Abstract: Infections and endotoxin (LPS) can affect hypothalamic CRH neurons and activate the HPA system. This can be prevented by IL-1 receptor antagonist and mimicked by IL-1. Chronic activation of the HPA system by repeated or chronic administration of IL-1 (1 week) to rats is associated with plastic changes in hypothalamic CRH neurons. Single administration IL-1β (5 μg/kg i.p.) to male Wistar or Lewis rats induced a similar form of neuroplasticity 1-3 weeks later. This is characterized by a selective increase in coproduction, costorage, and cosecretion of AVP in hypothalamic CRH neurons. Exposure of IL-1-primed rats 1-2 weeks later to foot shocks or IL-1 resulted in exaggerated ACTH and CORT responses as compared to vehicle-primed controls. Thus, rats are hyperresponsive to stressors weeks after IL-1 exposure. In IL-1-primed animals, CRH binding and CRH- and V1b receptor mRNA levels in the pituitary glands are not altered by IL-1 exposure 2 weeks earlier. We conclude that IL-1-induced, long-lasting hyperresponsiveness to stressors is primarily caused by functional alterations in the brain that may be directly related to observed plasticity of hypothalamic CRH neurons.