We reported in previous studies that prostaglandin E2 (PGE2) has central effects of augmenting wakefulness and suppressing slow-wave sleep (SWS) and paradoxical sleep (PS) in rats. In the present study, we tested the effect of AH 6809, an antagonist of PGE2 receptors, on sleep-wake activities. AH 6809 in saline was infused continuously into the third ventricle of freely moving rats at a rate of 2.1, 6.3, and 21 pmol/min from 2300 to 0500 hr. During the infusion at 21 pmol/min, wakefulness decreased to 82%, and SWS and PS increased to 122% and 161%, of the respective baseline values. These changes can be explained by AH 6809 antagonizing the endogenous PGE2 that acts to augment wakefulness in the brain. This explanation is supported by the fact that the infusion of AH 6809 at 21 pmol/min inhibited the wakefulness-promoting effect of PGE2 infused at 10 pmol/min. Moreover, the PGE2-related mechanisms for regulating sleep-wake activities may be different from those producing hyperthermia, because AH 6809 at 21 pmol/min had no primary effect on brain temperature and did not antagonize the hyperthermia produced by the PGE2 infusion. A diurnal infusion (1200 to 1800 hr) of AH 6809 at 21 pmol/min produced similar effects on sleep-wake activities compared with the nocturnal infusion (2300 to 0500 hr), although the PS increase was not significant, suggesting that the PGE2-related mechanisms are acting all day long with or without a circadian rhythm. These findings strongly suggest that endogenous PGE2 in the brain is involved in the physiological mechanisms for regulating sleep-wake activities.