A time‐dependent contribution of hippocampal CB₁, CB₂ and PPARγ receptors to cannabidiol‐induced disruption of fear memory consolidation

Abstract

Background and Purpose In preclinical studies, cannabidiol (CBD) mitigates fear memories by facilitating their extinction or interfering with their generalization and reconsolidation. The brain regions and mechanisms underlying these effects, and their temporal window, are still poorly understood. Here, we have investigated related questions in the dorsal hippocampus (DH) during contextual fear consolidation. Experimental Approach Adult male Wistar rats received CBD (10–30 pmol) intra‐DH immediately, 1 or 3 hr after fear conditioning. Effects of CBD on consolidation were inferred behaviourally and by analysing expression of the activity‐regulated, cytoskeleton‐associated (Arc) protein. The contribution of anandamide, CB1, CB2, 5‐HT1A, A2A, and PPARγ receptors was also assessed. Key Results CBD impaired memory consolidation when given immediately or 1 hr after fear conditioning, but not after 3 hr. Expression of Arc protein in DH was reduced by systemic CBD treatment in both cases. Immediately after fear conditioning, CBD effects were abolished by CB1 or CB2 receptor blockade, partly reduced by 5‐HT1A or A2A antagonism, and remained unchanged after antagonism of PPARγ receptors. One hour after fear conditioning, CBD effects were prevented only by PPARγ receptor antagonism. Also, inhibition of fatty acid amide hydrolase by URB597, impaired memory consolidation when infused immediately, but not 1 hr after fear conditioning. Conclusions and Implications CBD disrupts memory consolidation up to 1 hr after fear conditioning, allowing an extended window of opportunity to mitigate aversive memories after their acquisition. Our results suggest time‐dependent participation of anandamide, CB1, CB2 and PPARγ receptors in the DH, during this process.

Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders

“…However, infralimbic prefrontal cortex infusion showed contradictory results, increasing freezing [ 118 ] or facilitating fear extinction [ 119 ], depending on the total number of microinjections given. Indeed, CBD seems to disrupt aversive memory consolidation [ 109 , 120 ], involving anandamide, CB 1 r, CB 2 r, and peroxisome proliferator-activated receptor gamma (PPARγ) receptors in a time-dependent manner [ 70 , 119 , 120 ]. CBD also reduced the influence of PFC on corticolimbic circuits, modulating dopamine and immediate gene expression (c-fos and zif-268 proteins) [ 118 , 141 ], and it functionally modified the mesolimbic circuit through the direct activation of 5-HT 1A receptors [ 142 , 143 ].…”

Self-Assembly System Based on Cyclodextrin for Targeted Delivery of Cannabidiol

“…CBD is a component of cannabis with no psychoactive properties ( Vrechi et al, 2021 ). Using an inverse agonist of CB2 receptors, an agonist of TRPA1, TRPV1, TRPV2, 5HT-1A, and PPARγ receptors, as well as an antagonist of CB1 receptor and GPR55 ( Pisanti et al, 2017 ; Rong et al, 2017 ; Ferro et al, 2018 ; Raymundi et al, 2020 ). CBD also exhibits a wide range of anti-tumor activities, which can induce programmed death of different types of cancer cells according to reports ( Olea-Herrero et al, 2009 ; Aviello et al, 2012 ; Pacher, 2013 ; Fonseca et al, 2018 ; Yang et al, 2020 ), including human prostate cancer, human breast carcinoma, human glioblastoma, human cervical cancer, human lung cancer, lymphocytic, and monocytic leukemias, endometrial cancer, pancreatic cancer.…”

Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System

“…O'Sullivan et al [74] determined the direct binding of CBD to PPARγ ligand binding domain performing fluorescence polarization assay, being CBD less potent than rosiglitazone and AJA. PPARγ and not CB 1 R/CB 2 R has been associated with CBD effects on a amyloid β-induced neurotoxicity animal model [112], and more recently on fear memory consolidation [111] and on blood-brain barrier (BBB) permeability following ischemia [119]. Caprioglio et al [191] performed oxidative reactions on the phytocannabinoids CBD, cannabigerol (CBG), cannabichromene (CBC), and cannabinol (CBN) that led to hydroxyquinones (cannabinoquinoids: CBDQ (also known as HU-331), CBGQ, CBCQ, CBNQ respectively; Figure 1).…”