title: Blocking metabotropic glutamate receptor subtype 5 relieves maladaptive chronic stress consequences.
abstract: Etiology and pharmacotherapy of stress-related psychiatric conditions and somatoform disorders are areas of high unmet medical need. Stressors holding chronic plus psychosocial components thereby bear the highest health risk. Although the metabotropic glutamate receptor subtype 5 (mGlu5) is well studied in the context of acute stress-induced behaviors and physiology, virtually nothing is known about its potential involvement in chronic psychosocial stress. Using the mGlu5 negative allosteric modulator CTEP (2-chloro-4-[2-[2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazol-4yl]ethynyl]pyridine), a close analogue of the clinically active drug basimglurant - but optimized for rodent studies, as well as mGlu5-deficient mice in combination with a mouse model of male subordination (termed CSC, chronic subordinate colony housing), we demonstrate that mGlu5 mediates multiple physiological, immunological, and behavioral consequences of chronic psychosocial stressor exposure. For instance, CTEP dose-dependently relieved hypothalamo-pituitary-adrenal axis dysfunctions, colonic inflammation as well as the CSC-induced increase in innate anxiety; genetic ablation of mGlu5 in mice largely reproduced the stress-protective effects of CTEP and additionally ameliorated CSC-induced physiological anxiety. Interestingly, CSC also induced an upregulation of mGlu5 in the hippocampus, a stress-regulating brain area. Taken together, our findings provide evidence that mGlu5 is an important mediator for a wide range of chronic psychosocial stress-induced alterations and a potentially valuable drug target for the treatment of chronic stress-related pathologies in man.
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Peterlik
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Stangl
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Bludau
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Keller
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Grabski
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Killian
authors.affiliation: Institute of Immunology, University of Regensburg, D-93042 Regensburg, Germany.
authors.forename: Dominic
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Zajicek
authors.affiliation: Roche Pharmaceutical Research and Early Development, Discovery Chemistry, Roche Innovation Center Basel, CH-4070 Basel, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Jaeschke
authors.affiliation: Roche Pharmaceutical Research and Early Development, Discovery Neuroscience, Neuroscience, Ophthalmology, and Rare Diseases, Roche Innovation Center Basel, CH-4070 Basel, Switzerland.
authors.forename: Lothar
authors.initials: L
authors.lastname: Lindemann
authors.affiliation: Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, D-89081 Ulm, Germany.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Reber
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany. Electronic address: peter.flor@ur.de.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Flor
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany. Electronic address: nicole.uschold@ur.de.
authors.forename: Nicole
authors.initials: N
authors.lastname: Uschold-Schmidt
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000523:psychology; D002908:Chronic Disease; D004291:Dominance-Subordination; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000209:etiology / Q000503:physiopathology; D006854:Hydrocortisone / Q000097:blood; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011725:Pyridines / Q000627:therapeutic use*; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000235:genetics; D012931:Social Environment; D013315:Stress, Psychological / Q000523:psychology*; D015854:Up-Regulation
chemical_list: C000596770:2-chloro-4-(1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl)pyridine; C578936:Grm5 protein, mouse; D007093:Imidazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone
keywords: CTEP; Chronic psychosocial stress; Chronic subordinate colony housing; Knockout; Stress-protective phenotype; mGlu5