Herpes simplex virus type I (HSV-1) encephalitis may present with fever and behavioral changes, to the extent of a psychotic state and psychomotor agitation. We developed a clinically relevant experimental model of HSV-1 encephalitis and investigated host brain responses associated with its clinical signs and whether these responses depend on the presence of circulating glucocorticoids. Intracerebral inoculation of HSV-1 in rats induced fever, motor hyperactivity and aggressive behavior. In adrenalectomized rats HSV-1 failed to induce these signs, although mortality rate was identical to sham-operated rats. Hypophysectomy or blocking glucocorticoid receptors also prevented HSV-1-induced fever. Dexamethasone replacement therapy to adrenalectomized rats restored the HSV-1-induced fever and behavioral abnormalities. HSV-1 inoculation produced hyperproduction of prostaglandin E-2 by brain slices. This effect was abolished in adrenalectomized rats and was restored by dexamethasone treatment. In intact rats HSV-1 induced brain interleukin-1 beta (IL-1 beta) gene expression. Adrenalectomy alone caused brain IL-1 beta expression, which did not increase after HSV-1 infection. Similarly, HSV-1 induced IL-1 beta expression in astrocyte cultures. Removal of cortisol from the culture medium caused basal IL-1 beta mRNA expression which was not increased by infection. In conclusion, fever, motor hyperactivity and aggressive behavior during experimental HSV-1 encephalitis are dependent on brain responses, including prostaglandin E-2 and IL-1 beta synthesis. Circulating glucocorticoids play an essential permissive role in the induction of these host brain responses. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.