Intraperitoneal injection of purified recombinant interleukin-1 (IL-1) into mice increased the cerebral concentration of the norepinephrine (NE) catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG), probably reflecting increased activity of noradrenergic neurons. This effect was dose-dependent and was largest in the hypothalamus, especially the medial division. Tryptophan concentrations were also increased throughout the brain. The increase of MHPG peaked around 4 hours after IL-1 administration, parallelling the increase of plasma corticosterone. Both the alpha- and beta-forms of IL-1 were effective, but the activity was lost after heat treatment of the IL-1. Noradrenergic neurons with terminals in the hypothalamus are known to regulate the secretion of corticotropin-releasing factor, thus our results suggest that IL-1 activates the hypothalamic-pituitary-adrenal axis by activating these neurons. Because initiation of an immune response is known to cause systemic release of IL-1, IL-1 may be an immunotransmitter communicating the immunologic activation to the brain. The IL-1-induced changes in hypothalamic MHPG may explain the increases of electrophysiological activity, the changes of hypothalamic NE metabolism, and the increases in circulating glucocorticoids previously reported to be associated with immunologic activation and frequently observed in infected animals.