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Stress and immune activation are associated with increases in plasma concentrations of corticosterone (CS). To determine whether the catecholaminergic innervation of neurons in the hypothalamic paraventricular nucleus (PVN) is involved in these responses, selective lesions were made using 6-hydroxydopamine (6-OHDA). Injection of 6-OHDA into the PVN depleted its norepinephrine (NE) content by 85% and reduced by 80-82% the increase in plasma CS concentrations following intraperitoneal injection of recombinant human interleukin-1 alpha (IL-1), but did not affect the adrenocortical response to 20 min restraint. Injection of 6-OHDA into the ventral noradrenergic ascending bundle depleted PVN NE content by 77%. This lesion reduced the CS response to human IL-1 alpha by 82-86%, but did not alter that to 20 min restraint, although there was a nonsignificant decrease in the CS response following 3 min of restraint. These results suggest that the noradrenergic innervation of the PVN mediates the activation of the hypothalamic-pituitary-adrenal (HPA) axis by intraperitoneally injected IL-1. There may be a noradrenergic contribution to the HPA response to restraint, but other neural pathways probably also participate in this response.