Effects of recombinant interferon alpha (rhIFN alpha) and interleukin-1 beta (rhIL-1 beta) on the activity of glucose-responsive and glucose-unresponsive neurons in the ventromedial hypothalamus (VMH) were investigated with rat tissue slice preparations. While the majority of neurons which increased the activity in response to a rise in glucose concentration were excited by perfusion of rhIFN alpha (100-5000 U/ml) and rhIL-1 beta (40-160 ng/ml), most of the neurons which increased their activity to a fall in glucose concentration were inhibited by rhIFN beta. The majority of glucose-unresponsive neurons were not affected by the cytokines. These neuronal responses are appropriate in explaining the anorexia induced by IFN alpha and IL-1. Concurrent application of sodium salicylate, an inhibitor of prostaglandin synthesis, blocked both the increase and decrease in activities of VMH neurons by rhIL-1 beta, but not those by rhIFN alpha. Alpha-melanocyte stimulating hormone (alpha-MSH) (8 x 10(-9)-6.4 x 10(-7) M), an endogenous antipyretics and a possible antagonist of IL-1 at lymphocytes, specifically depressed the responses to rhIL-1 beta, but not those to rhIFN alpha. As has been previously shown in preoptic and anterior hypothalamic neurons, naloxone could block the responses of VMH neurons to rhIFN alpha, suggesting the opioid receptor mediation of IFN alpha's actions on the VMH neurons.