Cannabidiol impairs fear memory reconsolidation in female rats through dorsal hippocampus CB1 but not CB2 receptor interaction

Women present increased susceptibility to anxiety- and stress-related disorders compared to men. A potentially promising pharmacological-based strategy to regulate abnormal aversive memories disrupts their reconsolidation stage after reactivation and destabilization. Male rodent findings indicate that cannabidiol (CBD), a relatively safe and effective treatment for several mental health conditions, can impair the reconsolidation of aversive memories. However, whether and how CBD influences it in females is still unknown. The present study addressed this question in contextually fear-conditioned female rats. We report that systemically administered CBD impaired their reconsolidation, reducing freezing expression for over a week. This action was restricted to a time when the reconsolidation presumably lasted (< six hours post-retrieval) and depended on memory reactivation/destabilization. Moreover, the impairing effects of CBD on memory reconsolidation relied on the activation of cannabinoid type-1 but not type-2 receptors located in the CA1 subregion of the dorsal hippocampus. CBD applied directly to this brain area was sufficient to reproduce the effects of systemic CBD treatment. Contextual fear memories attenuated by CBD did not show reinstatement, an extinction-related feature. By demonstrating that destabilized fear memories are sensitive to CBD and how it hinders mechanisms in the DH CA1 that may restabilize them in female rats, the present findings concur that reconsolidation blockers are viable and could be effective in disrupting abnormally persistent and distressing aversive memories such as those related to posttraumatic stress disorder.