Sex-specific effects of CB1 receptor antagonism and stress in adolescence on anxiety, corticosterone concentrations, and contextual fear in adulthood in rats

There is a paucity of research regarding the role of endogenous cannabinoid signalling in adolescence on brain and behaviour development. We previously demonstrated effects of repeated CB1 receptor antagonism in adolescence on socioemotional behaviours and neural protein expression 24-48 h after the last drug administration in female rats, with no effect in males. Here we investigate whether greater effects would be manifested after a lengthier delay. In Experiment 1, male and female rats were administered either 1 mg / kg of the CB1 receptor-selective antagonist AM251, vehicle (VEH), or did not receive injections (NoINJ) daily on postnatal days (PND) 30-44 either alone (no adolescent confinement stress; noACS), or in tandem with 1 h ACS. On PND 70, adolescent AM251 exposure reduced anxiety in an elevated plus maze in males, irrespective of ACS, with no effects in females. On PND 73, there were no group differences in either sex in plasma corticosterone concentrations before or after 30 min of restraint stress, although injection stress resulted in higher baseline concentrations in males. Brains were collected on PND 74, with negligible effects of either AM251 or ACS on protein markers of synaptic plasticity and of the endocannabinoid system in the hippocampus and medial prefrontal cortex. In Experiment 2, rats from both sexes were treated with vehicle or AM251 on PND 30-44 and were tested for contextual fear conditioning and extinction in adulthood. AM251 females had greater fear recall than VEH females 24 h after conditioning, with no group differences in within- or between-session fear extinction. There were no group differences in long-term extinction memory, although AM251 females froze more during a reconditioning trial compared with VEH females. There were no group differences on any of the fear conditioning measures in males. Together, these findings indicate a modest, sex-specific role of CB1 receptor signalling in adolescence on anxiety-like behaviour in males and conditioned fear behaviour in females.