Sleep-suppressive activity of prostaglandin synthesis inhibitors, diclofenac sodium (DF) and indomethacin (IM), was examined in unrestrained male rats. An intraperitoneal injection of 5 mg/kg IM, or an oral administration of 5 mg/kg DF and 10 mg/kg IM at an early phase of the light period transiently decreased slow wave sleep (SWS) and paradoxical sleep (PS) to 30-62% and 0-38%, respectively, of the control level in the first hour. An intravenous infusion of 0.4 mg DF or 0.4 mg IM or an intracerebroventricular infusion of 0.04 mg DF continuously during a 10-h diurnal period resulted in a significant decrease in SWS and PS by 9-17% and 17-21%, respectively, from the baseline value in the 12-h light period. The DF infusion was accompanied by a rebound rise in the nocturnal SWS and PS and the subsequent diurnal PS. The results indicate that the depletion of prostaglandin(s) in the brain is responsible for the DF- and IM-induced suppression of sleep.