Psychosocial stress contributes to the development of psychiatric disorders. Repeated social defeat (RSD) is a murine stressor that causes a release of inflammatory monocytes into circulation. Moreover, RSD-induced anxiety-like behavior is dependent on the recruitment of these monocytes to the brain. Activation of the endocannabinoid (ECB) system may modulate both neuroendocrine and inflammatory responses mediated by stress. Therefore, we hypothesized that a cannabinoid receptor agonist would attenuate RSD-induced inflammation, anxiety, and stress sensitization. To test this hypothesis, mice received an injection of the synthetic cannabinoid_1/2 receptor agonist, WIN55,212-2 (WIN; 1 mg/kg, intraperitoneally) daily for six consecutive days, 30 min before each exposure to RSD. Anxiety-like behavior, immune activation, neuroinflammation, and microglial reactivity were determined 14 h after RSD. RSD-induced anxiety-like behavior in the open field and in the EPM was reversed by WIN55,212-2. Moreover, WIN55,212-2 reduced the accumulation of inflammatory monocytes in circulation and brain after RSD and attenuated RSD-induced interleukin-1β (IL-1β) messenger RNA (mRNA) expression in microglia/macrophages. Increased ex vivo reactivity of microglia/monocytes to lipopolysaccharides (LPS) after RSD was also attenuated by WIN55,212-2. Next, fear expression, extinction, and recall were evaluated 24 and 48 h, respectively, after contextual fear conditioning, which took place 7 days after RSD. Here, RSD caused prolonged fear expression and impaired fear extinction recall, which was associated with increased IL-1β mRNA in the brain. Moreover, these stress-induced effects were reversed by WIN55,212-2. In conclusion, activation of cannabinoid receptors limited the immune and neuroinflammatory responses to RSD and reversed the short-term and long-term behavioral deficits associated with RSD.

中文翻译：

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大麻素受体激动剂WIN55,212-2减弱了反复的社交失败诱发的神经炎症，焦虑样行为和对恐惧消灭的抵抗力。

社会心理压力助长了精神疾病的发展。反复社交衰竭（RSD）是一种鼠类应激源，可引起炎症性单核细胞释放进入循环。此外，RSD诱导的焦虑样行为取决于这些单核细胞向大脑的募集。内源性大麻素（ECB）系统的激活可能会调节神经内分泌和压力介导的炎症反应。因此，我们假设大麻素受体激动剂会减弱RSD引起的炎症，焦虑和应激敏感性。为了验证这一假设，小鼠接受了合成大麻素_1/2的注射受体激动剂，WIN55,212-2（WIN； 1 mg / kg，腹膜内）每天连续六天，每次暴露于RSD前30分钟。在RSD后14小时确定焦虑样行为，免疫激活，神经炎症和小胶质细胞反应性。WIN55,212-2逆转了RSD在旷野和EPM中引起的焦虑样行为。此外，WIN55,212-2减少了RSD后循环和大脑中炎性单核细胞的积累，并减弱了RSD诱导的小胶质细胞/巨噬细胞中白介素1β（IL-1β）信使RNA（mRNA）的表达。WIN55,212-2也减弱了RSD后小胶质细胞/单核细胞对脂多糖（LPS）的离体反应性增加。接下来，在情境恐惧条件调整后（分别是RSD后7天），分别对恐惧表达，绝种和召回进行了评估，分别为24小时和48小时。这里，RSD导致恐惧表达时间延长和恐惧消退回忆受损，这与大脑中IL-1βmRNA的增加有关。此外，WIN55,212-2逆转了这些压力诱导的效应。总之，大麻素受体的激活限制了对RSD的免疫和神经炎症反应，并逆转了与RSD相关的短期和长期行为缺陷。