Pro-inflammatory cytokines, interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha) synthesized by activated macrophages and monocytes in response to administration of lipopolysaccharide (LPS), are considered important mediators of fever and sickness behavior. We administered rat-specific antisera for TNF-alpha, IL-1beta, IL-6 and leptin, to determine the involvement of peripherally released cytokines in LPS-induced fever and sickness behavior, measured as suppression of voluntary wheel-running and food intake. Male Sprague-Dawley rats (approximately 200 g) selected for their predisposition to spontaneously run on running wheels were anaesthetized with a combination of ketamine hydrochloride (80 mg/kg i.m.) and xylazine (4 mg/kg i.m.) and implanted intra-abdominally with temperature-sensitive radiotelemeters. Rats were injected intraperitoneally with anti-rat sera to one of the following, TNF-alpha, IL-1beta, IL-6 or leptin or with pre-immune sheep serum, followed by a subcutaneous injection of either LPS (250 microg/kg) or sterile saline. Lipopolysaccharide administration induced a approximately 1.3 (0.2) degrees C fever lasting approximately 10 h and reduced voluntary running by 93 (8.6)% and food intake by 51 (21.3)% compared to the saline response (ANOVA, P<0.05). Injection of anti-IL-6 serum or anti-leptin serum abolished the LPS-induced fever, anti-TNF-alpha serum affected only the early phase of fever and anti-IL-1beta serum had no effect on fever (ANOVA, P<0.05). LPS-induced suppression of voluntary running and food intake were attenuated in rats receiving anti-IL-6 serum, while the decrease in food intake was totally abolished in rats receiving anti-leptin serum (ANOVA, P<0.05). Injection of anti-TNF-alpha or anti-IL-1beta serum had no effect on LPS-induced sickness behavior. Peripherally released IL-6 and leptin therefore appear to be important in regulating LPS-induced fever and sickness behavior.