ENDOCANNABINOID REGULATION OF ADOLESCENT DEVELOPMENT IN MALE AND FEMALE RATS
The present thesis investigated the contributions of adolescent endocannabinoid signalling to brain and behaviour development in male and female rats. In chapter 2, daily administration of the CB1 antagonist AM251, alone or in tandem with a psychological stressor, increased social interactions, reduced dorsal hippocampal CB1 expression, and increased mPFC GAD67 expression in female rats 24-48 h after treatment, with no effects in males. In chapter 3, adolescent CB1 antagonism reduced anxiety in adult males, with no effects in females. Conversely, adolescent AM251 increased contextual fear in adult females, with no effects in males. In chapter 4, AM251 females spent more time initiating social interactions after a 5-day drug washout period than vehicle females, with no effects in males. To identify brain regions underlying the effects of AM251 on social behaviours, I repeated social interaction testing in vehicle and AM251 females and collected brains for immunohistochemical labelling of EGR-1 as a marker of neural activation in the CA1, CA2, and CA3 subfields of the dorsal hippocampus and the shell and core divisions of the nucleus accumbens (NAc). Consistent with my previous findings, AM251 females spent more time initiating social interactions and had greater EGR-1 cell counts in the NAc shell than vehicle females, with no group differences in the NAc core or in any of the hippocampal subfields investigated. EGR-1 cell counts in the dCA2 were negatively correlated with social interactions in vehicle and AM251 females. A positive correlation between NAc shell EGR-1 cell counts and social interactions was observed only in AM251 females. Regression analysis using drug treatment and EGR-1 cell counts in dCA2 and NAc shell resulted in a model with an adjusted R2 of 0.90. Both drug treatment and EGR-1 cell counts in the dorsal CA2 emerged as unique predictors of individual differences in social interaction, and drug and NAc shell EGR-1 cell counts interacted to significantly predict social interactions in AM251 females only. Together, these studies provide support for sex-specific contributions of endocannabinoid signalling to the development of brain and behaviour in adolescence in male and female rats.