Department of Pharmacology, Federal University of Parana, Curitiba, Brazil.
Cannabis Cannabinoid Res. 2024 Aug;9(4):e1063-e1074. doi: 10.1089/can.2022.0329. Epub 2023 Apr 3.
Sex differences in the response to the anxiety-related effects of cannabinoid drugs have been reported, with females being more sensitive than males. Evidence suggests that, according to sex and estrous cycle phase (ECP), the content of the endocannabinoids (eCBs) N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) varies in brain areas involved in the anxiety-like behavior. Considering the lack of studies evaluating sex and ECP differences in the eCB system in anxiety, using URB597, a fatty acid amide hydrolase inhibitor, or MJN110, a monoacylglycerol lipase inhibitor, we explored the effects of increasing AEA or 2-AG levels, respectively, in cycling and ovariectomized (OVX) female adult Wistar rats, as well as males, subjected to the elevated plus maze. The administration of URB597 (0.1 or 0.3mg/kg; intraperitoneally) either increased or reduced the percentage of open arms time (%OAT) and open arms entries (%OAE), being anxiolytic in diestrus and anxiogenic in estrus. No effects were observed in proestrus or when all ECPs were analyzed together. Both doses produced anxiolytic-like effects in males. In OVX females, the anxiolytic-like effect of URB597 0.1 was associated with low levels of estradiol, whereas the anxiogenic-like effect of URB597 0.3 was spared by estradiol pretreatment. The systemic administration of MJN110 3.0 mg/kg reduced the risk assessment behavior (RAB), suggesting an anxiolytic-like effect independent of the ECP. When considering the ECP, MJN110 3.0 increased the %OAT and reduced the RAB, being anxiolytic in estrus and diestrus. No effects were observed in proestrus. Both doses of MJN110 were anxiogenic in males. In OVX females, the anxiolytic-like effect of MJN110 was dependent on low estradiol levels. Together, our findings support the evidence that females react differently to the effects of cannabinoids in the anxiety-like behavior; in addition, AEA and 2-AG modulation elicits anxiety-like responses that are closely influenced by hormone levels, mainly estradiol.
已有研究报道，大麻素类药物引起的焦虑相关效应存在性别差异，女性比男性更为敏感。有证据表明，根据性别和动情周期阶段（ECP），参与类似焦虑行为的大脑区域中的内源性大麻素（eCBs）N-花生四烯酸乙醇胺（AEA）和 2-花生四烯酸甘油（2-AG）的含量会发生变化。考虑到缺乏评估焦虑症中 eCB 系统的性别和 ECP 差异的研究，我们使用脂肪酸酰胺水解酶抑制剂 URB597 或单酰基甘油脂肪酶抑制剂 MJN110，分别在发情和去卵巢（OVX）成年 Wistar 雌性大鼠以及雄性大鼠中探索增加 AEA 或 2-AG 水平的影响，然后将其置于高架十字迷宫上。URB597（0.1 或 0.3mg/kg；腹腔内给药）给药要么增加要么减少开放臂时间百分比（%OAT）和开放臂进入次数百分比（%OAE），在发情期具有抗焦虑作用，在动情前期具有焦虑作用。在动情前期或当所有 ECP 一起分析时，均未观察到这些效果。两种剂量在雄性大鼠中均产生类似抗焦虑的作用。在 OVX 雌性大鼠中，URB597 0.1 的类似抗焦虑作用与低水平的雌二醇有关，而 URB597 0.3 的类似致焦虑作用则不受雌二醇预处理的影响。全身给予 MJN110 3.0mg/kg 可降低风险评估行为（RAB），提示具有独立于 ECP 的类似抗焦虑作用。当考虑 ECP 时，MJN110 3.0 增加了%OAT 并减少了 RAB，在发情期和发情后期具有抗焦虑作用。在动情前期未观察到这些效果。两种剂量的 MJN110 在雄性大鼠中均具有致焦虑作用。在 OVX 雌性大鼠中，MJN110 的类似抗焦虑作用依赖于低水平的雌二醇。总之，我们的研究结果支持这样的证据，即女性对大麻素类药物在类似焦虑行为中的作用有不同的反应；此外，AEA 和 2-AG 的调节会引起类似焦虑的反应，这些反应受到激素水平的密切影响，主要是雌二醇。
