Central administration of insulin-like growth factor-I (IGF-I) attenuates sickness behavior in response to the cytokine inducer lipopolysaccharide. The present study was designed to determine the respective roles of the two main proinflammatory cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta), in these effects. Male CD1 mice were injected into the lateral ventricle (i.c.v.) of the brain with optimal amounts of either TNFalpha (50 ng) or IL-1beta (2 ng) that induce sickness behavior. Behavioral responses to IGF-I (0, .1, and 1 microg) also given i.c.v. were measured at various time intervals before and after treatment with the two proinflammatory cytokines. Mice treated with TNFalpha and IL-1beta lost body weight and displayed equivalent reductions in social exploration and instances of immobility. At the dose of .1 microg, IGF-I attenuated these signs of sickness in TNFalpha-but not in IL-1beta-treated mice. At the dose of 1 microg, IGF-I attenuated IL-1beta-induced immobility and the reduction in social exploration but had no effect on loss of body weight. These findings indicate that IGF-I is more potent in attenuating sickness behavior induced by TNFalpha than that caused by IL-1beta, which is consistent with the relative specificity of the TNFalpha/IGF-I interactions in the brain.