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

BACKGROUND AND PURPOSE:

Preclinical studies have shown that 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. The present paper aimed at investigating 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 h after fear conditioning. The CBD-induced effects on consolidation were inferred behaviorally and by the analysis of the activity-regulated cytoskeleton-associated (Arc) protein expression. The relative contribution of anandamide, CB1, CB2, 5-HT_1A , A_2A , and PPARγ receptors was also examined.

KEY RESULTS:

CBD impaired memory consolidation when given immediately or 1 h after fear conditioning, but not after 3 h. The DH Arc expression was reduced by systemic CBD treatment in both cases. Immediately after fear conditioning, the CBD effect was abolished by CB1 or CB2 receptor blockade, partly reduced by 5-HT_1A or A_2A antagonism, and remained unchanged after antagonism of PPARγ receptors. 1 h after fear conditioning, the CBD effect was only prevented by PPARγ receptor antagonism. Besides, the FAAH inhibition impaired memory consolidation when URB597 was infused immediately, but not 1 hour after fear conditioning.

CONCLUSIONS AND IMPLICATIONS:

CBD disrupts memory consolidation up to 1 h after fear conditioning, allowing an extended window of opportunity to mitigate aversive memories after their acquisition. The results suggest time-dependent participation of DH anandamide, CB1, CB2, and PPARγ receptors in this process.

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