Persistent behavioural consequences of chronic adolescent cannabidiol (CBD) in a mouse model with increased susceptibility to Δ9-tetrahydrocannabinol and schizophrenia

Abstract

Increasingly, the cannabis sativa plant compound cannabidiol (CBD) is used to treat various psychiatric and neurological health conditions which occur in early life or adolescence, including schizophrenia and autism spectrum disorder. However, behavioural effects CBD during adolescence have received limited attention, and the long-lasting behavioural consequences of adolescent CBD treatment are unknown. Thus, this study investigated the effects of chronic CBD in adolescence on behaviours in adulthood, in a mouse model of susceptibility to cannabinoid drugs and schizophrenia, i.e. Neuregulin 1 transmembrane domain heterozygous (Nrg1 TM HET) and wildtype-like (WT) controls. We also assessed if adolescent CBD may affect behavioural responses to acute low dose Δ⁹-tetrahydrocannabinol (THC) in adulthood. Male Nrg1 TM HET mice and WT controls were administered 30 mg/kg CBD daily intraperitoneally for 3 weeks in adolescence, and then at 5–6 months of age were tested for locomotion, social behaviour, sensorimotor gating and cognition, as well as sensitivity to acute THC-induced behaviours. Adolescent CBD supressed locomotion, exploration, and social behaviours, and reduced anxiety-like behaviours in adult mice. An acute THC challenge in adulthood suppressed social behaviours and acoustic startle in all mice, and adolescent CBD exacerbated THC-induced suppression of acoustic startle in Nrg1 mutant mice. CBD did not alter schizophrenia-relevant behaviours in Nrg1 TM HET mice. To conclude, adolescent CBD exposure had persistent effects on behavioural domains in adulthood including anxiety, locomotion and social behaviours. Furthermore, CBD exposure early in life affected behavioural responses to acute THC in the presence of a risk gene which enhances cannabinoid sensitivity.