Psychology Department, Bar-Ilan University, Ramat Gan 5290002, Israel.
Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel.
Int J Mol Sci. 2023 Feb 14;24(4):3828. doi: 10.3390/ijms24043828.
The pathophysiology of major depressive disorder (MDD) is diverse and multi-factorial, yet treatment strategies remain limited. While women are twice as likely to develop the disorder as men, many animal model studies of antidepressant response rely solely on male subjects. The endocannabinoid system has been linked to depression in clinical and pre-clinical studies. Cannabidiolic Acid-Methyl Ester (CBDA-ME, EPM-301) demonstrated anti-depressive-like effects in male rats. Here, we explored acute effects of CBDA-ME and some possible mediating mechanisms, using a depressive-like genetic animal model, the Wistar-Kyoto (WKY) rat. In Experiment 1, Female WKY rats underwent the Forced swim test (FST) following acute CBDA-ME oral ingestion (1/5/10 mg/kg). In Experiment 2, Male and female WKY rats underwent the FST after injection of CB1 (AM-251) and CB2 (AM-630) receptor antagonists 30 min before acute CBDA-ME ingestion (1 mg/kg, males; 5 mg/kg, females). Serum levels of Brain-Derived Neurotrophic Factor (BDNF), numerous endocannabinoids and hippocampal Fatty Acid Amide Hydrolase (FAAH) levels were assessed. Results indicate that females required higher doses of CBDA-ME (5 and 10 mg/kg) to induce an anti-depressive-like effect in the FST. AM-630 blocked the antidepressant-like effect in females, but not in males. The effect of CBDA-ME in females was accompanied by elevated serum BDNF and some endocannabinoids and low hippocampal expression of FAAH. This study shows a sexually diverse behavioral anti-depressive response to CBDA-ME and possible underlying mechanisms in females, supporting its potential use for treating MDD and related disorders.
重度抑郁症（MDD）的病理生理学是多样化和多因素的，但治疗策略仍然有限。尽管女性患这种疾病的可能性是男性的两倍，但许多抗抑郁反应的动物模型研究仅依赖于雄性动物。内源性大麻素系统在临床和临床前研究中与抑郁症有关。大麻二酚酸甲酯（CBDA-ME，EPM-301）在雄性大鼠中表现出抗抑郁样作用。在这里，我们使用抑郁样遗传动物模型——Wistar-Kyoto（WKY）大鼠，探索了 CBDA-ME 的急性作用及其可能的介导机制。在实验 1 中，雌性 WKY 大鼠在急性 CBDA-ME 口服摄入后进行强迫游泳试验（FST）（1/5/10mg/kg）。在实验 2 中，雄性和雌性 WKY 大鼠在注射 CB1（AM-251）和 CB2（AM-630）受体拮抗剂 30 分钟后，进行急性 CBDA-ME 摄入（1mg/kg，雄性；5mg/kg，雌性）。评估血清脑源性神经营养因子（BDNF）、多种内源性大麻素和海马脂肪酸酰胺水解酶（FAAH）水平。结果表明，雌性大鼠需要更高剂量的 CBDA-ME（5 和 10mg/kg）才能在 FST 中诱导抗抑郁样作用。AM-630 阻断了雌性动物的抗抑郁样作用，但对雄性动物没有作用。CBDA-ME 在雌性动物中的作用伴随着血清 BDNF 和一些内源性大麻素的升高和海马 FAAH 表达的降低。这项研究表明，CBDA-ME 在女性中表现出性别多样化的行为抗抑郁反应及其潜在的机制，支持其在治疗 MDD 和相关疾病中的潜在用途。
