Cannabidiol attenuates fear memory expression in female rats via hippocampal 5-HT1A but not CB1 or CB2 receptors. (1st February 2023)

• Record Type: Journal Article
• Authors: Franzen, Jaqueline M.; Werle, Isabel; Vanz, Felipe; de Oliveira, Bruno Biscaia; Martins Nascimento, Laura Maria; Guimarães, Francisco S.; Bertoglio, Leandro J.
• Is Part Of: Neuropharmacology. Volume 223(2023)
• Publication Date: 2023-02-01
• Subjects: Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.109316
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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. Graphical abstract: Image 1 Highlights: Systemic CBD impaired contextual fear memory retrieval/expression in female rats. Dorsal hippocampus (DH) 5-HT1A receptor antagonism prevented this CBD action. Pre-retrieval CBD impaired memory reconsolidation and lowered fear during early extinction. CBD infusion into the DH CA1 reproduced the abovementioned systemic effects. Systemic CBD attenuated anxiety in female rats tested in the elevated plus-maze.