The circumventricular organs (CVOs) are ideal locations at which circulating pyrogens may act to communicate with the CNS during an immune challenge. Their dense vasculature and fenestrated capillaries allow direct access of these pyrogens to CNS tissue without impediment of the blood-brain barrier (BBB). One such CVO, the subfornical organ (SFO), has been implicated as a site at which the circulating endogenous pyrogen interleukin 1beta (IL-1beta) acts to initiate the febrile response. This study was designed to determine the response of rat SFO neurons to IL-1beta (1 nM to 100 fM) using whole-cell current-clamp and voltage-damp techniques. We found that physiological(subseptic) concentrations of IL-1beta (1 pM, 500 fM, 100 fm) induced a transient depolarization in SFO neurons accompanied by a significant increase in spike frequency. In contrast,pharmacological (septic) concentrations of IL-1beta (1 nM) evoked a sustained hyperpolarization. While depolarizations in response to IL-1beta were abolished by treatment of cells with the IL-1 receptor antagonist (IL-1ra), hyperpolarizations were still observed. Voltage-clamp analysis revealed that the majority (85 %) of SFO neurons responding to IL-1beta with depolarization (29 of 34 cells) exhibited an electrophysiological profile characterized by a dominant delayed rectifier potassium current (DIK), a conductance that we also found to be reduced to 84.4 +/- 3.3 % of control by bath application of IL-1beta. In addition, using slow voltage ramps we demonstrated that IL-1beta activates a non-selective cationic current (INSC) with a reversal potential of -38.8 +/- 1.8 mV. These studies identify the cellular mechanisms through which IL-1beta can influence the excitability of SFO neurons and, as a consequence of such actions, initiate the febrile response to exogenous pyrogens.