakamura","year":"2010","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S0028-3908(03)00027-3","article-title":"Endogenous activation of group-II metabotropic glutamate receptors inhibits the hypothalamic-pituitary-adrenocortical axis","volume":"44","author":"Scaccianoce","year":"2003","journal-title":"Neuropharmacology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6573","DOI":"10.1523\/JNEUROSCI.1497-06.2006","article-title":"Concomitant Deficits in Working Memory and Fear Extinction Are Functionally Dissociated from Reduced Anxiety in Metabotropic Glutamate Receptor 7-Deficient Mice","volume":"26","author":"Beckers","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1046\/j.1460-9568.2003.02667.x","article-title":"Antidepressant and anxiolytic-like effects in mice lacking the group III metabotropic glutamate receptor mGluR7","volume":"17","author":"Cryan","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10975","DOI":"10.1074\/jbc.M113.542654","article-title":"Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the venus flytrap domain (VFTD) inhibits amygdala plasticity, stress, and anxiety-related behavior","volume":"289","author":"Gee","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1124\/jpet.112.200915","article-title":"ADX71743, a Potent and Selective Negative Allosteric Modulator of Metabotropic Glutamate Receptor 7: In Vitro and In Vivo Characterization","volume":"344","author":"Kalinichev","year":"2013","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1021\/acs.jmedchem.8b01810","article-title":"Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu 7 Negative Allosteric Modulator (NAM) in Vivo Tool Compound: N-(2-(1 H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962)","volume":"62","author":"Reed","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/sj.mp.4002073","article-title":"mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity","volume":"13","author":"Fendt","year":"2008","journal-title":"Mol. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.neuropharm.2013.03.028","article-title":"Adult siRNA-induced knockdown of mGlu7 receptors reduces anxiety in the mouse","volume":"72","author":"Thakker","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1210\/en.2006-0983","article-title":"Adrenal insufficiency and colonic inflammation after a novel chronic psycho-social stress paradigm in mice: Implications and mechanisms","volume":"148","author":"Reber","year":"2007","journal-title":"Endocrinology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1016\/j.psyneuen.2012.02.015","article-title":"Chronic psychosocial stress results in sensitization of the HPA axis to acute heterotypic stressors despite a reduction of adrenal in vitro ACTH responsiveness","volume":"37","author":"Nyuyki","year":"2012","journal-title":"Psychoneuroendocrinology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.neuropharm.2016.04.036","article-title":"Relief from detrimental consequences of chronic psychosocial stress in mice deficient for the metabotropic glutamate receptor subtype 7","volume":"115","author":"Peterlik","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.bbi.2016.08.007","article-title":"Blocking metabotropic glutamate receptor subtype 5 relieves maladaptive chronic stress consequences","volume":"59","author":"Peterlik","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1080\/10253890802042082","article-title":"Effect of chronic psychosocial stress-induced by subordinate colony (CSC) housing on brain neuronal activity patterns in mice","volume":"12","author":"Singewald","year":"2009","journal-title":"Stress"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/S0306-4530(02)00039-2","article-title":"Individual housing induces altered immuno-endocrine responses to psychological stress in male mice","volume":"28","author":"Bartolomucci","year":"2003","journal-title":"Psychoneuroendocrinology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.bbr.2005.06.003","article-title":"Social and structural housing conditions influence the development of a depressive-like phenotype in the learned helplessness paradigm in male mice","volume":"164","author":"Chourbaji","year":"2005","journal-title":"Behav. Brain Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.physbeh.2005.06.014","article-title":"Pair housing affects anxiety-like behaviors induced by a social but not by a physiological stressor in male Swiss mice","volume":"85","author":"Gasparotto","year":"2005","journal-title":"Physiol. Behav."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1530\/JOE-13-0027","article-title":"HPA axis changes during the initial phase of psychosocial stressor exposure in male mice","volume":"218","author":"Peterlik","year":"2013","journal-title":"J. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15730","DOI":"10.1038\/s41598-017-15897-2","article-title":"Splenic glucocorticoid resistance following psychosocial stress requires physical injury","volume":"7","author":"Foertsch","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"104880","DOI":"10.1016\/j.psyneuen.2020.104880","article-title":"Changes in adrenal functioning induced by chronic psychosocial stress in male mice: A time course study","volume":"122","author":"Langgartner","year":"2020","journal-title":"Psychoneuroendocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.psyneuen.2011.09.002","article-title":"Behavioural consequences of two chronic psychosocial stress paradigms: Anxiety without depression","volume":"37","author":"Slattery","year":"2012","journal-title":"Psychoneuroendocrinology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e12627","DOI":"10.1111\/gbb.12627","article-title":"Metabotropic glutamate receptor subtype 7 controls maternal care, maternal motivation and maternal aggression in mice","volume":"19","author":"Gryksa","year":"2020","journal-title":"Genes Brain Behav."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"753822","DOI":"10.3389\/fimmu.2021.753822","article-title":"Changes in Functional Glucocorticoid Sensitivity of Isolated Splenocytes Induced by Chronic Psychosocial Stress\u2014A Time Course Study","volume":"12","author":"Kempter","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Langgartner, D., F\u00fcchsl, A.M., Kaiser, L.M., Meier, T., Foertsch, S., Buske, C., Reber, S.O., and Mulaw, M.A. (2018). Biomarkers for classification and class prediction of stress in a murine model of chronic subordination stress. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202471"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1196\/annals.1410.003","article-title":"Defensive behavioral strategies and enhanced state anxiety during chronic subordinate colony housing are accompanied by reduced hypothalamic vasopressin, but not oxytocin, expression","volume":"1148","author":"Reber","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"387","DOI":"10.3389\/fnmol.2018.00387","article-title":"Metabotropic glutamate receptor 7: A new therapeutic target in neurodevelopmental disorders","volume":"11","author":"Fisher","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/S0021-9258(17)42247-2","article-title":"Molecular characterization of a new metabotropic glutamate receptor mGluR7 coupled to inhibitory cyclic AMP signal transduction","volume":"269","author":"Okamoto","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s00441-006-0266-5","article-title":"Metabotropic glutamate receptors","volume":"326","author":"Ferraguti","year":"2006","journal-title":"Cell Tissue Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/0306-4522(95)00244-D","article-title":"Distribution of metabotropic glutamate receptor 7 messenger RNA in the developing and adult rat brain","volume":"69","author":"Kinzie","year":"1995","journal-title":"Neuroscience"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1046\/j.1471-4159.2000.0750889.x","article-title":"Regulation of neurotransmitter release by metabotropic glutamate receptors","volume":"75","author":"Cartmell","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.yfrne.2010.04.001","article-title":"Neuroendocrinology of coping styles: Towards understanding the biology of individual variation","volume":"31","author":"Koolhaas","year":"2010","journal-title":"Front. Neuroendocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.physbeh.2011.01.006","article-title":"Repeated social defeat increases reactive emotional coping behavior and alters functional responses in serotonergic neurons in the rat dorsal raphe nucleus","volume":"104","author":"Paul","year":"2011","journal-title":"Physiol. Behav."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1210\/en.2009-1026","article-title":"Individual differences in reactivity to social stress predict susceptibility and resilience to a depressive phenotype: Role of corticotropin-releasing factor","volume":"151","author":"Wood","year":"2010","journal-title":"Endocrinology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1080\/026990500120826","article-title":"Coping style and post-traumatic stress disorder following severe traumatic brain injury","volume":"14","author":"Bryant","year":"2000","journal-title":"Brain Inj."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"E3130","DOI":"10.1073\/pnas.1600324113","article-title":"Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice","volume":"113","author":"Reber","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/11\/1817\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:23:38Z","timestamp":1760138618000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/11\/1817"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,2]]},"references-count":45,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["cells11111817"],"URL":"https:\/\/doi.org\/10.3390\/cells11111817","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,2]]}}}