Cannabidiol (CBD) reduces anxiety-related behavior in mice via an FMRP-independent mechanism

Fragile X Syndrome is a neurodevelopmental disorder which affects intellectual, social and physical development due to mutation of the Fragile X mental retardation 1 (<i>FMR1</i>) gene. The resultant loss of Fragile X mental retardation protein can be modelled by <i>Fmr1</i> gene knockout (KO) in mice. The current study investigated the behavioural effects of cannabidiol (CBD; a non-psychoactive phytocannabinoid) in male <i>Fmr1</i> KO mice as a preclinical model for therapeutic discovery. Vehicle or CBD (5 or 20 mg/kg body weight) was administered to adult <i>Fmr1</i> KO and wild type-like (WT) mice before they were tested in behavioural tasks including: open field (OF), elevated plus maze (EPM), spontaneous alternation, social preference, and passive avoidance tasks. <i>Fmr1</i> KO mice were hyperlocomotive and hyperexplorative and habituated more slowly to a novel environment compared to control animals. Furthermore, <i>Fmr1</i> KO mice showed fewer anxiety-related behaviours across tests. Effects of CBD were subtle and limited to the EPM, where CBD decreased the anxiety response of all mice tested. Acute CBD had no impact on locomotion or anxiety-related parameters in the OF. Cognitive performance of <i>Fmr1</i> KO mice was equivalent to controls and not affected by CBD treatment. Brain concentrations of CBD were equivalent between genotypes, but in animals sacrificed 90 min post-administration, decreased plasma CBD in <i>Fmr1</i> KO mice compared to WT suggested more rapid clearance of CBD by transgenic animals. Overall, acute CBD at the doses chosen did not selectively normalize behavioural abnormalities in <i>Fmr1</i> KO mice, but reduced anxiety-like behaviour in both <i>Fmr1</i> KO and WT mice.