Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine

Depression is a chronic and debilitating illness that interferes severely with many human behaviors, and is the leading cause of disability in the world. There is data suggesting that deficits in serotonin neurotransmission can contribute to the development of depression. Indeed, >90% of prescrib...

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Autores: López-Gil, Xavier, Jiménez-Sánchez, Laura, Campa, Leticia, Castro, Elena, Frago, Clara, Adell, Albert
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/201768
Acceso en línea:http://hdl.handle.net/10261/201768
Access Level:acceso abierto
Palabra clave:Depression
Raphe
Serotonin
Noradrenaline
Glutamate
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spelling Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of KetamineLópez-Gil, XavierJiménez-Sánchez, LauraCampa, LeticiaCastro, ElenaFrago, ClaraAdell, AlbertDepressionRapheSerotoninNoradrenalineGlutamateDepression is a chronic and debilitating illness that interferes severely with many human behaviors, and is the leading cause of disability in the world. There is data suggesting that deficits in serotonin neurotransmission can contribute to the development of depression. Indeed, >90% of prescribed antidepressant drugs act by increasing serotonergic transmission at the synapse. However, this increase is offset by a negative feedback operating at the level of the cell body of the serotonin neurons in the raphe nuclei. In the present work, we demonstrate: first, the intracortical infusion of ketamine induced an antidepressant-like effect in the forced swim test, comparable to that produced by systemic ketamine; second, systemic and intracortical ketamine increased serotonin and noradrenaline efflux in the prefrontal cortex, but not in the dorsal raphe nucleus; third, systemic and intracortical administration of ketamine increased the efflux of glutamate in the prefrontal cortex and dorsal raphe nucleus; fourth, systemic ketamine did not alter the functionality of 5-HT1A receptors in the dorsal raphe nucleus. Taken together, these findings suggest that the antidepressant-like effects of ketamine are caused by the stimulation of the prefrontal projection to the dorsal raphe nucleus and locus coeruleus caused by an elevated glutamate in the medial prefrontal cortex, which would stimulate release of serotonin and noradrenaline in the same area. The impact of both monoamines in the antidepressant response to ketamine seems to have different time frames.This work was supported by the Instituto de Salud Carlos III, Subdirección General del Evaluación y Fomento de la Investigacion (FIS Grants PI13-00038 and PI16-00217) that ́ were cofunded by the European Regional Development Fund (“A way to build Europe”). Funding from the Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM) ́ is also acknowledged. We also acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).American Chemical SocietyInstituto de Salud Carlos IIIEuropean CommissionCentro de Investigación Biomédica en Red Salud Mental (España)CSIC - Unidad de Recursos de Información Científica para la Investigación (URICI)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/201768reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1021/acschemneuro.9b00288Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2017682026-05-22T06:33:51Z
dc.title.none.fl_str_mv Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine
title Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine
spellingShingle Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine
López-Gil, Xavier
Depression
Raphe
Serotonin
Noradrenaline
Glutamate
title_short Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine
title_full Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine
title_fullStr Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine
title_full_unstemmed Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine
title_sort Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine
dc.creator.none.fl_str_mv López-Gil, Xavier
Jiménez-Sánchez, Laura
Campa, Leticia
Castro, Elena
Frago, Clara
Adell, Albert
author López-Gil, Xavier
author_facet López-Gil, Xavier
Jiménez-Sánchez, Laura
Campa, Leticia
Castro, Elena
Frago, Clara
Adell, Albert
author_role author
author2 Jiménez-Sánchez, Laura
Campa, Leticia
Castro, Elena
Frago, Clara
Adell, Albert
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Centro de Investigación Biomédica en Red Salud Mental (España)
CSIC - Unidad de Recursos de Información Científica para la Investigación (URICI)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Depression
Raphe
Serotonin
Noradrenaline
Glutamate
topic Depression
Raphe
Serotonin
Noradrenaline
Glutamate
description Depression is a chronic and debilitating illness that interferes severely with many human behaviors, and is the leading cause of disability in the world. There is data suggesting that deficits in serotonin neurotransmission can contribute to the development of depression. Indeed, >90% of prescribed antidepressant drugs act by increasing serotonergic transmission at the synapse. However, this increase is offset by a negative feedback operating at the level of the cell body of the serotonin neurons in the raphe nuclei. In the present work, we demonstrate: first, the intracortical infusion of ketamine induced an antidepressant-like effect in the forced swim test, comparable to that produced by systemic ketamine; second, systemic and intracortical ketamine increased serotonin and noradrenaline efflux in the prefrontal cortex, but not in the dorsal raphe nucleus; third, systemic and intracortical administration of ketamine increased the efflux of glutamate in the prefrontal cortex and dorsal raphe nucleus; fourth, systemic ketamine did not alter the functionality of 5-HT1A receptors in the dorsal raphe nucleus. Taken together, these findings suggest that the antidepressant-like effects of ketamine are caused by the stimulation of the prefrontal projection to the dorsal raphe nucleus and locus coeruleus caused by an elevated glutamate in the medial prefrontal cortex, which would stimulate release of serotonin and noradrenaline in the same area. The impact of both monoamines in the antidepressant response to ketamine seems to have different time frames.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/201768
url http://hdl.handle.net/10261/201768
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1021/acschemneuro.9b00288
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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