Developmental differences in the effects of CB1/2R agonist WIN55212-2 on extinction of learned fear

Abstract

Adolescence is characterised by substantial changes in emotion regulation and, in particular, impaired extinction consolidation and retention. In this study, we replicated the well-established finding that increasing the activation of cannabinoid receptor 1 (CB1R) via the agonist WIN55212–2 improves fear extinction in adult rodents before examining whether this adjunct would also rescue the extinction retention deficit seen in adolescent rodents. Contrary to the effects in adults, we found that WIN55212-2 impaired within-session acquisition of extinction in adolescent rats with no effect on extinction retention. The same effects of WIN55212-2 were observed for juvenile rats, and did not vary as a function of drug dose. Increased fear expression observed during extinction training was not a result of altered locomotor or anxiety-like behaviour in adolescent rats, as assessed by the open field test. Lastly, we observed a linear decrease in CB1R protein expression across age (i.e., from juveniles, to adolescents, and adults) in both the medial prefrontal cortex and amygdala, two regions implicated in fear expression and extinction, suggesting that there is continued refinement of the endocannabinoid system across development in two regions involved in extinction. Our findings suggest that the expression and extinction of fear in developing rats is differentially affected by CB1R agonism due to an immature endocannabinoid system.