The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents

Abstract Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanol...

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Autores principales:	Guy Griebel, Jeanne Stemmelin, Mati Lopez-Grancha, Valérie Fauchey, Franck Slowinski, Philippe Pichat, Gihad Dargazanli, Ahmed Abouabdellah, Caroline Cohen, Olivier E. Bergis
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/080f7bdc1656430e82c1cafc30cdcfa0
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spelling	oai:doaj.org-article:080f7bdc1656430e82c1cafc30cdcfa02021-12-02T15:08:53ZThe selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents10.1038/s41598-018-20895-z2045-2322https://doaj.org/article/080f7bdc1656430e82c1cafc30cdcfa02018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-20895-zhttps://doaj.org/toc/2045-2322Abstract Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.Guy GriebelJeanne StemmelinMati Lopez-GranchaValérie FaucheyFranck SlowinskiPhilippe PichatGihad DargazanliAhmed AbouabdellahCaroline CohenOlivier E. BergisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-25 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Guy Griebel Jeanne Stemmelin Mati Lopez-Grancha Valérie Fauchey Franck Slowinski Philippe Pichat Gihad Dargazanli Ahmed Abouabdellah Caroline Cohen Olivier E. Bergis The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents
description	Abstract Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.
format	article
author	Guy Griebel Jeanne Stemmelin Mati Lopez-Grancha Valérie Fauchey Franck Slowinski Philippe Pichat Gihad Dargazanli Ahmed Abouabdellah Caroline Cohen Olivier E. Bergis
author_facet	Guy Griebel Jeanne Stemmelin Mati Lopez-Grancha Valérie Fauchey Franck Slowinski Philippe Pichat Gihad Dargazanli Ahmed Abouabdellah Caroline Cohen Olivier E. Bergis
author_sort	Guy Griebel
title	The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents
title_short	The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents
title_full	The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents
title_fullStr	The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents
title_full_unstemmed	The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents
title_sort	selective reversible faah inhibitor, ssr411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/080f7bdc1656430e82c1cafc30cdcfa0
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The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents

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