Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB and Serotonin 5-HT Receptors
Viñals, Xavier (Universitat Pompeu Fabra. Laboratori de Neurofarmacologia)
Moreno, Estefanía (Universitat de Barcelona. Departament de Bioquímica i Biologia Molecular)
Lanfumey, Laurence (Université Paris Descartes. Institut de Psychiatrie et Neurosciences de Paris (UMR 894))
Cordomí Montoya, Arnau (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
Pastor, Antoni (Institut Hospital del Mar d'Investigacions Mèdiques)
De La Torre, Rafael (Institut Hospital del Mar d'Investigacions Mèdiques)
Gasperini, Paola (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Navarro Brugal, Gemma (Universitat de Barcelona. Departament de Bioquímica i Biologia Molecular)
Howell, Lesley A. (University of East Anglia. School of Pharmacy (United Kingdom))
Pardo Carrasco, Leonardo (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
Lluís, Carme (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Canela, Enric I. (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
McCormick, Peter J. (University of East Anglia. School of Pharmacy (United Kingdom))
Maldonado, Rafael 1961- (Universitat Pompeu Fabra. Laboratori de Neurofarmacologia)
Robledo, Patricia (Institut Hospital del Mar d'Investigacions Mèdiques)

Data:	2015
Resum:	Activation of cannabinoid CB1 receptors (CBR) 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-HT receptors (5-HTR) revealed a remarkable 5-HTR-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-HTR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CBR and 5-HTR 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-HTR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CBR, 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 CBR and 5-HTR mediating cognitive impairment. CBR-5-HTR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties. Specific subtypes of cannabinoid and serotonin receptors interact to form heterodimers that mediate the cognitive deficits-but not the analgesic effects-induced by tetrahydrocannabinol, the major psychoactive constituent in Cannabis sativa. Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects.
Ajuts:	Ministerio de Ciencia e Innovación SAF2011/29864 Ministerio de Ciencia e Innovación SAF2011/23813 Ministerio de Ciencia e Innovación SAF2010/18472 Ministerio de Economía y Competitividad SAF2014/59648-P Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-131 Instituto de Salud Carlos III P1070709 Instituto de Salud Carlos III PI14-00210
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	PLoS biology, Vol. 13, Num. 7 (July 2015) , art. e1002194, ISSN 1545-7885

DOI: 10.1371/journal.pbio.1002194
PMID: 26158621

40 p, 5.5 MB

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