Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice
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...
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MDPI AG
2022-06-01
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| author | Karolyne A. R. Estrela Lisa Senninger Josephine Arndt Melanie Kabas Ferdinand Schmid Larissa Dillmann Sophia Auer Thomas Stepfer Peter J. Flor Nicole Uschold-Schmidt |
| author_facet | Karolyne A. R. Estrela Lisa Senninger Josephine Arndt Melanie Kabas Ferdinand Schmid Larissa Dillmann Sophia Auer Thomas Stepfer Peter J. Flor Nicole Uschold-Schmidt |
| author_sort | Karolyne A. R. Estrela |
| collection | DOAJ |
| description | 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–pituitary–adrenal 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. |
| first_indexed | 2024-03-10T01:24:41Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T01:24:41Z |
| publishDate | 2022-06-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-43dc228532f44c2fa901b720cdb1d1a72023-11-23T13:53:16ZengMDPI AGCells2073-44092022-06-011111181710.3390/cells11111817Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in MiceKarolyne A. R. Estrela0Lisa Senninger1Josephine Arndt2Melanie Kabas3Ferdinand Schmid4Larissa Dillmann5Sophia Auer6Thomas Stepfer7Peter J. Flor8Nicole Uschold-Schmidt9Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, GermanyLaboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, GermanyLaboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, GermanyLaboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, GermanyLaboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, GermanyLaboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, GermanyLaboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, GermanyLaboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, GermanyLaboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, GermanyLaboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, GermanyChronic 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–pituitary–adrenal 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.https://www.mdpi.com/2073-4409/11/11/1817mGlu7XAP044chronic psychosocial stresschronic subordinate colony housing |
| spellingShingle | Karolyne A. R. Estrela Lisa Senninger Josephine Arndt Melanie Kabas Ferdinand Schmid Larissa Dillmann Sophia Auer Thomas Stepfer Peter J. Flor Nicole Uschold-Schmidt Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice Cells mGlu7 XAP044 chronic psychosocial stress chronic subordinate colony housing |
| title | Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice |
| title_full | Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice |
| title_fullStr | Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice |
| title_full_unstemmed | Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice |
| title_short | Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice |
| title_sort | blocking metabotropic glutamate receptor subtype 7 via the venus flytrap domain promotes a chronic stress resilient phenotype in mice |
| topic | mGlu7 XAP044 chronic psychosocial stress chronic subordinate colony housing |
| url | https://www.mdpi.com/2073-4409/11/11/1817 |
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