Administration of either endotoxin (lipopolysaccharide, LPS) or interleukin-1 (IL-1) activates the hypothalamic-pituitary-adrenal axis and cerebral catecholamine systems. Because LPS can stimulate IL-1 production in vivo, it is possible that the effects of LPS are mediated by IL-1. This hypothesis was evaluated by comparing the neurochemical and corticosterone responses to i.p. LPS and IL-1. In addition, the possibility that LPS acts by penetrating the brain was examined by comparing the neurochemical responses to i.p. and i.c.v. administration. Intraperitoneal injection of LPS increased mouse brain concentrations of the norepinephrine catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG), the dopamine catabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), and the 5-hydroxytryptamine catabolite, 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan in all brain regions examined. By contrast, i.p. IL-1 alpha and IL-1 beta increased cerebral concentrations of MHPG, 5-HIAA and tryptophan, but not DOPAC. The MHPG responses to IL-1 were substantially greater in hypothalamus than in other brain regions, whereas those to LPS were less regionally specific. The minimum effective doses of LPS and IL-1 were around 1 microgram and 10 ng, respectively. After i.p. LPS, plasma concentrations of corticosterone, DOPAC and MHPG peaked around 2 hr, whereas peak concentrations of tryptophan and 5-HIAA occurred around 8 hr. Intracerebroventricular LPS also elevated plasma corticosterone and cerebral concentrations of MHPG and 5-HIAA, but DOPAC was unchanged. LPS was not substantially more potent i.c.v. than i.p.(ABSTRACT TRUNCATED AT 250 WORDS)