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Prostaglandin (PG) D2 and four lipoxygenase-derived eicosanoids [lipoxins (LX) A4 and B4, and leukotrienes (LT) C4 and D4] were examined for their effects on sleep and brain temperature in freely-behaving rats. In the first series of experiments, PGD2 was infused into the third ventricle at four different locations between 23:00 and 05:00. In a location apposed to the medial preoptic area (MPO), PGD2 at doses 1, 10 and 100 pmol/min, increased the slow wave sleep (SWS) by 23% (p < or = 0.01), 35% (p < or = 0.05) and 44% (p < or = 0.01), respectively, during the infusion period. In the second series of experiments, LXs and LTs were infused at the location apposed to MPO. Significant increases in SWS were detected with LXA4 at 100 pmol/min (14%, p < or = 0.05), LXB4 at 100 pmol/min (20%, p < or = 0.05), and LTD at 10 pmol/min (17%, p < or = 0.05). An increase in paradoxical sleep (PS) was produced by PGD2 at 1 and 10 pmol/min infusion (p < or = 0.05), but not by any of the lipoxygenase-derived eicosanoids examined. PGD2 also elevated the mean brain temperature during infusion by 0.2 degrees C and 0.9 degrees C at infusion doses 10 and 100 pmol/min, respectively. But PGD2 infusion at 1 pmol/min did not elevate the brain temperature. LXs (excluding LXB4 at 100 pmol/min) and LTs did not alter the brain temperature significantly at the tested doses. We conclude that PGD2 is the most effective sleep promoter among the eicosanoids examined so far.

The site of action for the sleep-promoting effect of prostaglandin (PG) D2 was extensively examined in the brain of adult male rats (n = 231). PGD2 was administered at 100 pmol/0.2 microliter per min for 6 hr (2300-0500 hr) through chronically implanted microdialysis probes or infusion cannulae. Among the administrations of PDG2 by dialysis probes (n = 176), only those (n = 8) to a ventro-rostral part of the basal forebrain by the probes implanted on the midline consistently increased slow-wave sleep (SWS), by 51 +/- 6 min (mean +/- SEM) above the baseline value (111 +/- 11 min). Since this area is separated by a cleft into right and left regions, the results were interpreted to mean that, through this cleft, PGD2 diffused in the subarachnoid space over the adjacent ventral surface, where it had the effect of promoting sleep. When PGD2 was directly infused into the subarachnoid space (n = 55), extraordinary increases exceeding 90 min were consistently attained for the SWS at sites located between 0.5 and 2 mm rostral to the bregma and between 0 and 1.2 mm lateral to the midline defined according to the stereotaxic coordinates adopted from the brain atlas of Paxinos and Watson [Paxinos, G. & Watson, C. (1986) The Rat Brain in Stereotaxic Coordinates (Academic, San Diego)]. Thus, we demarcated a "PGD2-sensitive, sleep-promoting zone" within this region in the ventral surface of the rostral basal forebrain. During the bilateral infusion of PGD2 into the subarachnoid space of this zone, the hourly mean SWS level of the nocturnal animals (n = 6) in the night reached the maximum at the second hour of the infusion period; this maximum hourly SWS level, corresponding to the daytime level of the same animals, lasted until the end of PGD2 infusion.

Prostaglandin (PG) D2 has been postulated to be an endogenous sleep-promoting factor. Biosynthesis of PGD2 is catalyzed by PGD synthase (prostaglandin-H2 D-isomerase, EC 5.3.99.2), the activity of which is inhibited by inorganic selenium compounds such as SeCl4 and Na2SeO3. We recently examined the effect of intracerebroventricular administration of these selenium compounds on sleep in rats, and demonstrated time- and dose-dependent sleep inhibition. To establish whether this effect of selenium is also produced when the compound is administered systemically, we devised a procedure for intravenous catheterization and examined the effect of these selenocompounds on sleep-wake activity in freely moving rats (n = 35). Each test compound was administered into the inferior vena cava continuously between 11.00 and 17.00 h on the experimental day. SeCl4 time- and dose-dependently inhibited sleep at infusion rates of 5, 7.5, 10 and 20 nmol/microliters per min. During the SeCl4 infusion at 20 nmol/microliters per min, slow-wave sleep and paradoxical sleep were reduced to 63% and 50% of their respective baseline values. Na2SeO3 exhibited a similar sleep inhibition, though Na2SO3 was ineffective. Infusion of SeCl4 at 10 nmol/microliters per min or below produced no consistent changes in the mean brain temperature, or food and water intake during the infusion period. During the nocturnal period subsequent to SeCl4 infusion, sleep was increased by a rebound phenomenon, while a decrease in brain temperature and inhibition of food and water intake dose-dependently occurred. We conclude that systemic administration of these PGD synthase inhibitors has a sleep-reducing potency.