Depressive-like behavior induced by tumor necrosis factor-α in mice

• Published in: Neuropharmacology 2012-01, Vol.62 (1), p.419-426
• Main Authors: Kaster, Manuella P., Gadotti, Vinícius M., Calixto, João B., Santos, Adair R.S., Rodrigues, Ana Lúcia S.
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Antibodies - therapeutic use; Antidepressants; Antidepressive Agents - therapeutic use; Depression; Depression - chemically induced; Depression - drug therapy; Depression - genetics; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior - drug effects; Hindlimb Suspension - methods; Hindlimb Suspension - psychology; Inflammation; Injections, Intraperitoneal; Lymphotoxin-alpha - immunology; Lymphotoxin-alpha - toxicity; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Tumor Necrosis Factor, Type I - deficiency; Swimming - psychology; Thalidomide - therapeutic use; TNF-α
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2011.08.018

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) (0.1–1fg/site and 0.001fg/site, respectively), without altering the locomotor activity in the open-field test. In addition, anti-TNF-α antibody (0.1–1pg/site, i.c.v.), but not the inhibitor of TNF-α synthesis thalidomide (3–30mg/kg, s.c.) produced an antidepressant-like response in the FST. Moreover, either anti-TNF-α antibody (0.01pg/site, i.c.v) or thalidomide (30mg/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 (32mg/kg, i.p), imipramine (15mg/kg, i.p.) and desipramine (16mg/kg, i.p) prevented the depressant-like effect induced by TNF-α (0.1fg/site, i.c.v.) in the FST. In addition, TNF-α (0.1fg/site, i.c.v.) administration produced an anhedonic response in a sucrose intake test, which was prevented by anti-TNF-α antibody (0.01pg/site, i.c.v) or fluoxetine (32mg/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’. ► TNF-α administration caused a depressive-like effect and an anhedonic effect in mice. ► Classical antidepressants can revert the depressive and anhedonic effects of TNF-α. ► Anti-TNF-α antibody and thalidomide can reverse the TNF-α-induced depressive behavior.