Department of Pharmacotherapeutics, Showa Pharmaceutical University, 3-3165, Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
Department of Pharmacotherapeutics, Showa Pharmaceutical University, 3-3165, Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan; Department of Cognitive Behavioral Physiology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan; Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
Psychoneuroendocrinology. 2022 Apr;138:105688. doi: 10.1016/j.psyneuen.2022.105688. Epub 2022 Feb 12.
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.
创伤后应激障碍（PTSD）在女性中的患病率高于男性。在人类和小鼠中，女性表现出比男性更高的恐惧消退抵抗，这表明性别在恐惧消退过程中的差异与这种与恐惧相关的疾病的病理生理学有关。恐惧记忆和消退的分子机制中的性别差异尚不清楚。大麻素（CB）系统被广泛认为参与了恐惧记忆和消退，但这种参与主要基于使用雄性啮齿动物的实验。尚不清楚 CB 系统在恐惧记忆和消退中的作用是否存在性别差异。为了探索这种可能性，我们研究了 CB 系统的药理学操作对雄性和雌性小鼠的情境恐惧记忆的检索和消退的影响。WIN55,212-2，一种 CB 受体（CBR）激动剂，增强了两性的恐惧记忆检索，但 SR141716（一种 CB1R 拮抗剂）在两性中均未影响其作用。通过 JZL184（2-AG 水解酶单酰基甘油脂肪酶 [MAGL] 的抑制剂）增强 2-花生四烯酰甘油（2-AG，两种主要内源性大麻素之一）的作用，通过激活 CB1R 增强了雌性小鼠的恐惧记忆检索，但不通过 CB2R。相比之下，通过 URB597（一种内源性大麻素）的抑制剂（脂肪酸酰胺水解酶-1）增强 N-花生四烯酰乙醇胺（AEA，另一种主要内源性大麻素）的作用，在两性中均未显示出对恐惧记忆检索的任何影响。WIN55,212-2、SR141716 和 JZL184 抑制了无论性别如何的恐惧消退。URB 在第一次消退过程中处于发情期的雌性中增强了恐惧消退，但在雄性中没有。这些结果表明，尽管 CB1R 在情境恐惧记忆的检索和消退中的作用在雄性和雌性中是共同的，但内源性大麻素水平的增加对情境恐惧记忆的检索或消退的影响在两性之间存在差异。
