Bidirectional Effects of Cannabidiol on Contextual Fear Memory Extinction

Abstract

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.

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“…Systemic administration of CBD given acutely before extinction has been shown to affect contextual fear extinction depending on the strength of fear conditioning beforehand. CBD impaired extinction after weak conditioning but enhanced extinction after strong conditioning (Song et al , ). However, CBD given systemically before auditory fear extinction reduced fear expression acutely without affecting extinction memory (Jurkus et al , ).…”

On the transition from reconsolidation to extinction of contextual fear memories

“…MK-801 (Sigma-Aldrich) was diluted in sterile saline (0.1 mg/mL) and injected intraperitoneally (1 mL/kg) immediately after the reexposure session, or 30 min previously when specified (Lee et al 2006;Song et al 2016). Injections of MK-801 or vehicle were randomly distributed between animals.…”

“…No footshock was applied at either reexposure or test sessions. The aversive response (freezing) was automatically quantified during all sessions with a videotracking software (Viewpoint Life Sciences), and used as a memory index (Lee and Hynds 2013;Song et al 2016).…”

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“…53 Activation of the CB 1 receptor has been implicated in the facilitatory effect of CBD on fear extinction, possibly as an indirect consequence of enhancing endocannabinoids within the brain. [54][55][56] Fear extinction is a form of inhibitory learning that suppresses learned fear and forms the theoretical basis for exposure therapy in the treatment of certain anxiety disorders. 25 Interestingly, a study in humans showed that CBD also enhanced fear extinction in healthy volunteers, 57 raising the possibility that CBD might enhance the therapeutic effects of psychological treatments.…”