Delayed therapeutic responses and limited efficacy are the main challenges of existing antidepressant drugs, thereby incentivizing the search for new potential treatments. Cannabidiol (CBD), non-psychotomimetic component of cannabis, has shown promising antidepressant effects in different rodent models, but its mechanism of action remains unclear. Herein, we investigated the antidepressant-like effects of repeated CBD treatment on behavior, neuroplasticity markers and lipidomic profile in the prefrontal cortex (PFC) of Flinders Sensitive Line (FSL), a genetic animal model of depression, and their control counterparts Flinders Resistant Line (FRL) rats. Male FSL animals were treated with CBD (10 mg/kg; i.p.) or vehicle (7 days) followed by Open Field Test (OFT) and the Forced Swimming Test (FST). The PFC was analyzed by a) western blotting to assess markers of synaptic plasticity and cannabinoid signaling in synaptosome and cytosolic fractions; b) mass spectrometry-based lipidomics to investigate endocannabinoid levels (eCB). CBD attenuated the increased immobility observed in FSL, compared to FRL in FST, without changing the locomotor behavior in the OFT. In synaptosomes, CBD increased ERK1, mGluR5, and Synaptophysin, but failed to reverse the reduced CB1 and CB2 levels in FSL rats. In the cytosolic fraction, CBD increased ERK2 and decreased mGluR5 expression in FSL rats. Surprisingly, there were no significant changes in eCB levels in response to CBD treatment. These findings suggest that CBD effects in FSL animals are associated with changes in synaptic plasticity markers involving mGluR5, ERK1, ERK2, and synaptophysin signaling in the PFC, without increasing the levels of endocannabinoids in this brain region.

中文翻译：

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重复大麻二酚治疗会影响弗林德斯敏感线（FSL）大鼠抑郁模型前额皮质的神经可塑性和内源性大麻素信号传导。


治疗反应延迟和疗效有限是现有抗抑郁药物的主要挑战，从而激励人们寻找新的潜在治疗方法。大麻二酚（CBD）是大麻的非拟精神病成分，在不同的啮齿动物模型中显示出良好的抗抑郁作用，但其作用机制仍不清楚。在此，我们研究了重复 CBD 治疗对抑郁症遗传动物模型 Flinders Sensitive Line (FSL) 及其对照对应物 Flinders Resistant Line 的行为、神经可塑性标志物和前额皮质 (PFC) 脂质组学特征的抗抑郁样作用。 （FRL）大鼠。雄性 FSL 动物用 CBD（10 毫克/千克；腹腔注射）或媒介物（7 天）治疗，然后进行旷场测试 (OFT) 和强迫游泳测试 (FST)。通过 a) 蛋白质印迹分析 PFC，以评估突触可塑性标记物和突触体和胞质组分中的大麻素信号传导； b) 基于质谱的脂质组学研究内源性大麻素水平 (eCB)。与 FST 中的 FRL 相比，CBD 减弱了 FSL 中观察到的不动性增加，但没有改变 OFT 中的运动行为。在突触体中，CBD 增加了 FSL 大鼠中的 ERK1、mGluR5 和突触素，但未能逆转 CB1 和 CB2 水平降低。在细胞质部分中，CBD 增加了 FSL 大鼠中 ERK2 的表达并降低了 mGluR5 的表达。令人惊讶的是，CBD 治疗后 eCB 水平没有显着变化。这些发现表明，CBD 对 FSL 动物的影响与突触可塑性标记物的变化有关，这些标记物涉及 mGluR5、ERK1、ERK2 和 PFC 中的突触素信号传导，而不会增加该大脑区域内源性大麻素的水平。