Symptoms of bacterial infection include decreases in body mass (cachexia), induction of depressive-like hedonic tone (anhedonia), decreases in food intake (anorexia), and increases in body temperature (fever). Recognition of bacteria by the innate immune system triggers the release of proinflammatory cytokines which induce these sickness behaviors via actions at central and peripheral targets. In Siberian hamsters, exposure to short day lengths decreases both the production of proinflammatory cytokines and the magnitude of the symptoms of infection. Short-day attenuation of sickness behaviors may arise solely from decreased production of cytokines; alternatively, substrates responsible for the generation of sickness behaviors may be less responsive to cytokines in short days. To discriminate among these hypotheses, Siberian hamsters were treated with either bacterial lipopolysaccharide (LPS; 25 microg) or recombinant mouse IL-1beta (rIL-1beta; 100 ng) following 11 weeks of exposure to long (15 h light/day) and short (9 h light/day) photoperiods. Replicating earlier work, the magnitude and/or duration of LPS-induced anorexia, anhedonia, cachexia, and fever were greater in long-day relative to short-day hamsters. A comparable short-day attenuation of sickness behaviors and fever was obtained in response to rIL-1beta treatment, despite treatment with identical concentrations of cytokine. These data suggest that hamsters subjected to immunoenhancing short days exhibit diminished symptoms of infection not solely because infections elicit lower levels of cytokine production, but also because the substrates upon which cytokines act become relatively refractory.