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Brain Behav Immun. 2017 Jan;59:79-92. doi: 10.1016/j.bbi.2016.08.007. Epub 2016 Aug 11.

Blocking metabotropic glutamate receptor subtype 5 relieves maladaptive chronic stress consequences.

Author information

1
Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
2
Institute of Immunology, University of Regensburg, D-93042 Regensburg, Germany.
3
Roche Pharmaceutical Research and Early Development, Discovery Chemistry, Roche Innovation Center Basel, CH-4070 Basel, Switzerland.
4
Roche Pharmaceutical Research and Early Development, Discovery Neuroscience, Neuroscience, Ophthalmology, and Rare Diseases, Roche Innovation Center Basel, CH-4070 Basel, Switzerland.
5
Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, D-89081 Ulm, Germany.
6
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.
7
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.

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.

KEYWORDS:

CTEP; Chronic psychosocial stress; Chronic subordinate colony housing; Knockout; Stress-protective phenotype; mGlu5

PMID:
27524668
DOI:
10.1016/j.bbi.2016.08.007
[Indexed for MEDLINE]

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