title: Depressive-like behavior induced by tumor necrosis factor-α in mice.
abstract: 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'.
authors.affiliation: Centro de Ciências da Vida e da Saúde, Universidade Católica de Pelotas (UCPel), Rua Almirante Barroso, 1202 sala G109, 96010-280 Pelotas, RS, Brazil. manu.kaster@gmail.com
authors.forename: Manuella P
authors.initials: MP
authors.lastname: Kaster
authors.forename: Vinícius M
authors.initials: VM
authors.lastname: Gadotti
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
authors.forename: Adair R S
authors.initials: AR
authors.lastname: Santos
authors.forename: Ana Lúcia S
authors.initials: AL
authors.lastname: Rodrigues
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000627:therapeutic use; D003863:Depression / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D019417:Hindlimb Suspension / Q000379:methods / Q000523:psychology; D007274:Injections, Intraperitoneal; D008233:Lymphotoxin-alpha / Q000276:immunology / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D013550:Swimming / Q000523:psychology; D013792:Thalidomide / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D000928:Antidepressive Agents; D008233:Lymphotoxin-alpha; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D013792:Thalidomide