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Cannabidiol (CBD) has been established to have both acute and long-lasting effects to reduce fear memory expression. The long-lasting impact might be mediated by an enhancement of memory extinction or an impairment of memory reconsolidation. Here, we directly compared the effects of i.p. injections of cannabidiol (10 mg/kg) with those of the NMDA receptor antagonist MK-801 (0.1 mg/kg) and partial agonist D-cycloserine (DCS; 15 mg/kg) in order to determine the mnemonic basis of long-term fear reduction. We showed that under conditions of strong fear conditioning, CBD reduced contextual fear memory expression both acutely during the extinction session as well as later at a fear retention test. The latter test reduction was replicated by DCS, but MK-801 instead elevated test freezing. In contrast, when initial conditioning was weaker, CBD and MK-801 had similar effects to increase freezing at the fear retention test relative to vehicle controls, whereas DCS had no observable impact. This pattern of results is consistent with CBD enhancing contextual fear memory extinction when the initial conditioning is strong, but impairing extinction when conditioning is weak. This bidirectional effect of CBD may be related to stress levels induced by conditioning and evoked at retrieval during extinction, rather than the strength of the memory  per se .

Bidirectional Effects of Cannabidiol on Contextual Fear Memory Extinction