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'.
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