Centro de Ciências da Vida e da Saúde, Universidade Católica de Pelotas (UCPel), Rua Almirante Barroso, 1202 sala G109, 96010-280 Pelotas, RS, Brazil.
Neuropharmacology. 2012 Jan;62(1):419-26. doi: 10.1016/j.neuropharm.2011.08.018. Epub 2011 Aug 18.
Pro-inflammatory cytokines are implicated in the pathogenesis of depression. However, few animal models of cytokine-induced depression well characterized regarding its response to antidepressants are available. Hence, the aim of this study was to propose a model of depressive-like behavior induced by the administration of tumor necrosis factor-α (TNF-α) responsive to antidepressant treatments. TNF-α administered by i.c.v. route produced a depressive-like behavior in the forced swimming test (FST) and tail suspension test (TST) (0.1-1 fg/site and 0.001 fg/site, respectively), without altering the locomotor activity in the open-field test. In addition, anti-TNF-α antibody (0.1-1 pg/site, i.c.v.), but not the inhibitor of TNF-α synthesis thalidomide (3-30 mg/kg, s.c.) produced an antidepressant-like response in the FST. Moreover, either anti-TNF-α antibody (0.01 pg/site, i.c.v) or thalidomide (30 mg/kg, s.c.) reversed the depressive-like behavior induced by TNF- (0.1 fg/site, i.c.v.) in the FST. TNF-α receptor 1 (TNFR1) knockout mice exhibited an antidepressant-like behavior in the FST and in the TST as compared with the wild type mice. Treatment with fluoxetine (32 mg/kg, i.p), imipramine (15 mg/kg, i.p.) and desipramine (16 mg/kg, i.p) prevented the depressant-like effect induced by TNF-α (0.1 fg/site, i.c.v.) in the FST. In addition, TNF-α (0.1 fg/site, i.c.v.) administration produced an anhedonic response in a sucrose intake test, which was prevented by anti-TNF-α antibody (0.01 pg/site, i.c.v) or fluoxetine (32 mg/kg, i.p). Taken together, these results indicate that TNF-α produces a depressive-like state in mice, reinforcing the notion that an inflammatory component may play an important role in the pathophysiology of depression and suggesting that the central administration of TNF-α may be a novel approach to study the inflammatory component of depressive disorder. This article is part of a Special Issue entitled 'Anxiety and Depression'.
促炎细胞因子与抑郁症的发病机制有关。然而，很少有细胞因子诱导的抑郁症的动物模型能很好地描述其对抗抑郁药物的反应。因此，本研究的目的是提出一种通过给予肿瘤坏死因子-α（TNF-α）诱导的、对抗抑郁药物有反应的抑郁样行为模型。侧脑室给予 TNF-α（0.1-1 fg/部位和 0.001 fg/部位）导致强迫游泳试验（FST）和悬尾试验（TST）中出现抑郁样行为（0.1-1 fg/部位和 0.001 fg/部位），而不改变旷场试验中的运动活性。此外，抗 TNF-α 抗体（0.1-1 pg/部位，侧脑室），而不是 TNF-α 合成抑制剂沙利度胺（3-30 mg/kg，皮下），在 FST 中产生抗抑郁样反应。此外，抗 TNF-α 抗体（0.01 pg/部位，侧脑室）或沙利度胺（30 mg/kg，皮下）均可逆转 TNF-α（0.1 fg/部位，侧脑室）诱导的 FST 中抑郁样行为。与野生型小鼠相比，TNF-α 受体 1（TNFR1）敲除小鼠在 FST 和 TST 中表现出抗抑郁样行为。氟西汀（32 mg/kg，腹腔注射）、丙咪嗪（15 mg/kg，腹腔注射）和去甲丙咪嗪（16 mg/kg，腹腔注射）预防 TNF-α（0.1 fg/部位，侧脑室）在 FST 中引起的抑郁样效应。此外，TNF-α（0.1 fg/部位，侧脑室）给药在蔗糖摄入试验中引起快感缺失反应，该反应可被抗 TNF-α 抗体（0.01 pg/部位，侧脑室）或氟西汀（32 mg/kg，腹腔注射）预防。总之，这些结果表明 TNF-α 在小鼠中产生抑郁样状态，这强化了炎症成分可能在抑郁症的病理生理学中发挥重要作用的观点，并表明中枢给予 TNF-α 可能是研究抑郁障碍炎症成分的一种新方法。本文是题为“焦虑和抑郁”的特刊的一部分。
