GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations.
GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations.
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DOI：
10.1016/j.bbi.2015.08.011
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Sheridan JF
中科院分区：
文献类型：
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作者：
Ramirez K;Niraula A;Sheridan JF
社会心理压力与免疫力改变、焦虑和抑郁有关。重复社交失败 (RSD) 是一种社交压力模型，会触发炎症性骨髓祖细胞 (MPC；CD11b+ /Ly6Chi) 流出大脑，从而促进类似焦虑的行为。与此同时，RSD 增强神经炎症信号传导和持久的社交回避行为。劳拉西泮和氯硝西泮是常规处方抗焦虑药，通过增强大脑中的 GABA 活性来发挥作用。除了与中枢神经系统 (CNS) 中的中央苯二氮卓结合位点 (CBBS) 结合外，劳拉西泮还以高亲和力与易位蛋白 (TSPO) 结合，从而引起免疫调节。氯硝西泮以 CBBS 为靶标，对 TSPO 的亲和力较低。这里的目的是确定劳拉西泮和氯硝西泮是否能够：1）预防应激引起的外周和中枢炎症反应，2）阻止 RSD 小鼠的焦虑和社交回避行为。 C57/BL6 小鼠被分为实验组，并用劳拉西泮 (0.10mg/kg)、氯硝西泮 (0.25mg/kg) 或载体 (0.9%NaCl) 治疗。最后一个 RSD 周期后的第二天早上收集行为数据和组织。劳拉西泮和氯硝西泮可有效减弱 RSD 小鼠下丘脑中 CRH 的 mRNA 表达和血浆中皮质酮的表达。这两种药物均可阻断应激诱导的血浆中 IL-6 水平。劳拉西泮和氯硝西泮对应激诱导的骨髓生成增强和抑制循环中单核细胞和粒细胞的运输具有不同的作用。此外，劳拉西泮（而非氯硝西泮）在 RSD 后抑制脾肿大和脾脏中促炎细胞因子的产生。此外，劳拉西泮和氯硝西泮可阻止应激诱导的中枢神经系统中巨噬细胞（CD11b+/CD45high）的积累。以类似的方式，劳拉西泮和氯硝西泮都能阻止神经炎症信号传导，并逆转暴露于 RSD 的小鼠的焦虑样和抑郁样行为。这些数据支持这样的观点：劳拉西泮和氯硝西泮除了发挥抗焦虑和抗抑郁作用外，在心理社会压力期间可能具有作为神经免疫调节剂的治疗潜力。 RSD 诱导的行为结果的逆转可能是由于 GABA 能神经传递的增强，或其他一些脱靶效应。劳拉西泮（而非氯硝西泮）的外周作用似乎是由 TSPO 激活介导的。
Psychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b+ /Ly6Chi) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: 1) prevent stress-induced peripheral and central inflammatory responses, and 2) block anxiety and social avoidance behavior in mice subjected to RSD. C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10mg/kg), clonazepam (0.25 mg/kg) or vehicle (0.9%NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD. Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b+/CD45high) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior in mice exposed to RSD. These data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress. The reversal of RSD-induced behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation.