Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors

• DOI: 10.1371/journal.pbio.1002194
• Publication Date: 2015-07-09T20:08:28Z
• Authors: Xavier Viñals; Estefanía Moreno; Laurence Lanfumey; Arnau Cordomí; Antoni Pastor; Rafael de La Torre; Paola Gasperini; Gemma Navarro; Lesley A. Howell; Leonardo Pardo; Carmen Lluís; Enric I. Canela; Peter J. McCormick; Rafael Maldonado; Patricia Robledo
• Keywords: Anxiogenic

Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) produces a variety negative effects with major consequences in cannabis users that constitute important drawbacks for the use cannabinoids as therapeutic agents. For this reason, there is tremendous medical interest harnessing beneficial THC. Behavioral studies carried out mice lacking 5-HT2A (5-HT2AR) revealed remarkable 5-HT2AR-dependent dissociation antinociceptive THC and its detrimental amnesic properties. We found specific such memory deficits, anxiolytic-like effects, social interaction are under control 5-HT2AR, but acute hypolocomotor, hypothermic, anxiogenic, not. In biochemical studies, we show CB1R 5-HT2AR form heteromers expressed functionally active brain regions involved impairment. Remarkably, our functional data shows costimulation both agonists reduces cell signaling, antagonist binding to one receptor blocks signaling interacting receptor, heteromer formation leads switch G-protein coupling from Gq Gi proteins. Synthetic peptides sequence transmembrane helices 5 6 CB1R, fused cell-penetrating peptide, were able disrupt heteromerization vivo, leading selective abrogation impairments caused exposure These reveal novel molecular mechanism between mediating cognitive CB1R-5-HT2AR thus good targets dissociate deficits induced