During onset of heatstroke, rats displayed higher values of hypothalamic serotonin release and score f hypothalamic neuronal damage, and lower values of mean arterial pressure and hypothalamic blood flow compared with normothermic control rats. In another group in which interleukin-1 receptor antagonist (IL-1 ra; 200 micrograms/kg, i.v.) was injected 30 or 60 min after the start of heat exposure, the augmented hypothalamic serotonin release, diminished hypothalamic blood flow, arterial hypotension and hypothalamic neuronal damage during heatstroke were reduced as compared to the saline control group. The survival time (interval between onset of heatstroke and death) of the heatstroke rats was prolonged by treatment with IL-1 ra. The data indicate that IL-1 ra increases survival during rat heatstroke by reducing hypothalamic serotonin release.