Interleukin-1-beta (IL-1 beta) is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the release of corticosteroids from the adrenal glands. This effect is evident after both central and peripheral administration, and controversy surrounds the mechanism(s) by which systemic administration of this peptide, which should not cross the blood-brain barrier, may activate the HPA axis. In the present study, IL-1 beta was administered systemically (5 micrograms/kg i.p.) or centrally (100 ng i.c.v.) to male rats. Both routes of administration of IL-1 beta resulted in significant and comparable activation of the HPA axis, as assessed by analysis of plasma conrticosterone. In addition, both routes of administration of IL-1 beta resulted in c-fos mRNA induction in specific regions, as determined by in situ hybridization. These included the meninges, cerebral vasculature, choroid plexus and circumventricular organs. Semiquantitative analysis revealed that both routes of administration resulted in significant and comparable induction of c-fos mRNA in the paraventricular nucleus of the hypothalamus, as compared with control animals. In contrast, in the nucleus tractus solitarius (NTS) and central nucleus of the amygdala (CeA), levels of c-fos mRNA were 3-4 times higher in animals treated intraperitoneally compared with intracerebroventricularly. A similar differential activation of c-fos mRNA was observed in the lateral divisions of the parabrachial nucleus (PBN) and bed nucleus of the stria terminalis (BNST). These data indicate that following systemic administration, IL-1 beta may activate specific brain areas through mechanisms distinct from those involved following central administration. The differential magnitude of the c-fos mRNA response in the NTS, PBN, CeA and BNST is consistent with vagal activation. Physiologically, these results suggest that IL-1 beta may have differential central effects depending on its source or point of entry to the brain.