Phosphodiesterase 4 inhibition after retrieval switches the memory fate favoring extinction instead of reconsolidation.

Phosphodiesterase 4 (PDE4), an enzyme expressed in the dorsal hippocampus (DH), hydrolyzes the cAMP, limiting the PKA-induced CREB phosphorylation (pCREB) and BDNF expression. Depending on the brain region, PKA and pCREB mediate reconsolidation or extinction, whereas BDNF is mainly related to extinction facilitation. The mechanisms underpinning the switch between reconsolidation and extinction are relatively unknown. Here, we tested the hypothesis that PDE4 might control these processes. We showed in Wistar rats submitted to contextual fear conditioning that PDE4 inhibition with roflumilast (ROF) within the DH, after a short retrieval, did not change freezing behavior after one day (TestA1). After 10 days, the ROF-treated group significantly reduced the expression of freezing behavior. This effect depended on retrieval, Test A1 exposure, and reinstated after a remainder foot shock, suggesting an extinction facilitation. The ROF effect depended on PKA after retrieval or, protein synthesis after Test A1. After retrieval, ROF treatment did not change the pCREB/CREB ratio in the DH. It enhanced proBDNF expression without changing pre-proBDNF or mature BDNF in the DH after Test A1. The results suggest that the inhibition of PDE4 in the DH after a short retrieval changes the memory sensibility from reconsolidation to extinction via regulating proBDNF expression.

Effects of delta-9 tetrahydrocannabinol on fear memory labilization and reconsolidation: A putative role of GluN2B-NMDA receptor within the dorsal hippocampus.

Cannabis preparations could be an effective reconsolidation-based treatment for post-traumatic stress disorder. However, the effects of Δ9-tetrahydrocannabinol (THC) in fear memory labilization, a critical condition for retrieval-induced reconsolidation, are undetermined. We sought to investigate the effect of a conventional and an ultra-low dose of THC in memory labilization of adult male Wistar rats submitted to contextual fear conditioning. Pretreatment with THC 0.002, but not THC 0.3 mg/kg, i. p., before memory retrieval, did not change memory expression during the retrieval but impaired reconsolidation. No treatment changed freezing expression in an unpaired context. Before retrieval, THC 0.3, but not THC 0.002, decreased GluN2A-NMDA expression and the GluN2A/GluN2B ratio in the dorsal hippocampus (DH) 24 h later. No changes were observed immediately after retrieval. Pretreatment with THC 0.3 abolished the reconsolidation-impairing effect of anisomycin injected into the DH, suggesting an impairment in memory labilization. This effect was associated with an increased freezing expression in the unpaired context and was not observed with the THC ultra-low dose. The GluN2B-NMDA antagonism increased fear generalization in the anisomycin-treated group but restored its reconsolidation-impairing effect and reduced fear generalization when animals were pretreated with THC 0.3. GluN2A-NMDA antagonism or inhibition of the ubiquitin-proteasome system in the DH did not interfere with the effects of THC 0.3. Our findings indicate that THC causes a bidirectional effect on fear memory labilization that depends on hippocampal GluN2B-NMDA receptors' involvement in fear memory generalization.