Depression is a leading cause of disability worldwide and current treatments are often inadequate for many patients. Increasing evidence indicates that inflammation contributes to susceptibility to depression. We hypothesized that targeting Toll-like receptor 4 (TLR4), one of the main signaling pathways for triggering an inflammatory response, would lessen stress-induced depression-like behaviors in male mice. TLR4 inhibition with the CNS-penetrating drug (+)-naloxone that is a TLR4 antagonist but is inactive at opiate receptors increased resistance to the learned helplessness model of depression and provided an antidepressant-like effect in the tail suspension test. (+)-Naloxone administration also reversed chronic restraint stress-induced impairments in social behavior and novel object recognition. These effects involved blockade of stress-induced activation of glycogen synthase kinase 3β (GSK3β), NF-κB, IFN regulatory factor 3 (IRF3) and nitric oxide production, and reduced levels of the cytokines tumor necrosis factor-α (TNFα) and interferon-β (IFNβ). These findings demonstrate that blocking TLR4 with (+)-naloxone effectively diminishes several detrimental responses to stress and raise the possibility that (+)-naloxone may be a feasible intervention for depression.

中文翻译：

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(+)-Naloxone 阻断 Toll 样受体 4 以减轻压力对雄性小鼠行为的有害影响

抑郁症是世界范围内导致残疾的主要原因，目前的治疗对许多患者来说往往是不够的。越来越多的证据表明炎症有助于抑郁症的易感性。我们假设靶向 Toll 样受体 4 (TLR4)（触发炎症反应的主要信号通路之一）会减轻雄性小鼠的压力诱导的抑郁样行为。用 CNS 穿透药物 (+)-纳洛酮抑制 TLR4，它是一种 TLR4 拮抗剂，但对阿片受体无活性，增加了对抑郁习得性无助模型的抵抗力，并在尾悬试验中提供了类似抗抑郁药的作用。(+)-纳洛酮给药还逆转了慢性束缚应激引起的社交行为和新物体识别障碍。这些作用包括阻断压力诱导的糖原合酶激酶 3β (GSK3β)、NF-κB、IFN 调节因子 3 (IRF3) 和一氧化氮的产生，并降低细胞因子肿瘤坏死因子-α (TNFα) 和干扰素的水平-β (IFNβ)。这些发现表明，用 (+)-纳洛酮阻断 TLR4 有效地减少了对压力的几种有害反应，并提高了 (+)-纳洛酮可能是一种可行的抑郁症干预措施的可能性。