Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Activation of cannabinoid CB1 receptors (CB 1 R) by delta9-tetrahydrocannabinol (THC) pro- duces a variety of negative effects with major consequences in cannabis users that consti- tute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous med...

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Autores: Viñals, Xavier, Moreno Guillén, Estefanía, Lanfumey, Laurence, Cordomí, Arnau, Pastor, Antoni, Torre Fornell, Rafael de la, Navarro Brugal, Gemma, Gasperini, Paola, Howell, Lesley A., Pardo, Leonardo, Lluís i Biset, Carme, Canela Campos, Enric I. (Enric Isidre), 1949-, McCormick, Peter J., Maldonado, Rafael, 1961-, Robledo, Patricia
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/104689
Acceso en línea:https://hdl.handle.net/2445/104689
Access Level:acceso abierto
Palabra clave:Cànnabis
Trastorns de la cognició
Receptors de serotonina
Rates (Animals de laboratori)
Cannabis
Cognition disorders
Serotonin receptors
Rats as laboratory animals
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spelling Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptorsViñals, XavierMoreno Guillén, EstefaníaLanfumey, LaurenceCordomí, ArnauPastor, AntoniTorre Fornell, Rafael de laNavarro Brugal, GemmaGasperini, PaolaHowell, Lesley A.Pardo, LeonardoLluís i Biset, CarmeCanela Campos, Enric I. (Enric Isidre), 1949-McCormick, Peter J.Maldonado, Rafael, 1961-Robledo, PatriciaCànnabisTrastorns de la cognicióReceptors de serotoninaRates (Animals de laboratori)CannabisCognition disordersSerotonin receptorsRats as laboratory animalsActivation of cannabinoid CB1 receptors (CB 1 R) by delta9-tetrahydrocannabinol (THC) pro- duces a variety of negative effects with major consequences in cannabis users that consti- tute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT 2A receptors (5-HT 2A R) revealed a remarkable 5-HT 2A R-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5- HT 2A R, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB 1 R and 5-HT 2A R form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT 2A R from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB 1 R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB 1 R and 5-HT 2A R mediating cognitive impairment. CB 1 R-5-HT 2A R heteromersare thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.Public Library of Science (PLoS)2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/104689Articles publicats en revistes (Bioquímica i Fisiologia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1371/journal.pbio.1002194PLoS Biology, 2015https://doi.org/10.1371/journal.pbio.1002194cc-by (c) Viñals, Xavier. et al., 2015http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1046892026-05-27T06:46:51Z
dc.title.none.fl_str_mv Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors
title Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors
spellingShingle Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors
Viñals, Xavier
Cànnabis
Trastorns de la cognició
Receptors de serotonina
Rates (Animals de laboratori)
Cannabis
Cognition disorders
Serotonin receptors
Rats as laboratory animals
title_short Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors
title_full Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors
title_fullStr Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors
title_full_unstemmed Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors
title_sort Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors
dc.creator.none.fl_str_mv Viñals, Xavier
Moreno Guillén, Estefanía
Lanfumey, Laurence
Cordomí, Arnau
Pastor, Antoni
Torre Fornell, Rafael de la
Navarro Brugal, Gemma
Gasperini, Paola
Howell, Lesley A.
Pardo, Leonardo
Lluís i Biset, Carme
Canela Campos, Enric I. (Enric Isidre), 1949-
McCormick, Peter J.
Maldonado, Rafael, 1961-
Robledo, Patricia
author Viñals, Xavier
author_facet Viñals, Xavier
Moreno Guillén, Estefanía
Lanfumey, Laurence
Cordomí, Arnau
Pastor, Antoni
Torre Fornell, Rafael de la
Navarro Brugal, Gemma
Gasperini, Paola
Howell, Lesley A.
Pardo, Leonardo
Lluís i Biset, Carme
Canela Campos, Enric I. (Enric Isidre), 1949-
McCormick, Peter J.
Maldonado, Rafael, 1961-
Robledo, Patricia
author_role author
author2 Moreno Guillén, Estefanía
Lanfumey, Laurence
Cordomí, Arnau
Pastor, Antoni
Torre Fornell, Rafael de la
Navarro Brugal, Gemma
Gasperini, Paola
Howell, Lesley A.
Pardo, Leonardo
Lluís i Biset, Carme
Canela Campos, Enric I. (Enric Isidre), 1949-
McCormick, Peter J.
Maldonado, Rafael, 1961-
Robledo, Patricia
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cànnabis
Trastorns de la cognició
Receptors de serotonina
Rates (Animals de laboratori)
Cannabis
Cognition disorders
Serotonin receptors
Rats as laboratory animals
topic Cànnabis
Trastorns de la cognició
Receptors de serotonina
Rates (Animals de laboratori)
Cannabis
Cognition disorders
Serotonin receptors
Rats as laboratory animals
description Activation of cannabinoid CB1 receptors (CB 1 R) by delta9-tetrahydrocannabinol (THC) pro- duces a variety of negative effects with major consequences in cannabis users that consti- tute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT 2A receptors (5-HT 2A R) revealed a remarkable 5-HT 2A R-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5- HT 2A R, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB 1 R and 5-HT 2A R form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT 2A R from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB 1 R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB 1 R and 5-HT 2A R mediating cognitive impairment. CB 1 R-5-HT 2A R heteromersare thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/104689
url https://hdl.handle.net/2445/104689
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1371/journal.pbio.1002194
PLoS Biology, 2015
https://doi.org/10.1371/journal.pbio.1002194
dc.rights.none.fl_str_mv cc-by (c) Viñals, Xavier. et al., 2015
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Viñals, Xavier. et al., 2015
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Fisiologia)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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