Cannabidiol attenuates fear memory expression in female rats via hippocampal 5-HT1A but not CB1 or CB2 receptors.

Growing evidence from male rodent and human studies suggests that cannabidiol (CBD) modulates the expression of aversive memories and anxiety-related responses. The limited data on whether and how CBD influences these aspects in females could have therapeutic implications given the increased susceptibility of women to anxiety- and stress-related disorders relative to men. Female studies are also essential to examine inherent aspects that potentially contribute to differences in responsiveness to CBD. Here we addressed these questions in adult female rats. Contextually fear-conditioned animals acutely treated with CBD (1.0-10 mg/kg) were tested 45 min later. In subsequent experiments, we investigated the estrous cycle effects and the contribution of dorsal hippocampus (DH) serotonin 1A (5-HT1A) and cannabinoid types 1 (CB1) and 2 (CB2) receptors to CBD-induced effects on memory retrieval/expression. The effects of pre-retrieval systemic or intra-DH CBD administration on subsequent fear extinction were also assessed. Lastly, we evaluated the open arms avoidance and stretched-attend postures in females exposed to the elevated plus-maze after systemic CBD treatment. CBD 3.0 and 10 mg/kg administered before conditioned context exposure reduced females' freezing. This action remained unchanged across the estrous cycle and involved DH 5-HT1A receptors activation. Pre-retrieval CBD impaired memory reconsolidation and lowered fear during early extinction. CBD applied directly to the DH was sufficient to reproduce the effects of systemic CBD treatment. CBD 3.0 and 10 mg/kg reduced anxiety-related responses scored in the elevated plus-maze. Our findings demonstrate that CBD attenuates the behavioral manifestation of learned fear and anxiety in female rats.

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.

Dissociating retrieval-dependent contextual aversive memory processes in female rats: Are there cycle-dependent differences?

Upon retrieval, aversive associative memories may engage alternative processes depending on the conditioned stimulus exposure length. Generally, a short session maintains it through reconsolidation, and a long session inhibits it because of extinction learning. However, various experimental interventions have produced no memory changes when given after intermediate conditioned stimulus exposure events. The lack of effectiveness in the latter case has been explained by a stage of transition from reconsolidation to extinction, during which both phases are engaged but neither prevails. Alternatively, it would represent a novel, intermediate phase between reconsolidation and extinction. By combining a varying time of exposure to the paired context with the amnesic agent midazolam, and the introduction of a reinstatement procedure in the protocol to investigate the occurrence of extinction and/or reconsolidation, we aimed at addressing this question in female rats. Midazolam disrupted the reconsolidation of the original aversive memory and the consolidation of extinction memory when given after short (2 or 5 min, but not 1 min) and long (30 min) exposure to the paired context, respectively. There was reinstatement in the latter case only. Midazolam produced no memory changes when given after a session of 7 or 10 min, with reinstatement data suggesting the absence of reconsolidation in both cases. Noteworthy, drug effects on reconsolidation or extinction and the lack of action on the intermediate process were similar across the estrous cycle. Altogether, it was possible to check and dissociate three retrieval-dependent contextual fear memory processes using a more nuanced approach in females.