Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1

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• dc.contributor.author Ten-Blanco, Marc
• dc.contributor.author Flores de los Heros, África, 1985-
• dc.contributor.author Pereda-Pérez, Inmaculada
• dc.contributor.author Piscitelli, Fabiana
• dc.contributor.author Izquierdo-Luengo, Cristina
• dc.contributor.author Cristino, Luigia
• dc.contributor.author Romero, Julián
• dc.contributor.author Hillard, Cecilia J.
• dc.contributor.author Maldonado, Rafael, 1961-
• dc.contributor.author Di Marzo, Vicenzo
• dc.contributor.author Berrendero Díaz, Fernando, 1971-
• dc.date.accessioned 2022-06-09T06:04:14Z
• dc.date.available 2022-06-09T06:04:14Z
• dc.date.issued 2022
• dc.description.abstract 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.
• dc.description.sponsorship 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Ten-Blanco M, Flores Á, Pereda-Pérez I, Piscitelli F, Izquierdo-Luengo C, Cristino L, Romero J, Hillard CJ, Maldonado R, Di Marzo V, Berrendero F. Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1. Biomed Pharmacother. 2022 May;149:112925. DOI: 10.1016/j.biopha.2022.112925
• dc.identifier.doi http://dx.doi.org/10.1016/j.biopha.2022.112925
• dc.identifier.issn 0753-3322
• dc.identifier.uri http://hdl.handle.net/10230/53421
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Biomed Pharmacother. 2022 May;149:112925
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-116579RB-100
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-85299-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-108992-RB-100
• dc.rights © 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/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Orexin
• dc.subject.keyword Fear extinction
• dc.subject.keyword Amygdala
• dc.subject.keyword 2-AG
• dc.subject.keyword CB2R
• dc.subject.keyword Microglia
• dc.title Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion