Involvement of the brain metabotropic glutamate receptor ^subtypes 5 and 7 in chronic psychosocial stress
Final Report Abstract
Despite the overall well-established link between mGlu5 and mGlu7 and acute stress-related behavior and physiology, the roles these receptors play in chronic stress-related conditions were only little explored. The CSC paradigm represents a powerful animal model as it displays harmful behavioral, physiological and immunological changes induced by chronic psychosocial stress. Those consequences are relevant for the development of psychiatric, somatic and/or gastrointestinal disorders in humans and the question whether mGlu5 and mGlu7 have the potential to exert control on these pathological consequences is of great interest, and it may suggest future therapeutic strategies for the treatment of chronic stressrelated disorders in humans, i.e. a wide clinical application spectrum. In a first step, we assessed molecular changes that occur within the mGlu receptor system in response to CSC. We found specific dysregulation of mGlu5 and mGlu7 expression upon CSC exposure in stress-sensitive brain regions involved in the regulation of behavior and HPA axis functionality, providing early evidence towards a role of these specific mGlu receptor subtypes in chronic psychosocial stress-induced pathophysiology. In a next step, the influence of genetic ablation of mGlu7 on behavioral, physiological and immunological consequences of CSC was analyzed to reveal the potential role of the endogenous mGlu7 receptor during chronic psychosocial stress. Indeed, genetic ablation of mGlu7 relieved multiple CSC induced alterations; mGlu7 deficient mice were protected against the CSC-induced anxiety-prone phenotype as well as against several CSC-induced physiological and immunological consequences, such as HPA axis dysfunction and colonic inflammation, respectively. These findings point to a distinct role of mGlu7 in modulating a wide range of affective and somatic alterations that occur upon CSC exposure. Moreover, the stress-protective phenotype of genetic mGlu7 ablation suggests mGlu7 pharmacological blockade to be a possible treatment strategy for chronic stress-related emotional and somatic conditions in man. As there were already indications for this kind of modulation to be stress-protective in 2012/2013, our group in collaboration with an industry partner intensively advanced the development of the first orthosteric-like mGlu7 antagonist XAP044. XAP044 is able to selectively block LTP in the lateral amygdala in an mGlu7-dependent manner and it has a wide spectrum of acute anti-stress and antidepressantand anxiolytic-like efficacy in rodent behavioral paradigms. These findings strongly suggest XAP044 to be a suitable research tool to study mGlu7 pharmacological blockade in the context of chronic psychosocial stress in future projects. Finally, the potentially beneficial role of genetic and pharmacological mGlu5 inhibition on CSC-induced alterations was analyzed. Interestingly, also mGlu5 deficient mice were protected against a variety of CSC-induced physiological and behavioral changes, including the newly established CSC-induced increase in SIH response. Moreover, we also assessed the effects of the mGlu5 negative allosteric modulator CTEP, a close analogue to the clinically active drug basimglurant with long half-life in rodents, on a wider range of CSC- affected parameters. Here, CTEP relieved in a dose-dependent manner various CSC-induced consequences such as HPA axis dysfunction, immunological alterations, colonic inflammation, and the anxiety-prone phenotype. These findings suggest that mGlu5 is a relevant mediator for a wide range of alterations induced by chronic psychosocial stress and a potentially valuable drug target for the treatment of stress-related somatic pathologies. In conclusion, our results provide clear evidence for the importance of mGlu5 and mGlu7 receptor subtypes in the regulation of acute and chronic stress-related behavior and physiology. Moreover, these studies lend further support towards future development of mGlu5- and mGlu7-selective antagonists such as CTEP and XAP044, respectively, and their administration as therapy for stress-related psychiatric and somatic disorders in humans.
Publications
- Orthosteric versus allosteric GPCR activation: the great challenge of group-III mGluRs. Biochemical Pharmacology 84(4):414-24
Flor PJ, Acher FC
(See online at https://doi.org/10.1016/j.bcp.2012.04.013) - Blocking Metabotropic Glutamate Receptor Subtype 7 (mGlu7) via the Venus Flytrap Domain (VFTD) Inhibits Amygdala Plasticity, Stress, and Anxiety-related Behavior. 8th International Meeting on Metabotropic Glutamate Receptors, October 3rd, Taormina, Sicily, Italy
Peterlik, Daniel
- Blocking Metabotropic Glutamate Receptor Subtype 7 (mGlu7) via the Venus Flytrap Domain (VFTD) Inhibits Amygdala Plasticity, Stress, and Anxiety-related Behavior. Journal of Biological Chemistry 289(16):10975-87
Gee CE, Peterlik D, Neuhäuser C, Bouhelal R, Kaupmann K, Laue G, Uschold- Schmidt N, Feuerbach D, Zimmermann K, Ofner S, Cryan JF, van der Putten H, Fendt M, Vranesic I, Glatthar R, Flor PJ
(See online at https://doi.org/10.1074/jbc.M113.542654) - mGlu7 Receptor Modulation Relieves Behavioral and Physiological Consequences Induced by Chronic Psychosocial Stress. 8th International Meeting on Metabotropic Glutamate Receptors, October 3rd, Taormina, Sicily, Italy
Uschold-Schmidt, Nicole
- Protection against Chronic Stress-induced Dysfunctions via mGlu7 Receptor Modulation. Neurobiology of Stress Workshop, June 17th, Cincinnati, Ohio, USA
Peterlik, Daniel
- Blocking Metabotropic Glutamate Receptor Subtype 5 Relieves Maladaptive Chronic Stress Consequences. Brain, Behavior, and Immunity
Peterlik D, Stangl C, Bauer A, Bludau A, Keller J, Grabski D, Killian T, Schmidt D, Zajicek F, Jaeschke G, Lindemann L, Reber SO, Flor PJ, Uschold- Schmidt N
(See online at https://doi.org/10.1016/j.bbi.2016.08.007) - Metabotropic Glutamate Receptor Subtype 7 in the Bed Nucleus of the Stria Terminalis is Essential for Intermale Aggression. Neuropsychopharmacology 41, 726–735
Masugi-Tokita M, Flor PJ and Kawata M
(See online at https://dx.doi.org/10.1038/npp.2015.198) - Metabotropic Glutamate Receptors – Regulation of Acute and Chronic Stress-related Behavior and Physiology, University of Regensburg, Regensburg, Germany
Peterlik, Daniel
- Relief from detrimental consequences of chronic psychosocial stress in mice deficient for the metabotropic glutamate receptor subtype 7. Neuropharmacology
Peterlik D, Stangl C, Bludau A, Grabski D, Strasser R, Schmidt D, Flor PJ, Uschold-Schmidt N
(See online at https://doi.org/10.1016/j.neuropharm.2016.04.036) - The Emerging Role of Metabotropic Glutamate Receptors in the Pathophysiology of Chronic Stress-Related Disorders. Current Neuropharamacology 14(5):514-539
Peterlik D, Flor PJ, Uschold-Schmidt N
(See online at https://dx.doi.org/10.2174/1570159X13666150515234920)
