title: Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors.
abstract: Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) produces a variety of negative effects with major consequences in cannabis users that constitute 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-HT2A receptors (5-HT2AR) revealed a remarkable 5-HT2AR-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-HT2AR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB1R and 5-HT2AR 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-HT2AR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB1R, 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 CB1R and 5-HT2AR mediating cognitive impairment. CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.
authors.affiliation: Neuropharmacology Laboratory, University Pompeu Fabra, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Viñals
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.affiliation: CPN, INSERM UMR S894, Université Paris Descartes, UMR S894, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lanfumey
authors.affiliation: Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Cordomí
authors.affiliation: Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Pastor
authors.affiliation: Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: de La Torre
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain; School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Paola
authors.initials: P
authors.lastname: Gasperini
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Howell
authors.affiliation: Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lluís
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Enric I
authors.initials: EI
authors.lastname: Canela
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain; School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCormick
authors.affiliation: Neuropharmacology Laboratory, University Pompeu Fabra, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: Neuropharmacology Laboratory, University Pompeu Fabra, Barcelona, Spain; Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Robledo
mesh_terms: D000647:Amnesia / Q000139:chemically induced; D000698:Analgesia; D000818:Animals; D001007:Anxiety / Q000139:chemically induced; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced*; D019281:Dimerization; D065847:Dorsal Raphe Nucleus / Q000187:drug effects; D013759:Dronabinol / Q000009:adverse effects*; D057809:HEK293 Cells; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D008124:Locomotion / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism*
chemical_list: D043884:Receptor, Cannabinoid, CB1; D044402:Receptor, Serotonin, 5-HT2A; D013759:Dronabinol