Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1
Anxiety and stress disorders are often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear...
| Autores: | , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10230/53421 |
| Acceso en línea: | http://hdl.handle.net/10230/53421 http://dx.doi.org/10.1016/j.biopha.2022.112925 |
| Access Level: | acceso abierto |
| Palabra clave: | Orexin Fear extinction Amygdala 2-AG CB2R Microglia |
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Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1Ten-Blanco, MarcFlores de los Heros, África, 1985-Pereda-Pérez, InmaculadaPiscitelli, FabianaIzquierdo-Luengo, CristinaCristino, LuigiaRomero, JuliánHillard, Cecilia J.Maldonado, Rafael, 1961-Di Marzo, VicenzoBerrendero Díaz, Fernando, 1971-OrexinFear extinctionAmygdala2-AGCB2RMicrogliaAnxiety and stress disorders are often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which orexins regulate fear are unknown. Here we investigated the role of the endogenous cannabinoid system in the impaired fear extinction induced by orexin-A (OXA) in male mice. The selective inhibitor of 2-arachidonoylglycerol (2-AG) biosynthesis O7460 abolished the fear extinction deficits induced by OXA. Accordingly, increased 2-AG levels were observed in the amygdala and hippocampus of mice treated with OXA that do not extinguish fear, suggesting that high levels of this endocannabinoid are related to poor extinction. Impairment of fear extinction induced by OXA was associated with increased expression of CB2 cannabinoid receptor (CB2R) in microglial cells of the basolateral amygdala. Consistently, the intra-amygdala infusion of the CB2R antagonist AM630 completely blocked the impaired extinction promoted by OXA. Microglial and CB2R expression depletion in the amygdala with PLX5622 chow also prevented these extinction deficits. These results show that overactivation of the orexin system leads to impaired fear extinction through 2-AG and amygdalar CB2R. This novel mechanism could be of relevance for the development of novel potential approaches to treat diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder, panic anxiety and phobias.This work was supported by MICINN [PID2020-116579RB-100/AEI/10.13039/501100011033] and "Ministerio de Economía y Competitividad" MINECO/FEDER, UE [SAF2017-85299-R] to FB and [PID2019-108992-RB-100] to JR, "Plan Nacional sobre Drogas" [#2019I024] to FB and “Proyectos de investigación Universidad Francisco de Vitoria [2018-2019]" to FB. M.T-B and C.I-L are supported by a predoctoral fellowship from Universidad Francisco de Vitoria. Any of the funding sources were involved in the study design and preparation. We are grateful to Dr Rosa María Tolón for her guidance on RT-PCR analyses, and Dr M. Ruth Pazos and Mario Amores for their assistance with microscopy evaluation.Elsevier202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/53421http://dx.doi.org/10.1016/j.biopha.2022.112925reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésBiomed Pharmacother. 2022 May;149:112925info:eu-repo/grantAgreement/ES/2PE/PID2020-116579RB-100info:eu-repo/grantAgreement/ES/2PE/SAF2017-85299-Rinfo:eu-repo/grantAgreement/ES/2PE/PID2019-108992-RB-100© 2022 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/534212026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1 |
| title |
Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1 |
| spellingShingle |
Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1 Ten-Blanco, Marc Orexin Fear extinction Amygdala 2-AG CB2R Microglia |
| title_short |
Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1 |
| title_full |
Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1 |
| title_fullStr |
Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1 |
| title_full_unstemmed |
Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1 |
| title_sort |
Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1 |
| dc.creator.none.fl_str_mv |
Ten-Blanco, Marc Flores de los Heros, África, 1985- Pereda-Pérez, Inmaculada Piscitelli, Fabiana Izquierdo-Luengo, Cristina Cristino, Luigia Romero, Julián Hillard, Cecilia J. Maldonado, Rafael, 1961- Di Marzo, Vicenzo Berrendero Díaz, Fernando, 1971- |
| author |
Ten-Blanco, Marc |
| author_facet |
Ten-Blanco, Marc Flores de los Heros, África, 1985- Pereda-Pérez, Inmaculada Piscitelli, Fabiana Izquierdo-Luengo, Cristina Cristino, Luigia Romero, Julián Hillard, Cecilia J. Maldonado, Rafael, 1961- Di Marzo, Vicenzo Berrendero Díaz, Fernando, 1971- |
| author_role |
author |
| author2 |
Flores de los Heros, África, 1985- Pereda-Pérez, Inmaculada Piscitelli, Fabiana Izquierdo-Luengo, Cristina Cristino, Luigia Romero, Julián Hillard, Cecilia J. Maldonado, Rafael, 1961- Di Marzo, Vicenzo Berrendero Díaz, Fernando, 1971- |
| author2_role |
author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Orexin Fear extinction Amygdala 2-AG CB2R Microglia |
| topic |
Orexin Fear extinction Amygdala 2-AG CB2R Microglia |
| description |
Anxiety and stress disorders are often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which orexins regulate fear are unknown. Here we investigated the role of the endogenous cannabinoid system in the impaired fear extinction induced by orexin-A (OXA) in male mice. The selective inhibitor of 2-arachidonoylglycerol (2-AG) biosynthesis O7460 abolished the fear extinction deficits induced by OXA. Accordingly, increased 2-AG levels were observed in the amygdala and hippocampus of mice treated with OXA that do not extinguish fear, suggesting that high levels of this endocannabinoid are related to poor extinction. Impairment of fear extinction induced by OXA was associated with increased expression of CB2 cannabinoid receptor (CB2R) in microglial cells of the basolateral amygdala. Consistently, the intra-amygdala infusion of the CB2R antagonist AM630 completely blocked the impaired extinction promoted by OXA. Microglial and CB2R expression depletion in the amygdala with PLX5622 chow also prevented these extinction deficits. These results show that overactivation of the orexin system leads to impaired fear extinction through 2-AG and amygdalar CB2R. This novel mechanism could be of relevance for the development of novel potential approaches to treat diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder, panic anxiety and phobias. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2022 2022 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10230/53421 http://dx.doi.org/10.1016/j.biopha.2022.112925 |
| url |
http://hdl.handle.net/10230/53421 http://dx.doi.org/10.1016/j.biopha.2022.112925 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Biomed Pharmacother. 2022 May;149:112925 info:eu-repo/grantAgreement/ES/2PE/PID2020-116579RB-100 info:eu-repo/grantAgreement/ES/2PE/SAF2017-85299-R info:eu-repo/grantAgreement/ES/2PE/PID2019-108992-RB-100 |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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application/pdf application/pdf |
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Elsevier |
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Elsevier |
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