Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: reduced dopaminergic modulation and immediate gene expression in limbic circuits

摘要

The prefrontal cortex (PFC), amygdala and hippocampusdisplay a coordinated activity during acquisitionof associative fear memories. Evidence indicates that PFCengagement in aversive memory formation does not progresslinearly as previously thought. Instead, it seems tobe recruited at specific time windows after memory acquisition,which has implications for the treatment of posttraumaticstress disorders. Cannabidiol (CBD), the majornon-psychotomimetic phytocannabinoid of the Cannabissativa plant, is known to modulate contextual fear memoryacquisition in rodents. However, it is still not clear howCBD interferes with PFC-dependent processes duringpost-training memory consolidation. Here, we testedwhether intra-PFC infusions of CBD immediately after or5 h following contextual fear conditioning was able to interferewith memory consolidation. Neurochemical and cellularcorrelates of the CBD treatment were evaluated by the quantificationof extracellular levels of dopamine (DA), serotonin,and their metabolites in the PFC and by measuring the cellularexpression of activity-dependent transcription factors incortical and limbic regions. Our results indicate that bilateralintra-PFC CBD infusion impaired contextual fear memoryconsolidation when applied 5 h after conditioning, but hadno effect when applied immediately after it. This effect wasassociated with a reduction in DA turnover in the PFC followingretrieval 5 days after training. We also observed thatpost-conditioning infusion of CBD reduced c-fos and zif-268protein expression in the hippocampus, PFC, and thalamus.Our findings support that CBD interferes with contextualfear memory consolidation by reducing PFC influence oncortico-limbic circuits.