Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors
PLoS Biology July 9, 2015 Xavier Viñals, Estefanía Moreno, Laurence Lanfumey et al. 211 citations
Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) causes negative effects including memory deficits, limiting therapeutic use. Behavioral studies in mice lacking 5-HT2A receptors (5-HT2AR) showed a dissociation: THC's antinociceptive effects remained, but its amnesic, anxiolytic-like, and social interaction effects depended on 5-HT2AR, while hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects did not. Biochemical studies revealed CB1R and 5-HT2AR form heteromers in brain regions involved in memory, altering cell signaling and G-protein coupling. Synthetic peptides disrupting heteromerization selectively prevented THC-induced memory impairments, identifying CB1R-5-HT2AR heteromers as targets to separate cognitive deficits from beneficial pain relief.