TNFα signaling in depression and anxiety:: Behavioral consequences of individual receptor targeting

Background: Increased serum levels of TNF alpha and other pro-inflammatory cytokines have been found in patients with major depression and several other psychiatric conditions. In rodents, these cytokines produce symptoms commonly referred to as "sickness" behavioi," Some of these, including reduced feeding and decreased social and exploratory behavior, are reminiscent of those seen in depressed patients. Interpretation of these effects is complicated by the malaise caused by acute injections of pro-inflammatory cytokines, however. Thus, it is unclear whether cytokines are involved in the etiology of depressive symptoms. Methods: We used a panel of bebavioral assays to assess TNFR1(-/-) and TNFR2(-/-) mice for anxiety and depression-like bebaviors. Results: We show that deletion of either TNRF1 or TNFR2 leads to an antidepressant-like response in the forced swim test and that mice lacking TNFR2 demonstrate a bedonic response in a sucrose drinking test compared with wildtype littermates. In addition, deletion of TNFR1 leads to decreased fear conditioning. There were no differences in behavior in anxiety tests for either null mutant. Conclusions: These results are consistent with the hypothesis that TNF alpha can induce depression-like symptoms even in the absence of malaise and demonstrate that both receptor subtypes can be involved in this response.