Prostaglandins and adenosine in the regulation of sleep and wakefulness Zhi-Li Huang1,2, Yoshihiro Urade1 and Osamu Hayaishi1 Prostaglandin (PG) D2 and adenosine are potent humoral sleep-inducing factors that accumulate in the brain during prolonged wakefulness. PGD2 is produced in the brain by lipocalin-type PGD synthase, which is localized mainly in the leptomeninges, choroid plexus and oligodendrocytes, and circulates in the cerebrospinal fluid as a sleep hormone. It stimulates DP1 receptors on leptomeningeal cells of the basal forebrain to release adenosine as a paracrine signaling molecule to promote sleep. Adenosine activates adenosine A2A receptor-expressing sleep-active neurons in the basal forebrain and the ventrolateral preoptic area. Sleep-promoting neurons in the ventrolateral preoptic area send inhibitory signals to suppress the histaminergic neurons in the tuberomammillary nucleus, which contribute to arousal through histamine H1 receptors. Increased knowledge of the molecular mechanisms by which PGD2 induces sleep through activation of adenosine A2A receptors and inhibition of the histaminergic arousal system will be useful both for a better understanding of sleep/wake regulation and for the development of novel types of sleeping pills or anti-doze drugs. Addresses 1 Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan 2 State Key Laboratory of Medical Neurobiology, Shanghai Medical College of Fudan University, Shanghai 200032, China Corresponding author: Urade, Yoshihiro (uradey@obi.or.jp)
Current Opinion in Pharmacology 2007, 7:33–38 This review comes from a themed issue on Neurosciences Edited by Karima Chergui, Bertil Fredholm and Per Svenningsson Available online 28th November 2006 1471-4892/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2006.09.004
Introduction The drive to sleep begins with the onset of wakefulness and dissipates slowly with sleep. Endogenous sleep factors acting on specific neurons in the brain are hypothesized to regulate the waxing and waning of the sleep drive [1]. Two such sleep factors are prostaglandin (PG) D2, an eicosanoid acting as a tissue or local hormone [2], and adenosine, a naturally occurring purine nucleoside present in all cells [3 ], both of which are released as neuromodulators in the brain. Here, the molecular mechanism(s) through which these two substances regwww.sciencedirect.com
ulate sleep are discussed, with particular emphasis on the recent progress made following studies on gene-manipulated mice.
PGD2 induces physiological sleep PGD2 is the most abundant prostanoid in the brains of rats and other mammals, including humans [4]. PGD2 is produced in the brain by the action of the enzyme PGD synthase (PGDS; PGH2 D-isomerase, EC.5.3.99.2) [5] on the substrate PGH2, which in turn is produced by cyclooxygenase from arachidonic acid. PGH2 serves as the common precursor of various prostanoids. When PGD2 at an amount as small as a few picomoles per minute was infused continuously into the third ventricle of freely moving rats during the night (i.e. when rats are awake most of the time), both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep increased significantly in a dose-dependent manner during the time of infusion [6]. Most importantly, sleep induced by PGD2 was indistinguishable from physiological sleep, as judged by several behavioral and electrophysiological criteria, including power spectral analysis [7]. PGD2 infused into the lateral ventricle increases sleep in wild-type (WT) mice in a dose-dependent manner, but has no effect in DP1 receptor (DP1R) knockout (KO) mice [8]. Infusion of a novel antagonist of DP1Rs — ONO-4127 — into sleeping rats effectively reduced the amounts of both NREM and REM sleep during the period of infusion [2]. These results indicate that PGD2 is a potent endogenous sleep-substance that regulates physiological sleep through activation of the DP1R. There are two distinct types of PGDS involved in the production of PGD2 in the central nervous system: lipocalin-type PGDS (L-PGDS), expressed mainly in the arachnoid membrane, choroid plexus and oligodendrocytes [9]; and hematopoietic PGDS (H-PGDS), localized in microglia [10]. PGD2 produced by either of these enzymes is secreted into the cerebrospinal fluid (CSF), where its level exhibits a circadian rhythm in freely moving rats [11]. Furthermore, when rats were administered inorganic tetravalent selenium compounds such as selenium tetrachloride (SeCl4), which are specific and reversible inhibitors of PGDS [12], sleep was inhibited time- and dose-dependently and also reversibly [13]. Recently, Lee et al. [14] reported that the intracerebroventricular infusion of SeCl4 increased arousal-like behavior in unanesthetized fetal sheep and that this effect could be abolished by subsequent administration of Current Opinion in Pharmacology 2007, 7:33–38
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PGD2. By using gene-manipulated mice lacking L-PGDS and/or H-PGDS or DP1R, we found that SeCl4 inhibited sleep during the day time (when mice are normally sleep) in WT and H-PGDS KO mice, but not in L-PGDS KO, L- and H-PGDS double KO, and DP1R KO mice [15]. These findings indicate that L-PGDS is a major enzyme for the production of PGD2 involved in physiological sleep. Sleep depends upon prior wakefulness, and sleep pressure increases during wakefulness or sleep deprivation. The PGD2 content in the brain increases during sleep deprivation and induces NREM and REM sleep rebound after sleep deprivation in WT mice. However, the PGD2 content in the brain remained unchanged in L-PGDS KO mice after sleep deprivation; furthermore, NREM sleep rebound was not observed in either L-PGDS KO or DP1R KO mice, indicating that the L-PGDS/PGD2/DP1R system plays a crucial role in the homeostatic regulation of NREM sleep [2,16]. PGD2 is involved in the regulation of not only physiological sleep but also pathological sleep. For example, in patients in the late stage of African sleeping sickness, PGD2 levels in the CSF are selectively elevated by 100- to 1000-fold; this increase might account for the increased somnolence observed in these patients [17]. In situ hybridization, immunohistochemical and enzyme assay studies have revealed that L-PGDS is localized in the arachnoid membrane surrounding the brain, in the choroid plexus in the ventricle, and in oligodendrocytes in the brain parenchyma [9,18]. The DP1R was shown to be localized predominantly in the arachnoid membrane of the ventrorostral area of the basal forebrain. Very little, if any, L-PGDS or DP1R protein is detected in neurons of the brain parenchyma. Upon higher magnification, both L-PGDS and DP1R were found in arachnoid trabecular cells [8]. From its sites of synthesis, PGD2 is considered to enter the CSF, circulate within this area, and subsequently become bound to DP1R on the arachnoid trabecular cells of the basal forebrain. The binding of PGD2 to these receptors on the meninges is followed by an increase in the concentration of extracellular adenosine [8]. PGD2-induced sleep in rats has already been shown to be inhibited by pretreatment with KF17837, an antagonist of the adenosine A2A receptor (A2AR). Moreover, A2AR agonists, such as CGS 21680, mimicked the somnogenic effect of PGD2 when infused into the PGD2sensitive sleep-promoting zone of the basal forebrain of rats during the night [19], indicating that the adenosine/ A2AR system plays a pivotal role in sleep induction by PGD2.
Adenosine and its receptors are involved in sleep/wake regulation Long before studies into the involvement of adenosine in PGD2-induced sleep, adenosine had been proposed to be Current Opinion in Pharmacology 2007, 7:33–38
an endogenous sleep substance based on the results of a variety of pharmacological and behavioral experiments. For example, adenosine and stable adenosine analogues induce sleep when administered to rats, cats and other experimental animals [20]. The extracellular adenosine concentration increases in the cortex and basal forebrain during sleep deprivation of cats, and decreases during the recovery period after sleep deprivation [1,20]. Because energy restoration is one of the functions of sleep, adenosine is proposed to be a terminal product of energy metabolism and to act as a homeostatic regulator of energy in the brain during sleep. There are four subtypes of adenosine receptor expressed in the central nervous system: A1, A2A, A2B and A3 [21]. Several lines of evidence indicate that both A1R and A2AR subtypes are involved in sleep induction [2,20]. However, the magnitude of their contribution to sleep induction by adenosine remains controversial, as described below. Intraperitoneal or intracerebroventricular administration of the highly selective A1R agonist N6-cyclopentyladenosine (CPA) increased sleep propensity and electroencephalogram slow-wave activity during sleep, suggesting a role for A1R in sleep induction [22]. Adenosine stimulated calcium release in cholinergic but not non-cholinergic neurons via the A1R [23]. Furthermore, perfusion of A1R antisense oligonucleotides into the basal forebrain reduced NREM sleep and electroencephalogram delta power [24]. These two reports suggest that the somnogenic effect of adenosine is mediated by A1R in the cholinergic region of the basal forebrain. However, adenosine levels in the basal forebrain did not increase after 6 h of prolonged wakefulness in rats with 95% of their basal forebrain cholinergic neurons lesioned. The lesioned rats had an intact sleep drive after 6 h and 12 h of prolonged wakefulness. In the absence of cholinergic neurons in the basal forebrain, the selective A1R agonist N6-cyclohexyladenosine was able to induce sleep after administration to the basal forebrain [25]. Thus, neither the activity of cholinergic neurons nor the accumulation of adenosine in the basal forebrain during wakefulness is necessary for the sleep drive, which leaves the possibility (raised by both studies) that A1Rs on noncholinergic neurons could affect sleep. A2AR agonists, such as CGS 21680, induced NREM sleep in rats when infused during the night into the PGD2sensitive zone of the subarachnoid space under the basal forebrain, whereas A1R agonists, such as CPA, were ineffective. When infused into the lateral ventricle of WT mice, CGS 21680 induced both NREM and REM sleep in a dose- and time-dependent manner, whereas CPA did not affect their sleep/wake patterns [26]. High concentrations of CPA slightly increased the amount of NREM sleep in WT mice, but this effect was not observed in A2AR KO mice, suggesting that the www.sciencedirect.com
Prostaglandins and adenosine in the regulation of sleep and wakefulness Huang, Urade and Hayaishi 35
somnogenic effect resulted from a weak agonistic effect of CPA on A2AR. These results suggested the importance of the A2AR in sleep regulation. In contrast to adenosine, caffeine promotes wakefulness. Caffeine binds to A1R and A2AR with similar high affinities and acts as an antagonist at both receptor subtypes [27]. Recently, we demonstrated that caffeine promoted wakefulness in WT and A1R KO mice, but not in A2AR KO mice, indicating that the arousal effect of caffeine was caused by blockade of the A2AR [28 ]. Caffeine can also reduce the hypnotic effects of alcohol via the A2AR [29]. These results strongly suggest a predominant role for A2AR in sleep regulation, although the subtype of adenosine receptor responsible for sleep regulation is still a matter of debate [20,26]. Both A1R and A2AR KO mice showed clear circadian profiles of sleep-stage distribution and identical amounts of NREM and REM sleep to WT mice under basal conditions [28 ,30]. However, A2AR KO mice did not show NREM sleep rebound after sleep deprivation, but did exhibit a clear REM sleep rebound [31] similar to LPGDS KO and DP1R KO mice. Conversely, A1R KO mice showed clear rebound of both NREM and REM sleep after sleep deprivation, similar to WT mice [30]. These results indicate that the A2AR, but not the A1R, is essential for the homeostatic regulation of NREM sleep. Thus, the L-PGDS/DP1R/A2AR system plays a crucial role in the homeostatic regulation of NREM sleep [2].
sion of the TMN with the GABAA antagonist picrotoxin, suggesting that A2AR agonists induce sleep by increasing GABA release in the TMN, thus inhibiting the histaminergic arousal system. These results provide further evidence to support the original hypothesis of a ‘flip-flop mechanism’, in which sleep is promoted by the upregulation of the activity of sleep neurons in the VLPO and concurrent downregulation of the activity of wake neurons in the TMN [35,36 ]. The reversal of inhibition of VLPO sleep-active neurons by adenosine through reduction of GABA release was also suggested from intracellular recordings of VLPO neurons in rat brain slices [37]. These recordings demonstrated the existence of two distinct types of VLPO neurons — type-1 and -2 — in terms of their responses to serotonin and adenosine [38]. VLPO neurons were inhibited uniformly by two arousal neurotransmitters, noradrenaline and acetylcholine, and also by the A1R agonist CPA. Serotonin inhibited type-1 neurons but excited the type-2 neurons. The A2AR agonist CGS 21680 excited postsynaptically the type-2, but not type-1, neurons. These results suggest that type-2 neurons are involved in the initiation of sleep and that type-1 neurons contribute to sleep consolidation, as they are activated only when released from inhibition by arousal systems.
Histamine and wakefulness
To determine which neuronal groups respond to sleep induction by PGD2 and A2AR agonists, sleep-active neurons were mapped for c-Fos protein by immunostaining [32,33] after infusion of the A2AR agonist CGS 21680 for 2 h into the subarachnoid space of the rat basal forebrain, a PGD2-sensitive, sleep-promoting zone. A marked increase in the number of c-Fos-positive cells was observed in the ventrolateral preoptic area (VLPO), a sleep center in the anterior hypothalamus, concomitant with the induction of NREM sleep. By contrast, the number of c-Fos-positive neurons decreased markedly in the tuberomammillary nucleus (TMN), a histaminergic wake center in the posterior hypothalamus.
Histaminergic neurons reside in the TMN in the posterior hypothalamus and send widespread projections to various brain areas. A growing body of evidence has implicated histamine as a crucial player in mediating wakefulness in mammals. Histaminergic neurons discharge tonically and specifically during wakefulness [39]. The central release of histamine exhibits circadian variation that is associated with wakefulness [40]. Arousal is provoked by the enhancement of histaminergic transmission with ciproxifan [41 ] or orexin [42], as well as with PGE2 or an agonist of the EP4 PGE2 receptor subtype [43]. By contrast, sleep is promoted by hyperpolarization of the TMN with GABAergic agonists [44], as well as by inhibition of the TMN through increased GABA release evoked by an A2AR agonist [19], as described above. Histidine decarboxylase KO mice, which lack histamine in their brains, show deficits in waking, attention and interest in a new environment [45].
The VLPO sends inhibitory g-aminobutyric acid (GABA)ergic and galaninergic afferents to the TMN, where all cell bodies of the ascending histaminergic arousal system reside [34]. We recently demonstrated, by in vivo microdialysis of the rat brain, that CGS 21680 inhibited histamine release in both the frontal cortex and the medial preoptic area in a dose-dependent manner, and increased GABA release in the TMN but not in the frontal cortex [19]. Furthermore, the CGS 21680-induced inhibition of histamine release was antagonized by perfu-
Four subtypes of histamine receptors (H1–H4) have been cloned. Among them, H1, H2 and H3 receptors are expressed in the brain, and each shows a distinctive distribution pattern. These receptors mediate the characteristic actions of histamine at the cellular, synaptic and behavioral levels. The classic anti-histamines, which are H1 receptor (H1R) antagonists, are associated with wellknown sedative effects owing to the excitatory actions that H1Rs exert on whole-brain activity. We previously demonstrated that orexin induced wakefulness in WT
Neural networks involved in sleep/wake regulation
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Figure 1
Molecular mechanisms of sleep/wake regulation by PGD2, adenosine and histamine. PGD2 is produced by the action of L-PGDS in arachnoid trabecular cells of the leptomeninges, choroid plexus and oligodendrocytes, and circulates in the CSF. It activates the DP1R on these trabecular cells to promote sleep by stimulating them to release a paracrine signaling molecule, adenosine. The released adenosine activates A2AR-expressing neurons located in the ventral region of the basal forebrain, the activation of which subsequently excites the VLPO. VLPO neurons then send inhibitory signals to downregulate the histaminergic TMN, which contributes to arousal through histamine H1Rs. Conversely, wakefulness is promoted by activation of the TMN through either PGE2 or orexin. Green colouring represents the L-PGDS/PGD2/DP1R system; blue, the adenosine system; and red, the histamine system. EP4, PGE2 receptor subtype 4; OX2, orexin receptor subtype 2.
mice but not in H1R KO mice, indicating a functional connection between histaminergic pathways and orexininduced wakefulness [42]. Recently, we characterized the sleep/wake pattern of H1R KO mice and found that the circadian rhythm and amount of time spent in sleep and wakefulness were unchanged in H1R KO mice, but that these KO mice showed alterations in the regulation of state transitions from NREM sleep to wakefulness and a shorter latency in onset of NREM sleep after noxious stimulation [41 ].
aid for scientific research from the Japan Society for the Promotion of Science (to OH and ZLH), the National Natural Science Foundation of China (30570581 and 30625021 to ZLH), Shanghai Pujiang Program (06PJ14008 to ZLH), the Program for Promotion of Basic Research Activities for Innovative Biosciences (to YU), the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to YU), Sankyo Foundation (to ZLH), Takeda Pharmaceutical Co Ltd (to OH), Ono Pharmaceutical Co Ltd (to OH), and Osaka City.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest
Conclusions The endogenous sleep-promoting factor PGD2 accumulates in the brain during wakefulness and induces physiological sleep through DP1R-mediated adenosine release. The released adenosine stimulates A2AR, but not A1R, to induce sleep. These two humoral factors — PGD2 and adenosine — activate sleep-active neurons in the VLPO, which in turn downregulate wake-active neurons in the TMN through GABAergic or galaninergic inhibitory signals from the VLPO to the TMN. Conversely, orexin and PGE2 activate the histaminergic system to induce wakefulness through the histamine H1R. These findings indicate that the VLPO and TMN regulate sleep and wakefulness (Figure 1) by a ‘flip-flop’ mechanism, operating in an anti-coincident manner during sleep/wake state transitions.
Acknowledgements We thank L Frye for critical reading of the manuscript. The experiments conducted in the authors’ laboratory were supported mainly by grants-inCurrent Opinion in Pharmacology 2007, 7:33–38
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