A time-dependent contribution of hippocampal CB1, CB2 and PPAR gamma receptors to cannabidiol-induced disruption of fear memory consolidation

Author(s)

Raymundi, Ana Maria ; da Silva, Thiago R. ; Zampronio, Aleksander R. ; Guimaraes, Francisco S. ; Bertoglio, Leandro J. ; Stern, Cristina A. J.

• Document type: Journal article
• Source: British Journal of Pharmacology; v. 177, n. 4, p. 13-pg., 2020-01-21.

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, A(2A), and PPAR gamma 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 A(2A) antagonism, and remained unchanged after antagonism of PPAR gamma receptors. One hour after fear conditioning, CBD effects were prevented only by PPAR gamma 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 PPAR gamma receptors in the DH, during this process. (AU)

• FAPESP's process: 17/24304-0 - New perspectives in the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders
• Grantee: Francisco Silveira Guimaraes
• Support Opportunities: Research Projects - Thematic Grants