Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Estrela, Karolyne A. R., Senninger, Lisa, Arndt, Josephine, Kabas, Melanie, Schmid, Ferdinand, Dillmann, Larissa, Auer, Sophia, Stepfer, Thomas, Flor, Peter J., Uschold-Schmidt, Nicole
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9180111/
https://www.ncbi.nlm.nih.gov/pubmed/35681512
http://dx.doi.org/10.3390/cells11111817
_version_ 1784723436689424384
author Estrela, Karolyne A. R.
Senninger, Lisa
Arndt, Josephine
Kabas, Melanie
Schmid, Ferdinand
Dillmann, Larissa
Auer, Sophia
Stepfer, Thomas
Flor, Peter J.
Uschold-Schmidt, Nicole
author_facet Estrela, Karolyne A. R.
Senninger, Lisa
Arndt, Josephine
Kabas, Melanie
Schmid, Ferdinand
Dillmann, Larissa
Auer, Sophia
Stepfer, Thomas
Flor, Peter J.
Uschold-Schmidt, Nicole
author_sort Estrela, Karolyne A. R.
collection PubMed
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.
format Online
Article
Text
id pubmed-9180111
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-91801112022-06-10 Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice Estrela, Karolyne A. R. Senninger, Lisa Arndt, Josephine Kabas, Melanie Schmid, Ferdinand Dillmann, Larissa Auer, Sophia Stepfer, Thomas Flor, Peter J. Uschold-Schmidt, Nicole Cells Article 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. MDPI 2022-06-02 /pmc/articles/PMC9180111/ /pubmed/35681512 http://dx.doi.org/10.3390/cells11111817 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Estrela, Karolyne A. R.
Senninger, Lisa
Arndt, Josephine
Kabas, Melanie
Schmid, Ferdinand
Dillmann, Larissa
Auer, Sophia
Stepfer, Thomas
Flor, Peter J.
Uschold-Schmidt, Nicole
Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9180111/
https://www.ncbi.nlm.nih.gov/pubmed/35681512
http://dx.doi.org/10.3390/cells11111817
work_keys_str_mv AT estrelakarolynear blockingmetabotropicglutamatereceptorsubtype7viathevenusflytrapdomainpromotesachronicstressresilientphenotypeinmice
AT senningerlisa blockingmetabotropicglutamatereceptorsubtype7viathevenusflytrapdomainpromotesachronicstressresilientphenotypeinmice
AT arndtjosephine blockingmetabotropicglutamatereceptorsubtype7viathevenusflytrapdomainpromotesachronicstressresilientphenotypeinmice
AT kabasmelanie blockingmetabotropicglutamatereceptorsubtype7viathevenusflytrapdomainpromotesachronicstressresilientphenotypeinmice
AT schmidferdinand blockingmetabotropicglutamatereceptorsubtype7viathevenusflytrapdomainpromotesachronicstressresilientphenotypeinmice
AT dillmannlarissa blockingmetabotropicglutamatereceptorsubtype7viathevenusflytrapdomainpromotesachronicstressresilientphenotypeinmice
AT auersophia blockingmetabotropicglutamatereceptorsubtype7viathevenusflytrapdomainpromotesachronicstressresilientphenotypeinmice
AT stepferthomas blockingmetabotropicglutamatereceptorsubtype7viathevenusflytrapdomainpromotesachronicstressresilientphenotypeinmice
AT florpeterj blockingmetabotropicglutamatereceptorsubtype7viathevenusflytrapdomainpromotesachronicstressresilientphenotypeinmice
AT uscholdschmidtnicole blockingmetabotropicglutamatereceptorsubtype7viathevenusflytrapdomainpromotesachronicstressresilientphenotypeinmice