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Endocannabinoids are involved in various physiological functions, including synaptic plasticity and memory, and some psychiatric disorders, such as posttraumatic stress disorder (PTSD), through the activation of cannabinoid (CB) receptors. Patients with PTSD often show excessive fear memory and impairment of fear extinction (FE). It has been reported that the stability of acquired fear memory is altered through multiple memory stages, such as consolidation and reconsolidation. FE also affects the stability of fear memory. Each stage of fear memory formation and FE are regulated by different molecular mechanisms, including the CB system. However, to the best of our knowledge, no review summarizes the role of the CB system during each stage of fear memory formation and FE. In this review, we summarize the roles of endocannabinoids in fear memory formation and FE. Moreover, based on the summary, we propose a new hypothesis for the role of endocannabinoids in fear regulation, and discuss treatment for PTSD using CB system-related drugs.

The prevalence of post-traumatic stress disorder (PTSD) is higher in women than in men. Among both humans and mice, females exhibit higher resistance to fear extinction than males, suggesting that differences between sexes in fear-extinction processes are involved in the pathophysiology of such fear-related diseases. Sex differences in molecular mechanisms underlying fear memory and extinction are unclear. The cannabinoid (CB) system is well known to be involved in fear memory and extinction, but this involvement is based mainly on experiments using male rodents. It is not known whether there are sex differences in the role of the CB system in fear memory and extinction. To explore this possibility, we investigated the effects of pharmacological manipulations of the CB system on the retrieval and extinction of contextual fear memory in male and female mice. WIN55,212-2, a CB receptor (CBR) agonist, augmented the retrieval of fear memory in both sexes, but SR141716 (a CB1R antagonist) did not affect it in either sex. An enhancement of 2-arachidonylglycerol (2-AG, one of the two major endocannabinoids) via JZL184 (an inhibitor of the 2-AG hydrolase monoacylglycerol lipase [MAGL]), augmented the retrieval of fear memory through the activation of CB1R but not CB2R in female mice. In contrast, the enhancement of N-arachidonylethanolamine (AEA, the other major endocannabinoid) via URB597, an inhibitor of an AEA hydrolase (fatty acid amide hydrolase-1) did not show any effects on the retrieval of fear memory in either sex. WIN55,212-2, SR141716, and JZL184 inhibited fear extinction irrespective of sex. URB enhanced fear extinction in females that were in diestrus phase at the first extinction session, but not in males. These results suggest that although the role of CB1R in the retrieval and extinction of contextual fear memory is common among males and females, the effects of an increase in endocannabinoid levels on the retrieval or extinction of contextual fear memory differ between the sexes.

Endocannabinoids are involved in various physiological functions, including synaptic plasticity and memory, and some psychiatric disorders, such as posttraumatic stress disorder (PTSD), through the activation of cannabinoid (CB) receptors. Patients with PTSD often show excessive fear memory and impairment of fear extinction (FE). It has been reported that the stability of acquired fear memory is altered through multiple memory stages, such as consolidation and reconsolidation. FE also affects the stability of fear memory. Each stage of fear memory formation and FE are regulated by different molecular mechanisms, including the CB system. However, to the best of our knowledge, no review summarizes the role of the CB system during each stage of fear memory formation and FE. In this review, we summarize the roles of endocannabinoids in fear memory formation and FE. Moreover, based on the summary, we propose a new hypothesis for the role of endocannabinoids in fear regulation, and discuss treatment for PTSD using CB system-related drugs.