Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity

Abstract

Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses. Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD. We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA). We also examined whether enhancing eCB signaling before extinction, using the fatty acid amide hydrolase (FAAH) inhibitor URB597, could prevent the shock/SRs-induced effects on fear response and plasticity. URB597 administered systemically (0.3 mg/kg) or locally into the CA1 or BLA (0.1 µg/side) prior to extinction decreased fear retrieval and this effect persisted throughout extinction training and did not recuperate during spontaneous recovery. A low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg i.p. or 0.01 µg/0.5 µl intra-CA1 or intra-BLA) blocked these effects suggesting that the effects of URB597 were CB1 receptor-dependent. Exposure to shock and reminders induced behavioral metaplasticity with opposite effects on long-term potentiation (LTP) in the hippocampus (impairment) and the BLA (enhancement). URB597 was found to prevent the opposite shock/SR-induced metaplasticity in hippocampal and BLA-LTP. Exposure to shock and reminders might cause variation in endogenous cannabinoid levels that could affect fear-circuit function. Indeed, exposure to shock and SRs affected eCB content: increased 2-arachidonoyl-glycerol (2-AG) and N-arachidonylethanolamine (AEA) levels in the CA1, decreased serum and BLA AEA levels while shock exposure increased FAAH activity in the CA1 and BLA. FAAH inhibition before extinction abolished fear and modulated LTP in the hippocampus and amygdala, brain regions pertinent to emotional memory. The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA.

Kaempferol Facilitated Extinction Learning in Contextual Fear Conditioned Rats via Inhibition of Fatty-Acid Amide Hydrolase

“…An important player in stress is the endocannabinoid system (eCB) [ 8 ]. The eCB network is present in stress, anxiety, and fear-associated brain areas and constantly regulates processing of aversive memories [ 9 ]. Endocannabinoids are lipids based retrograde neurotransmitters, including anandamide ( N -arachidonoyl ethanolamide, AEA) and 2-AG (2-arachidonoylglycerol).…”

Cannabinoid Regulation of Fear and Anxiety: an Update

“…The effects of these cannabinoids in other paradigms or measures of learned fear, and its return after extinction, should be characterized to determine if their reported anxiolytic effects are enduring and more widely applicable [ 28 , 89 , 113 ]. In terms of the pharmacological mechanisms underlying the indirect cannabinoid receptor-dependent effects of CBD on extinction and fear memory reconsolidation, further research is needed to determine which endocannabinoid or endocannabinoids are involved.…”

“…Subsequent studies have added to these findings by showing that genetic variants of FAAH resulting in elevated anandamide levels also enhance fear extinction [ 59 , 82 •]. Moreover, pharmacological FAAH inhibitors were found to enhance fear extinction in a CB1 receptor-dependent manner [ 41 , 83 – 89 ], although the involvement of CB2 receptors in mediating anandamide regulation of fear extinction has not been characterized. In contrast to FAAH, genetic or pharmacological inhibition of MAGL impairs fear extinction [ 90 , 91 ], suggesting opposing roles for anandamide and 2-AG in modulating fear extinction.…”

Lights on Endocannabinoid-Mediated Synaptic Potentiation

“…During consolidation (III) eCB-mediated potentiation of inhibitory transmission and structural synaptic changes can stabilize acquired memory engrams (Monory et al, 2015;Ghosh et al, 2018;Hu et al, 2019). Finally, reactivation of memories (IV) especially emotional ones, increases eCB signaling, which can operate in feedback and control the lability of these memory traces by modifying the E/I balance (Li et al, 2008;Segev et al, 2018). plasticity expression and polarity ex vivo (Glangetas et al, 2013;Bosch-Bouju et al, 2016) and in vivo (Segev et al, 2018).…”