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.
Keywords: Cannabis; Endocannabinoid system; Fear conditioning; Generalization.
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