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Title: Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors
Author: Viñals, Xavier
Moreno Guillén, Estefanía
Lanfumey, Laurence
Cordomí, Arnau
Pastor Bosch, Antonio
Torre Fornell, Rafael de la
Navarro Brugal, Gemma
Gasperini, Paola
Howell, Lesley A.
Pardo, Leonardo
Lluís i Biset, Carme
Canela Campos, Enric I.
McCormick, Peter J.
Maldonado, Rafael, 1961-
Robledo, Patricia
Keywords: Cànnabis
Trastorns de la cognició
Receptors de serotonina
Rates (Animals de laboratori)
Cognition disorders
Serotonin receptors
Rats as laboratory animals
Issue Date: 9-Jul-2015
Publisher: Public Library of Science (PLoS)
Abstract: 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.
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It is part of: PLoS Biology, 2015
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ISSN: 1544-9173
Appears in Collections:Articles publicats en revistes (Bioquímica i Fisiologia)
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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