Wake Behavior

C H A P T E R

8 Adenosinergic Control of Sleep/Wake Behavior Xuzhao Zhou, Michael Lazarus International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan

I INTRODUCTION Adenosine is a purine nucleoside comprising an adenine attached to a β-D-ribofuranose moiety. Its derivatives are widely found in nature and have an important role in biochemical processes, such as energy transfer as adenosine triphosphate (ATP) and adenosine diphosphate (ADP) or signal transduction as cyclic adenosine monophosphate (cAMP). Adenosine itself can regulate cellular activity by acting on four evolutionarily well-conserved metabotropic receptors, that is, the purinergic G-proteincoupled A1, A2A, A2B, and A3 receptors that are present on most, if not all, cells. Although adenosine is released from nerve endings, adenosine is not a neurotransmitter or a typical neuromodulator, because its formation can be increased by various processes in all cell types and in all cell parts. Furthermore, the basal level of adenosine depends only on fundamental cell biology independent of nerve activity. Adenosine has the ability to modulate sleep by acting at A1 or A2A receptors (A1R and A2AR, respectively)—the main topic of this chapter. Emerging evidence suggests that A2AR allow the brain to sleep by suppressing wakefulness, that is, these receptors provide sleep gating, whereas A1R predominantly modulate the function of sleep, that is, these receptors mediate sleep need.

II ADENOSINE METABOLISM Adenosine metabolism is well studied (Fig. 8.1). It is formed by the hydrolysis of adenosine monophosphate (AMP) or S-adenosyl-L-homocysteine (SAH) (Fredholm, 2007; Schrader, 1983). Adenosine is formed from SAH by the enzyme SAH hydrolase, which can also act to trap adenosine in the presence of excess L-homocysteine. This takes place intracellularly, and the fact that the enzyme is bidirectional ensures the constant presence of a finite concentration of adenosine in the cell, although the Handbook of Sleep Research, Volume 30 ISSN: 1569-7339 https://doi.org/10.1016/B978-0-12-813743-7.00008-6

contribution of SAH hydrolase to the generation of adenosine in the brain remains controversial (Latini & Pedata, 2001). Adenosine is formed both intracellularly and extracellularly from 50 -AMP by 50 -nucleotidases (50 -NT), mediated by different enzymes (Zimmermann, 2000). In extracellular adenosine formation, an ecto-50 -NT is part of a cascade (together with ecto-ATPases) that terminates the action of nucleotides such as ATP as extracellular signaling molecules (Kovacs, Dobolyi, Kekesi, & Juhasz, 2013; Yegutkin, 2008; Zimmermann, 2000, 2006). Adenosine levels are decreased by the enzyme adenosine deaminase (ADA) when adenosine levels are high and by uptake into cells (Fredholm, Chen, Cunha, Svenningsson, & Vaugeois, 2005; Oishi, Huang, Fredholm, Urade, & Hayaishi, 2008; Parkinson et al., 2011). The adenosine taken up by cells is rapidly phosphorylated to AMP by adenosine kinase (AdK), an enzyme that effectively controls the intracellular adenosine concentration. Equilibrative nucleoside transporters bidirectionally regulate the concentration of adenosine available to cell surface adenosine receptors (Dos Santos-Rodrigues, Grane-Boladeras, Bicket, & Coe, 2014; Parkinson et al., 2011). Therefore, the formation and removal of extracellular adenosine regulate its levels. Under basal conditions, extracellular adenosine levels are low—approximately 30–300 nM (Ballarin, Fredholm, Ambrosio, & Mahy, 1991). Under more extreme conditions, such as mild hypoxia or strenuous exercise, adenosine levels can approach 1 μM or more, and in severely traumatic situations, including local ischemia, adenosine levels can reach up to several tens of micromolars (Fredholm, 2007).

III ADENOSINE RECEPTORS Extracellular adenosine acts on one of the four types of adenosine receptors, that is, A1R, A2AR, A2B (A2BR), and A3 receptors (A3R) (Fredholm, IJzerman, Jacobson,

125

© 2019 Elsevier B.V. All rights reserved.

126

8. ADENOSINERGIC CONTROL OF SLEEP/WAKE BEHAVIOR

FIG. 8.1 Scheme of metabolic adenosine pathways. Adenosine is

generated by intracellular or extracellular conversion of 50 -AMP catalyzed by 50 -nucleotidase (50 -NT) or by hydrolysis of S-adenosyl-Lhomocysteine (SAH) catalyzed by SAH hydrolase, although the latter pathway seems to be of less importance in the brain. Adenosine levels are regulated by adenosine deaminase (ADA) or adenosine kinase (AdK) by conversion to inosine or 50 -AMP, respectively. Equilibrative nucleoside transporters (ENT) bidirectionally regulate the concentration of adenosine available to cell surface A1, A2A, A2B, and A3 receptors (A1R, A2AR, A2BR, and A3R).

TABLE 8.1

Linden, & Muller, 2011). A1R and A3R are coupled with inhibitory Gi-proteins, whereas A2AR and A2BR are coupled with excitatory Gs-proteins (Fredholm et al., 2005). Activation of A1R or A3R inhibits adenylate cyclase activity, decreasing the production of cAMP from ATP, which in turn decreases the activity of cAMPdependent protein kinase and cAMP-response elementbinding protein phosphorylation. Therefore, Gi-coupled receptor activation has an inhibitory effect on cells. In contrast, activation of A2AR or A2BR increases cAMP production and thus enhances cAMP-dependent protein kinase activity, together with cAMP-response element-binding protein phosphorylation, resulting in cell stimulation (Cunha, 2001; Fredholm et al., 2011; Paes-deCarvalho, 2002). Adenosine receptors are expressed throughout the body in mammals (Table 8.1). A1R are widely distributed throughout the body, with the highest abundance in the brain, albeit with low-density expression (Daly & Padgett, 1992), whereas A2AR are expressed mainly in the spleen, lung, cardiovascular system, thymus, leukocytes, and basal ganglia in the brain (Fredholm et al., 2011; Fredholm, IJzerman, Jacobson, Klotz, & Linden, 2001). A2BR are mostly expressed in low abundance throughout the body, whereas the distribution of A3R is more restricted and differs among species. For example, in rats, A3R are present at high levels in the testis and mast cells, whereas in humans, A3R are abundantly expressed in the lung and liver (Linden et al., 1993; Salvatore, Jacobson, Taylor, Linden, & Johnson, 1993).

Distribution and Physiological/Pathophysiological Functions of Adenosine Receptors A1R

A2AR

A2BR

A3R

G-protein

Gi, Go

Gs, Golf

Gs, Gq

Gi

Central receptor distribution

Cortex, cerebellum, hippocampus, striatum, thalamus, low abundance in other areas

Caudate putamen, nucleus accumbens, globus pallidus, olfactory bulb

Widely distributed at a low density

Cerebellum, hippocampus

Peripheral receptor distribution

Widespread

Spleen, lung, cardiovascular system, thymus, leukocytes

Widely distributed at a low density

Species-specific

Physiological/ pathophysiological functions

• Obesity (Dong, Ginsberg, & Erlanger, 2001) • Pain (Wu et al., 2005) • Ischemia (Fredholm et al., 2001) • Arrhythmia (Fraser, Gao, Ozeck, & Belardinelli, 2003; Zablocki, Wu, Shryock, & Belardinelli, 2004) • Sleep (Bjorness et al., 2016; Oishi et al., 2008)

• Parkinson’s disease (Xu, Bastia, & Schwarzschild, 2005) • Asthma (Fozard, Ellis, Dantas, Tigani, & Mazzoni, 2002) • Neuroprotection (Chen et al., 1999; Monopoli, Lozza, Forlani, Mattavelli, & Ongini, 1998) • Inflammation (Sitkovsky et al., 2004) • Sleep (Lazarus et al., 2011; Oishi, Xu, et al., 2017)

• Asthma (Holgate, 2005) • Diabetes (Harada et al., 2001)

• Glaucoma (Avila, Stone, & Civan, 2002) • Cancer (Fishman, BarYehuda, Madi, & Cohn, 2002) • Arthritis (Baharav et al., 2005) • Ischemia (Auchampach et al., 1997; Shneyvays, Zinman, & Shainberg, 2004; Tracey, Magee, Masamune, Oleynek, & Hill, 1998) • Renal failure (Lee et al., 2003)

PART B. REGULATION OF WAKING AND SLEEPING

IV ASSOCIATION BETWEEN ADENOSINE LEVELS AND SLEEP

Adenosine appears to be equally potent at A1R, A2AR, and A3R, and basal adenosine levels are sufficient to activate these receptors under physiological conditions (Fredholm et al., 2011). On the other hand, higher concentrations of adenosine are needed to activate A2BR. Nevertheless, the potency of adenosine to activate one of its receptors depends on the number of receptors available. In the presence of only a few receptors, higher adenosine concentrations are required to see an effect. Only A1R and A2AR are known to be involved in sleep regulation (Lazarus, Chen, Huang, Urade, & Fredholm, 2017).

IV ASSOCIATION BETWEEN ADENOSINE LEVELS AND SLEEP Several circuit- and humoral-based models of sleep/ wake regulation have been proposed. The neuronal and cellular basis of sleep need or, alternatively, “sleep drive” remains unresolved but has been conceptualized as a homeostatic pressure that builds during the waking period and is dissipated by sleep. One theory is that endogenous somnogenic factors accumulate during wake and their gradual accumulation is the underpinning of sleep homeostatic pressure. Over 100 years ago, Ishimori (Ishimori, 1909) and Pieron (Legendre & Pieron, 1913) independently demonstrated the existence of sleep-promoting chemicals. Both researchers demonstrated the presence of hypnogenic substances or “hypnotoxins” in the cerebral spinal fluid of sleepdeprived dogs. Adenosine was first isolated from cardiac tissue extracts in 1929, and more than 60 years have passed since the discovery of the hypnotic effect of adenosine in the cat brain by Feldberg and Sherwood (1954) (Drury & Szent-Gyorgyi, 1929). Subsequently, similar somnogenic effects of adenosine were observed in a wide range of animals, including dogs, fowls, rats, and mice (Dunwiddie & Worth, 1982; Haulica, Ababei, Branisteanu, Braniste, & Topoliceanu, 1973; Marley & Nistico, 1972; Radulovacki, Virus, Djuricicnedelson, & Green, 1984; Radulovacki, Virus, Rapoza, & Crane, 1985; Ticho & Radulovacki, 1991). The principal role of adenosine in regulating sleep/wake behavior, the brain cell types involved in the sleep-promoting effects of adenosine, and the relative contributions of A1R and A2AR to sleep/wake regulation, however, remain controversial. Adenosine represents a state of relative energy deficiency. Therefore, early concepts of sleep/wake regulation hypothesized that the desire for sleep stems, at least in part, from the brain’s periodic need to replenish low energy stores (Pull & Mcilwain, 1972; Tobler & Scherschlicht, 1990; Vanwylen, Park, Rubio, & Berne, 1986). In fact, in vivo microdialysis measurements of extracellular adenosine

127

levels in the hippocampus and neostriatum of freely behaving rats revealed that adenosine levels are higher during the inactive period than the active period, providing the first evidence to support this theory (Huston et al., 1996). In addition, Benington, Kodali, and Heller (1995) hypothesized that extracellular adenosine levels allow the brain to assess the need for sleep following their discovery in rats that systemic or intracerebroventricular administration of N6-cyclopentyladenosine (CPA), a selective A1R agonist, produces dose-dependent increases in slow-wave activity (SWA) during sleep, similar to sleep deprivation. SWA is a slow oscillatory neocortical activity (0.5–4.0 Hz) that intensifies with wake duration and declines during sleep and is thus widely used as a marker of mammalian sleep homeostasis, that is, the balance between waking and sleep. Moreover, ATP depletion is positively correlated with an increase in extracellular adenosine levels (Kalinchuk et al., 2003) and with sleep (Porkka-Heiskanen et al., 1997). Adenosine levels in samples collected by in vivo microdialysis from several brain areas in cats during spontaneous sleep-wake cycles were higher during sleep than wakefulness for all probed brain areas (PorkkaHeiskanen et al., 1997; Porkka-Heiskanen, Strecker, & McCarley, 2000). In vivo microdialysis experiments in the cat brain also revealed a twofold increase in adenosine levels in the basal forebrain (BF) during a prolonged 6 h period of wakefulness compared with adenosine levels at the beginning of sleep deprivation (Porkka-Heiskanen et al., 1997, 2000). Adenosine is thus thought to exert control of BF neurons via A1R, because A1R mRNA is significantly increased in the BF after several hours of sleep deprivation and perfusion of adenosine or the A1R agonist cyclohexyladenosine into the BF induces sleep by inhibiting wake-active neurons, whereas the A1R antagonist 8-cyclopentyltheophylline (CPT) induces wakefulness (Basheer et al., 2001; Basheer, Porkka-Heiskanen, Strecker, Thakkar, & McCarley, 2000). Further, pharmacological inhibition of ADA, AdK, and equilibrative nucleoside transporters leads to an increase in sleep due to an increase in extracellular adenosine levels (Oishi et al., 2008; Okada et al., 2003; Porkka-Heiskanen et al., 1997; Radulovacki, Virus, Djuricicnedelson, & Green, 1983). In principle, adenosine (and ATP, which is rapidly degraded into adenosine) can be released from neurons or glial cells. Genetically engineered mice in which a dominant negative soluble N-ethylmaleimidesensitive factor attachment protein receptor (commonly abbreviated as dnSNARE) domain is selectively expressed in astrocytes to nonspecifically block the release of ATP exhibit decreased levels of extracellular adenosine (Chen & Scheller, 2001; Pascual et al., 2005; Raingo et al., 2012). Although in these mice the amount of wakefulness; slow-wave sleep (SWS), the major component of natural sleep characterized by slow and high-voltage brain waves;

PART B. REGULATION OF WAKING AND SLEEPING

128

8. ADENOSINERGIC CONTROL OF SLEEP/WAKE BEHAVIOR

and rapid eye movement (REM) sleep, a unique phase of sleep in mammals characterized by rapid eye movement, is indistinguishable from that in wild-type mice, they exhibit reduced SWA and recovery sleep after sleep deprivation (Halassa et al., 2009), suggesting that adenosine released from astrocytes is involved in an accumulation of sleep pressure. Direct proof is still lacking, however, and thus, the exact sources of adenosine remain unknown. Work by Greene and colleagues provides evidence for adenosine-mediated regulation of the homeostatic sleep need via activation of neuronal A1R controlled by glial AdK (Bjorness et al., 2016; Bjorness, Kelly, Gao, Poffenberger, & Greene, 2009). As a matter of fact, mice deficient in glial AdK exhibit increased SWA rebound and consolidation and an increased time constant of SWA during an average sleep episode. The energy hypothesis of sleep and its link to extracellular adenosine levels (Benington et al., 1995; Petit, BurletGodinot, Magistretti, & Allaman, 2015; Scharf, Naidoo, Zimmerman, & Pack, 2008) seem to be more complex than initially proposed. Glucose, which is the most important energy source in most organisms, however, is reported to inhibit orexin neurons that promote wakefulness and regulate feeding, whereas sleep-active neurons in the ventrolateral preoptic (VLPO) area, a well-described sleep center in the brain (Moore et al., 2012; Saper, Scammell, & Lu, 2005), are activated by glucose (Burdakov, Luckman, & Verkhratsky, 2005; Gallopin et al., 2000, 2005; Moore et al., 2012; Saper et al., 2005). Moreover, microinjection of glucose into the VLPO induces both sleep and expression of c-fos, a popular marker of neuronal activity (Varin et al., 2015). An increase in extracellular glucose increases extracellular adenosine levels in the VLPO to promote sleep, which can be blocked by the glial toxin fluoroacetate or the A2AR antagonist ZM 241385 (Scharbarg et al., 2016). These findings emphasize the important role of glial cells in coordinating neuronal firing with the local blood supply by astrocyte-derived adenosine and neuronal A2AR activation.

V ROLES OF A2AR IN THE CONTROL OF SLEEP AND AROUSAL A Role of A2AR in Mediating the Sleep-Inducing Effect of Prostaglandin D2 Prostaglandins (PGs) are involved in a large number of physiological processes at extremely low concentrations. The series 2 PGs are formed from arachidonic acid, which is metabolized by cyclooxygenase, a target of nonsteroidal anti-inflammatory drugs such as aspirin and indomethacin, to produce the cyclic endoperoxide PGH2. The latter PG is an important branching point to produce stable PGs, including PGD2, PGE2, and PGF2α, as well as

the more unstable thromboxane A2 and prostacyclin (PGI2). PGD2 has long been considered a minor and biologically relatively inactive PG, but the finding that PGD2 is the most abundant PG in the brains of rats (Narumiya, Ogorochi, Nakao, & Hayaishi, 1982) and other mammals, including humans (Ogorochi et al., 1984), suggests that PGD2 has an important function in the central nervous system. Interestingly, PGD2 is reported to be involved in the pathogenesis of mastocytosis, a disorder characterized by episodic and endogenous production of PGD2 accompanied by deep-sleep episodes (Roberts, Sweetman, Lewis, Austen, & Oates, 1980). Elevated PGD2 concentrations are also detected in the cerebral spinal fluid of patients with African sleeping sickness caused by infection with Trypanosoma brucei (Pentreath, Rees, Owolabi, Philip, & Doua, 1990). The effect of PGD2 on sleep was discovered following microinjection of nanomolar quantities of PGD2 into the rat brain, which profoundly enhanced both SWS and REM sleep (Inoue et al., 1984; Onoe et al., 1988). Two types of prostaglandin D2 synthases (PGDS) exist in the mammalian brain: lipocalin type and hematopoietic type (L-PGDS and H-PGDS). Inorganic tetravalent selenium compounds such as selenium tetrachloride (SeCl4) are potent and reversible inhibitors of PGDS (Islam, Watanabe, Morii, & Hayaishi, 1991), and administration of SeCl4 during the daytime induces almost complete insomnia within 1 h and diminishes SWS and REM sleep in wild-type mice during a 5 h period (Cherasse et al., 2018; Qu et al., 2006). On the other hand, SeCl4-induced sleep is abolished by knockout of L-PGDS or PGD2 receptor, subtype DP1, but not by knockout of H-PGDS in mice, suggesting that the selenium compound inhibits sleep by blocking the formation of endogenous PGD2 by L-PGDS and the subsequent activation of DP1 receptors by PGD2. The DP1 receptors are dominantly localized in the leptomeninges on the ventral surface of the rostral BF in proximity to the posterior hypothalamus, which contains sleep-promoting neurons in the VLPO, whereas other brain areas are almost completely devoid of DP1 receptors (Mizoguchi et al., 2001). Sleep is most effectively induced when PGD2 is infused into the subarachnoid space near the VLPO or directly into the VLPO (Gerashchenko et al., 1998; Matsumura et al., 1994). PGD2 infusion into the subarachnoid space below the rostral BF in mice increases extracellular adenosine levels, and the A2AR antagonist KF 17837 prevents the sleeppromoting effect of PGD2, suggesting that the adenosine/A2AR system has a pivotal role in mediating the somnogenic effect of PGD2 (Hong et al., 2005; Mizoguchi et al., 2001). A recent study, however, also revealed that PGD2-induced sleep in mice is mediated not only by A2AR but also by A2AR-independent systems, because SWS is increased when high PGD2 doses of 20 pmol/ min or more are intracerebroventricularly infused into

PART B. REGULATION OF WAKING AND SLEEPING

V ROLES OF A2AR IN THE CONTROL OF SLEEP AND AROUSAL

the brain of A2AR knockout mice, whereas lower doses do not affect the sleep/wake behavior of A2AR knockout mice (Zhang, Huang, Chen, Urade, & Qu, 2017).

B Roles of A2AR in the Gating and Maintenance of Sleep by Suppressing Arousal CGS 21680, a highly selective A2AR agonist, strongly increases SWS and REM sleep in mice after infusion into the subarachnoid space underlying the ventral surface region of the rostral BF or into the lateral ventricle (Satoh et al., 1999; Satoh, Matsumura, & Hayaishi, 1998; Satoh, Matsumura, Suzuki, & Hayaishi, 1996; Urade et al., 2003). In vivo microdialysis experiments demonstrated that histamine release in both the frontal cortex and medial preoptic area is inhibited in a dose-dependent manner by infusions of CGS 21680 into the BF, whereas the release of γ-aminobutyric acid (GABA) in the tuberomammillary nucleus (TMN) of the hypothalamus, but not the frontal cortex, is increased (Hong et al., 2005). CGS 21680-induced blockade of histamine release is antagonized when the TMN is perfused with the GABA antagonist picrotoxin, suggesting that the A2AR agonist induces sleep by inhibiting the histaminergic system through an increase in GABA release in the TMN. Sleep may be promoted by activating sleep neurons in the VLPO with reciprocal suppression of histaminergic wake neurons in the TMN through GABAergic and galaninergic inhibitory projections (Sherin, Elmquist, Torrealba, & Saper, 1998; Sherin, Shiromani, McCarley, & Saper, 1996). The existence of two distinct types of VLPO neurons in terms of their responses to serotonin and adenosine was demonstrated by whole-cell recordings of VLPO neurons in rat brain slices. VLPO neurons are uniformly inhibited by the arousing neurotransmitters noradrenaline and acetylcholine and primarily inhibited by an A1R agonist. Serotonin inhibits type 1 neurons but excites type 2 neurons, whereas an A2AR agonist postsynaptically excites type 2, but not type 1 neurons. These results implicate the involvement of type 2 neurons in the initiation of sleep, whereas type 1 neurons contribute to sleep consolidation, as they are only activated in the absence of inhibitory effects from the arousal systems (Gallopin et al., 2005). Administration of CGS 21680 into the rostral BF, however, produces c-fos expression not only in the VLPO but also within the nucleus accumbens (NAc) shell and the medial portion of the olfactory tubercle (Satoh et al., 1999; Scammell et al., 2001). Interestingly, direct perfusion of the A2AR agonist into the NAc induces SWS and REM sleep that corresponds to about three-quarters of the amount of sleep measured when the A2AR agonist is infused into the subarachnoid space (Satoh et al., 1999). These results may indicate that A2AR within or close to

129

the NAc predominantly promote sleep. Acting opposite to adenosine, caffeine enhances wakefulness because it acts as an antagonist of both the A1R and A2AR subtypes (Fredholm, B€attig, Holmen, Nehlig, & Zvartau, 1999). Experiments using global genetic knockouts of A1R and A2AR revealed that A2AR, but not A1R, mediate the arousal-inducing effect of caffeine (Fig. 8.2A; Huang et al., 2005). The specific role of A2AR in the basal ganglia was investigated using tools for site-specific gene manipulations, such as conditional A2AR knockout mice based on the Cre/lox technology, or local infection with adenoassociated virus carrying short-hairpin RNA of A2AR to silence the expression of the receptor subtype (Lazarus et al., 2011). Selective deletion of A2AR in the NAc shell blocks caffeine-induced wakefulness (Fig. 8.2B). Excitatory A2AR within the NAc shell must be tonically activated by adenosine for caffeine to be effective as an A2AR antagonist. This tonic activation probably occurs in the NAc shell because sufficient levels of adenosine are available under basal conditions and A2AR are abundantly expressed throughout the striatum, including the NAc shell (Rosin, Robeva, Woodard, Guyenet, & Linden, 1998; Svenningsson et al., 1999). Projections of NAc A2AR neurons were mapped using Cre-dependent adeno-associated virus encoding humanized Renilla green fluorescent protein as a tracer for long axonal pathways in mice expressing Cre recombinase under control of the A2AR promoter. The results revealed that NAc A2AR neurons strongly project to the lateral hypothalamus, the ventral tegmental area (VTA), the dorsal raphe, and the TMN, all of which contain wakepromoting neurons, suggesting that NAc A2AR neurons control sleep by suppressing wakefulness (Zhang et al., 2013). In fact, a recent study showed that chemogenetic or optogenetic activation of NAc core A2AR neurons projecting to the ventral pallidum in the BF strongly induces SWS, whereas chemogenetic inhibition of these neurons prevents sleep induction, but does not affect the homeostatic sleep rebound (Oishi, Xu, et al., 2017). Interestingly, motivational stimuli inhibit the activity of ventral pallidum-projecting NAc A2AR neurons and suppress sleep. The NAc medium spiny neurons, however, can be divided into two groups that respond differentially to stimulation by dopamine or adenosine. Direct pathway neurons express excitatory dopamine D1 receptors and inhibitory adenosine A1R, whereas neurons of the indirect pathway express inhibitory dopamine D2 receptors and excitatory A2AR. Previous findings based on in vivo electrophysiological recordings indicate that the sleep-active neurons are intermingled with wake-active neurons in the NAc region in rats (Callaway & Henriksen, 1992; Osaka & Matsumura, 1995; Tellez, Perez, Simon, & Gutierrez, 2012). As a matter of fact, optogenetic activation of NAc D1 receptor-expressing neurons projecting to the midbrain and lateral hypothalamus induces an immediate

PART B. REGULATION OF WAKING AND SLEEPING

130

8. ADENOSINERGIC CONTROL OF SLEEP/WAKE BEHAVIOR

A

A2AR WT

i.p.

60

∗∗

A2AR KO

i.p.

60

∗∗ ∗

40

Wakefulness (min/h)

FIG. 8.2 Caffeine-induced arousal in adenosine receptor gene-manipulated mice. (A) Caffeine-induced arousal in wild-type (WT) and A1 receptor knockout (A1R KO) mice, but not in A2A receptor knockout (A2AR KO) mice. (B) To identify the neurons that caffeine acts on to produce arousal, A2AR were focally depleted by bilateral injections of adenoassociated virus carrying short-hairpin RNA for A2AR into the nucleus accumbens (NAc) core (dashed green line in the left panel) or shell (dashed red line in the right panel) of rats. Typical EEG and EMG traces indicate that caffeine-induced arousal is strongly attenuated in rats with A2AR knockdown in the NAc shell, but not in the NAc core. (A) From Huang, Z. L., Qu, W. M., Eguchi, N., Chen, J. F., Schwarzschild, M. A., Fredholm, B. B., et al. (2005). Adenosine A2(A), but not A(1), receptors mediate the arousal effect of caffeine. Nature Neuroscience, 8(7), 858–859; (B) From Lazarus, M., Shen, H. Y., Cherasse, Y., Qu, W. M., Huang, Z. L., Bass, C. E., et al. (2011). Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens. Journal of Neuroscience, 31(27), 10067–10075.

40

20

20

0

0

Vehicle Caffeine 15 mg/kg

i.p.

60

∗∗ ∗∗

40

∗

i.p.

A1R WT

∗∗ ∗∗

60

A1R KO

∗

40 20

20

0

0 8:00

14:00

20:00

2:00

8:00

8:00

14:00

20:00

2:00

8:00

Clock time B

transition from SWS to wakefulness, and chemogenetic stimulation prolongs the arousal (Luo et al., 2018). The sleep-gating ability of the NAc indirect pathway may explain why we tend to fall asleep in the absence of motivating stimuli, that is, when bored. Dopamine produced by VTA neurons in the midbrain has a key role in processing reward, aversive, or cognitive signals (Bromberg-Martin, Matsumoto, & Hikosaka, 2010; Schultz, Carelli, & Wightman, 2015; Wise, 2004), and projections from VTA dopamine neurons to the NAc, known as the mesolimbic pathway, comprise a well-characterized reward circuit in the brain (Russo & Nestler, 2013; Volkow & Morales, 2015). The contribution of VTA dopamine neurons to wakefulness under baseline conditions was recently examined by chemogenetic inhibition in two independent studies. One study proposed that VTA

NAc-core

NAc-shell

dopamine neurons are necessary for baseline wakefulness in mice, as chemogenetic inhibition decreased the amount of wakefulness (Eban-Rothschild, Rothschild, Giardino, Jones, & de Lecea, 2016), whereas another study showed that chemogenetic inhibition of VTA dopamine neurons has no significant effect on baseline wakefulness in mice (Oishi, Suzuki, et al., 2017). A plausible explanation for the differences in the findings of these studies is that ectopic Cre is differentially expressed in the midbrain of the tyrosine hydroxylase-Cre mice used by EbanRothschild et al. (2016) or the dopamine transporter-Cre mice used by Oishi, Suzuki, et al. (2017) (Lammel et al., 2015). Dysfunction of the striatum leads to devastating motor disorders, including Parkinson’s disease, highlighting the central function of the striatum in the control of

PART B. REGULATION OF WAKING AND SLEEPING

131

VII CONCLUSIONS

movement (Crittenden & Graybiel, 2011). Ablation of the striatum in cats and rats decreases sleep (Mena-Segovia, Cintra, Prospero-Garcia, & Giordano, 2002; Villablanca, 1972), and chemogenetic activation of the A2AR neurons in the striatum induces sleep in a topographically organized manner: Activation of the A2AR-expressing neurons in the rostral, centromedial, and centrolateral striatum increases sleep, whereas A2AR-expressing neurons in the caudal striatum do not have the ability to promote sleep (Yuan et al., 2017). Although A2AR appear to be primarily involved in the regulation of SWS, a few studies suggest that A2AR are involved in the control of REM sleep. REM sleep is increased when CGS 21680 is infused into the medial pontine reticular formation area (Marks, Shaffery, Speciale, & Birabil, 2003). Moreover, a recent study found that blocking A2AR or A2AR-expressing neurons in the olfactory bulb of rodents increases REM sleep, suggesting that the olfactory bulb is a key site for regulating REM sleep by the adenosine/A2AR system (Wang et al., 2012). Because olfactory dysfunction can be ameliorated by an A2AR antagonist, for example, caffeine or ZM 241385 (Prediger, Batista, & Takahashi, 2005), it is possible that REM sleep is linked to the perception of odors in the olfactory bulb. Interestingly, the ability to smell is reduced in patients with REM sleep behavior disorders (Stiasny-Kolster, Clever, Moller, Oertel, & Mayer, 2007).

VI ROLES OF A1R IN SLEEP REGULATION AND HOMEOSTASIS The pharmacological effects of caffeine, the A1R antagonist CPT, and the nonselective A1R/A2AR antagonist alloxazine on sleep in rats (Virus, Ticho, Pilditch, & Radulovacki, 1990) might partially account for the prevailing opinion that A1R are more important in sleep-wake regulation than A2AR. The A1R agonist CPA produces dose-dependent increases in SWA in electroencephalography during SWS when administered systemically or intracerebroventricularly in rats (Benington et al., 1995), but lateral ventricle infusions of CPA in mice do not change the amounts of observed SWS and REM sleep (Urade et al., 2003), which may indicate opposing effects on sleep and wakefulness in different areas of the brain. Adenosine acting via A1R induces sleep by inhibiting arousal-related cell groups in the BF, such as the horizontal limb of the diagonal band of Broca and the substantia innominata (Alam, Szymusiak, Gong, King, & McGinty, 1999; Strecker et al., 2000). The BF contains glutamatergic, GABAergic, and cholinergic neurons that project to the cortex or other areas related to sleep/wake regulation, including the brain stem and hypothalamus (Gritti, Mainville, Mancia, & Jones, 1997; Zaborszky, Pang, Somogyi, Nadasdy, & Kallo, 1999). A popular model

proposes that SWS is generated by adenosine-/A1Rdriven inhibition of acetylcholine release from cholinergic BF neurons ( Jones, 2004), although the results of several studies indicate that cholinergic BF neurons are not essential for sleep induction (Anaclet et al., 2015; Blanco-Centurion et al., 2006; Chen et al., 2016; Kapas et al., 1996). Moreover, adenosine may promote sleep by A1R-mediated inhibition of glutamatergic inputs to cortically projecting cholinergic and GABA neurons of the BF (Yang, Franciosi, & Brown, 2013). Adenosine is also suggested to promote sleep by suppressing hypocretin/orexin neurons in the lateral hypothalamus, because an A1R agonist produced SWS and REM sleep and an A1R antagonist induced wakefulness (Rai et al., 2010; Thakkar, Engemann, Walsh, & Sahota, 2008; Thakkar, Winston, & McCarley, 2002). The TMN is enriched in histamine neurons containing A1R. Therefore, the histaminergic arousal system may be actively regulated by adenosine in the TMN. In fact, bilateral injections of the A1R agonist CPA into the rat TMN significantly increase the amount of SWS (Oishi et al., 2008). Moreover, bilateral injections of adenosine or ADA inhibitor coformycin into the rat TMN also increase SWS, which is completely abolished by coadministration of the selective A1R antagonist CPT. These results indicate that extracellular adenosine in the TMN promotes SWS by suppressing the histaminergic system via A1R. By contrast, activation of A1R in the lateral preoptic area of the hypothalamus by local infusion of an A1R agonist promotes wakefulness (Methippara, Kumar, Alam, Szymusiak, & McGinty, 2005).

VII CONCLUSIONS Adenosine is well known as a somnogenic substance that affects normal sleep-wake patterns. Adenosine tends to regulate the duration and spectral components of sleep. The source of the adenosine involved in sleep, however, is still poorly understood. Many cells and processes appear to play a role. Similarly, adenosine promotes sleep by several mechanisms in several locations via A1R or A2AR (Fig. 8.3). The possibility that adenosine receptor stimulation could be used as a potential treatment for insomnia should also be considered. Insomnia is a sleep disorder affecting millions of people around the world, and it frequently co-occurs with a wide range of psychiatric disorders (de Zambotti, Goldstone, Colrain, & Baker, 2018; Roth, 2007; Seow, Abdin, Chang, Chong, & Subramaniam, 2018). Although A2AR agonists strongly induce sleep, classical A2AR agonists have adverse cardiovascular effects and cannot be used clinically to treat sleep disorders. Moreover, the development of adenosine analogs for treating central nervous system disorders, including

PART B. REGULATION OF WAKING AND SLEEPING

132

8. ADENOSINERGIC CONTROL OF SLEEP/WAKE BEHAVIOR

FIG. 8.3 Differential effects of adenosine A1 or A2A receptors in sleep/wake behavior. Adenosine reacts with excitatory A2A receptors (A2AR) in the rostral, centromedial, and centrolateral striatum; nucleus accumbens (NAc); and ventrolateral preoptic area (VLPO) to induce slow-wave sleep (SWS) or in the olfactory bulb (OB) to inhibit REM sleep. Adenosine also reacts with inhibitory A1 receptors (A1R) on cholinergic neurons or glutamatergic terminals in the basal forebrain (BF), orexinergic perifornical-lateral hypothalamic area (PF-LHA) neurons, and histaminergic tuberomammillary nucleus (TMN) neurons to induce SWS, whereas A1R-mediated inhibition of lateral preoptic area (LPOA) neurons produces wakefulness.

insomnia, is hampered by the poor transport of these drugs across the blood-brain barrier. A small, recently identified blood-brain barrier-permeable monocarboxylate induces sleep by enhancing A2AR signaling in the brain, and surprisingly does not have the typical cardiovascular effects of A2AR agonists (Korkutata et al., 2019). Therefore, molecules that allosterically enhance A2AR signaling could help people with insomnia fall asleep and may also be a potential treatment for psychiatric illness.

References Alam, M. N., Szymusiak, R., Gong, H., King, J., & McGinty, D. (1999). Adenosinergic modulation of rat basal forebrain neurons during sleep and waking: neuronal recording with microdialysis. The Journal of Physiology, 521(3), 679–690. Anaclet, C., Pedersen, N. P., Ferrari, L. L., Venner, A., Bass, C. E., Arrigoni, E., et al. (2015). Basal forebrain control of wakefulness and cortical rhythms. Nature Communications, 6, 8744. Auchampach, J. A., Rizvi, A., Qiu, Y., Tang, X. L., Maldonado, C., Teschner, S., et al. (1997). Selective activation of A3 adenosine receptors with N6-(3-iodobenzyl)adenosine-5’-N-methyluronamide protects against myocardial stunning and infarction without hemodynamic changes in conscious rabbits. Circulation Research, 80(6), 800–809. Avila, M. Y., Stone, R. A., & Civan, M. M. (2002). Knockout of A3 adenosine receptors reduces mouse intraocular pressure. Investigative Ophthalmology & Visual Science, 43(9), 3021–3026. Baharav, E., Bar-Yehuda, S., Madi, L., Silberman, D., Rath-Wolfson, L., Halpren, M., et al. (2005). Antiinflammatory effect of A3 adenosine receptor agonists in murine autoimmune arthritis models. The Journal of Rheumatology, 32(3), 469–476. Ballarin, M., Fredholm, B. B., Ambrosio, S., & Mahy, N. (1991). Extracellular levels of adenosine and its metabolites in the striatum of awake rats: inhibition of uptake and metabolism. Acta Physiologica Scandinavica, 142(1), 97–103. Basheer, R., Halldner, L., Alanko, L., McCarley, R. W., Fredholm, B. B., & Porkka-Heiskanen, T. (2001). Opposite changes in adenosine A(1) and A(2A) receptor mRNA in the rat following sleep deprivation. Neuroreport, 12(8), 1577–1580. Basheer, R., Porkka-Heiskanen, T., Strecker, R. E., Thakkar, M. M., & McCarley, R. W. (2000). Adenosine as a biological signal mediating sleepiness following prolonged wakefulness. Biological Signals and Receptors, 9(6), 319–327.

Benington, J. H., Kodali, S. K., & Heller, H. C. (1995). Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation. Brain Research, 692(1–2), 79–85. Bjorness, T. E., Dale, N., Mettlach, G., Sonneborn, A., Sahin, B., Fienberg, A. A., et al. (2016). An adenosine-mediated glial-neuronal circuit for homeostatic sleep. The Journal of Neuroscience, 36(13), 3709–3721. Bjorness, T. E., Kelly, C. L., Gao, T. S., Poffenberger, V., & Greene, R. W. (2009). Control and function of the homeostatic sleep response by adenosine A(1) receptors. The Journal of Neuroscience, 29(5), 1267–1276. Blanco-Centurion, C., Xu, M., Murillo-Rodriguez, E., Gerashchenko, D., Shiromani, A. M., Salin-Pascual, R. J., et al. (2006). Adenosine and sleep homeostasis in the basal forebrain. The Journal of Neuroscience, 26(31), 8092–8100. Bromberg-Martin, E. S., Matsumoto, M., & Hikosaka, O. (2010). Dopamine in motivational control: rewarding, aversive, and alerting. Neuron, 68(5), 815–834. Burdakov, D., Luckman, S. M., & Verkhratsky, A. (2005). Glucose-sensing neurons of the hypothalamus. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 360(1464), 2227–2235. Callaway, C. W., & Henriksen, S. J. (1992). Neuronal firing in the nucleus accumbens is associated with the level of cortical arousal. Neuroscience, 51(3), 547–553. Chen, J. F., Huang, Z., Ma, J., Zhu, J., Moratalla, R., Standaert, D., et al. (1999). A(2A) adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. The Journal of Neuroscience, 19(21), 9192–9200. Chen, L., Yin, D., Wang, T. X., Guo, W., Dong, H., Xu, Q., et al. (2016). Basal forebrain cholinergic neurons primarily contribute to inhibition of electroencephalogram delta activity, rather than inducing behavioral wakefulness in mice. Neuropsychopharmacology, 41(8), 2133–2146. Chen, Y. A., & Scheller, R. H. (2001). Snare-mediated membrane fusion. Nature Reviews. Molecular Cell Biology, 2(2), 98–106. Cherasse, Y., Aritake, K., Oishi, Y., Kaushik, M. K., Korkutata, M., & Urade, Y. (2018). The leptomeninges produce prostaglandin D(2) involved in sleep regulation in mice. Frontiers in Cellular Neuroscience, 12. https://doi.org/10.3389/fncel.2018.00357. Crittenden, J. R., & Graybiel, A. M. (2011). Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments. Frontiers in Neuroanatomy, 5, 59. Cunha, R. A. (2001). Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochemistry International, 38(2), 107–125. Daly, J. W., & Padgett, W. L. (1992). Agonist activity of 2-substituted and 5’-substituted adenosine-analogs and their N6-cycloalkyl derivatives at adenosine-A1 and adenosine-A2 receptors coupled to adenylate-cyclase. Biochemical Pharmacology, 43(5), 1089–1093.

PART B. REGULATION OF WAKING AND SLEEPING

REFERENCES

de Zambotti, M., Goldstone, A., Colrain, I. M., & Baker, F. C. (2018). Insomnia disorder in adolescence: diagnosis, impact, and treatment. Sleep Medicine Reviews, 39, 12–24. Dong, Q., Ginsberg, H. N., & Erlanger, B. F. (2001). Overexpression of the A1 adenosine receptor in adipose tissue protects mice from obesity-related insulin resistance. Diabetes, Obesity & Metabolism, 3(5), 360–366. Dos Santos-Rodrigues, A., Grane-Boladeras, N., Bicket, A., & Coe, I. R. (2014). Nucleoside transporters in the purinome. Neurochemistry International, 73, 229–237. Drury, A. N., & Szent-Gyorgyi, A. (1929). The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. The Journal of Physiology, 68(3), 213–237. Dunwiddie, T. V., & Worth, T. (1982). Sedative and anticonvulsant effects of adenosine-analogs in mouse and rat. The Journal of Pharmacology and Experimental Therapeutics, 220(1), 70–76. Eban-Rothschild, A., Rothschild, G., Giardino, W. J., Jones, J. R., & de Lecea, L. (2016). VTA dopaminergic neurons regulate ethologically relevant sleep-wake behaviors. Nature Neuroscience, 19(10), 1356–1366. Feldberg, W., & Sherwood, S. L. (1954). Injections of drugs into the lateral ventricle of the cat. The Journal of Physiology, 123(1), 148–167. Fishman, P., Bar-Yehuda, S., Madi, L., & Cohn, I. (2002). A3 adenosine receptor as a target for cancer therapy. Anti-Cancer Drugs, 13(5), 437–443. Fozard, J. R., Ellis, K. M., Dantas, M. F. V., Tigani, B., & Mazzoni, L. (2002). Effects of CGS 21680, a selective adenosine A(2A) receptor agonist, on allergic airways inflammation in the rat. European Journal of Pharmacology, 438(3), 183–188. Fraser, H., Gao, Z., Ozeck, M. J., & Belardinelli, L. (2003). N-[3-(R)tetrahydrofuranyl]-6-aminopurine riboside, an A1 adenosine receptor agonist, antagonizes catecholamine-induced lipolysis without cardiovascular effects in awake rats. The Journal of Pharmacology and Experimental Therapeutics, 305(1), 225–231. Fredholm, B. B. (2007). Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death and Differentiation, 14(7), 1315–1323. Fredholm, B. B., IJzerman, A. P., Jacobson, K. A., Linden, J., & Muller, C. E. (2011). International union of basic and clinical pharmacology. LXXXI. Nomenclature and classification of adenosine receptors—an update. Pharmacological Reviews, 63(1), 1–34. Fredholm, B. B., B€ attig, K., Holmen, J., Nehlig, A., & Zvartau, E. E. (1999). Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacological Reviews, 51(1), 83–133. Fredholm, B. B., Chen, J. F., Cunha, R. A., Svenningsson, P., & Vaugeois, J. M. (2005). Adenosine and brain function. International Review of Neurobiology, 63, 191–270. Fredholm, B. B., IJzerman, A. P., Jacobson, K. A., Klotz, K. N., & Linden, J. (2001). International union of pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacological Reviews, 53(4), 527–552. Gallopin, T., Fort, P., Eggermann, E., Cauli, B., Luppi, P. H., Rossier, J., et al. (2000). Identification of sleep-promoting neurons in vitro. Nature, 404(6781), 992–995. Gallopin, T., Luppi, P. H., Cauli, B., Urade, Y., Rossier, J., Hayaishi, O., et al. (2005). The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A(2A) receptors in the ventrolateral preoptic nucleus. Neuroscience, 134(4), 1377–1390. Gerashchenko, D., Beuckmann, C. T., Kanaoka, Y., Eguchi, T., Gordon, W. C., Urade, Y., et al. (1998). Dominant expression of rat prostanoid DP receptor mRNA in leptomeninges, inner segments of photoreceptor cells, iris epithelium, and ciliary processes. Journal of Neurochemistry, 71(3), 937–945. Gritti, I., Mainville, L., Mancia, M., & Jones, B. E. (1997). GABAergic and other noncholinergic basal forebrain neurons, together with cholinergic neurons, project to the mesocortex and isocortex in the rat. The Journal of Comparative Neurology, 383(2), 163–177.

133

Halassa, M. M., Florian, C., Fellin, T., Munoz, J. R., Lee, S. Y., Abel, T., et al. (2009). Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron, 61(2), 213–219. Harada, H., Asano, O., Kawata, T., Inoue, T., Horizoe, T., Yasuda, N., et al. (2001). 2-Alkynyl-8-aryladenines possessing an amide moiety: their synthesis and structure-activity relationships of effects on hepatic glucose production induced via agonism of the A(2B) adenosine receptor. Bioorganic & Medicinal Chemistry, 9(10), 2709–2726. Haulica, I., Ababei, L., Branisteanu, D., Braniste, D., & Topoliceanu, F. (1973). Preliminary data on possible hypnogenic role of adenosine. Journal of Neurochemistry, 21(4), 1019–1020. Holgate, S. T. (2005). The identification of the adenosine A(2B) receptor as a novel therapeutic target in asthma. British Journal of Pharmacology, 145(8), 1009–1015. Hong, Z. Y., Huang, Z. L., Qu, W. M., Eguchi, N., Urade, Y., & Hayaishi, O. (2005). An adenosine A(2A) receptor agonist induces sleep by increasing GABA release in the tuberomammillary nucleus to inhibit histaminergic systems in rats. Journal of Neurochemistry, 92(6), 1542–1549. Huang, Z. L., Qu, W. M., Eguchi, N., Chen, J. F., Schwarzschild, M. A., Fredholm, B. B., et al. (2005). Adenosine A2(A), but not A(1), receptors mediate the arousal effect of caffeine. Nature Neuroscience, 8(7), 858–859. Huston, J. P., Haas, H. L., Boix, F., Pfister, M., Decking, U., Schrader, J., et al. (1996). Extracellular adenosine levels in neostriatum and hippocampus during rest and activity periods of rats. Neuroscience, 73(1), 99–107. Inoue, S., Honda, K., Komoda, Y., Uchizono, K., Ueno, R., & Hayaishi, O. (1984). Differential sleep-promoting effects of 5 sleep substances nocturnally infused in unrestrained rats. Proceedings of the National Academy of Sciences of the United States of America, 81(19), 6240–6244. Ishimori, K. (1909). True cause of sleep: a hypnogenic substance as evidenced in the brain of sleep-deprived animals. Tokyo Igakkai Zasshi, 23, 429–457. Islam, F., Watanabe, Y., Morii, H., & Hayaishi, O. (1991). Inhibition of rat brain prostaglandin D synthase by inorganic selenocompounds. Archives of Biochemistry and Biophysics, 289(1), 161–166. Jones, B. E. (2004). Activity, modulation and role of basal forebrain cholinergic neurons innervating the cerebral cortex. Progress in Brain Research, 145, 157–169. Kalinchuk, A. V., Urrila, A. -S., Alanko, L., Heiskanen, S., Wigren, H. -K., Suomela, M., et al. (2003). Local energy depletion in the basal forebrain increases sleep. The European Journal of Neuroscience, 17(4), 863–869. Kapas, L., Obal, F., Jr., Book, A. A., Schweitzer, J. B., Wiley, R. G., & Krueger, J. M. (1996). The effects of immunolesions of nerve growth factor-receptive neurons by 192 IgG-saporin on sleep. Brain Research, 712(1), 53–59. Korkutata, M., Saitoh, T., Cherasse, Y., Ioka, S., Duo, F., Qin, R., et al. (2019). Enhancing endogenous adenosine A(2A) receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function. Neuropharmacology, 144, 122–132. https:// doi.org/10.1016/j.neuropharm.2018.10.022. Kovacs, Z., Dobolyi, A., Kekesi, K. A., & Juhasz, G. (2013). 5’nucleotidases, nucleosides and their distribution in the brain: pathological and therapeutic implications. Current Medicinal Chemistry, 20(34), 4217–4240. Lammel, S., Steinberg, E. E., Foldy, C., Wall, N. R., Beier, K., Luo, L., et al. (2015). Diversity of transgenic mouse models for selective targeting of midbrain dopamine neurons. Neuron, 85(2), 429–438. Latini, S., & Pedata, F. (2001). Adenosine in the central nervous system: release mechanisms and extracellular concentrations. Journal of Neurochemistry, 79(3), 463–484. Lazarus, M., Chen, J. F., Huang, Z. L., Urade, Y., & Fredholm, B. B. (2017). Adenosine and sleep. Handbook of Experimental Pharmacology. https://doi.org/10.1007/164_2017_36.

PART B. REGULATION OF WAKING AND SLEEPING

134

8. ADENOSINERGIC CONTROL OF SLEEP/WAKE BEHAVIOR

Lazarus, M., Shen, H. Y., Cherasse, Y., Qu, W. M., Huang, Z. L., Bass, C. E., et al. (2011). Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens. The Journal of Neuroscience, 31(27), 10067–10075. Lee, H. T., Ota-Setlik, A., Xu, H., D’Agati, V. D., Jacobson, M. A., & Emala, C. W. (2003). A3 adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure. American Journal of Physiology. Renal Physiology, 284(2), F267–F273. Legendre, R., & Pieron, H. (1913). Recherches sur le besoin de sommeil consecutif a une veille prolongee. Zeitschrift f€ ur allgemeine Physiologie, 14, 235–262. Linden, J., Taylor, H. E., Robeva, A. S., Tucker, A. L., Stehle, J. H., Rivkees, S. A., et al. (1993). Molecular cloning and functional expression of a sheep A3 adenosine receptor with widespread tissue distribution. Molecular Pharmacology, 44(3), 524–532. Luo, Y. J., Li, Y. D., Wang, L., Yang, S. R., Yuan, X. S., Wang, J., et al. (2018). Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D1 receptors. Nature Communications, 9(1), 1576. Marks, G. A., Shaffery, J. P., Speciale, S. G., & Birabil, C. G. (2003). Enhancement of rapid eye movement sleep in the rat by actions at A1 and A2a adenosine receptor subtypes with a differential sensitivity to atropine. Neuroscience, 116(3), 913–920. Marley, E., & Nistico, G. (1972). Effects of catecholamines and adenosine derivatives given into brain of fowls. British Journal of Pharmacology, 46(4), 619–636. Matsumura, H., Nakajima, T., Osaka, T., Satoh, S., Kawase, K., Kubo, E., et al. (1994). Prostaglandin D2-sensitive, sleep-promoting zone defined in the ventral surface of the rostral basal forebrain. Proceedings of the National Academy of Sciences of the United States of America, 91(25), 11998–12002. Mena-Segovia, J., Cintra, L., Prospero-Garcia, O., & Giordano, M. (2002). Changes in sleep-waking cycle after striatal excitotoxic lesions. Behavioural Brain Research, 136(2), 475–481. Methippara, M. M., Kumar, S., Alam, M. N., Szymusiak, R., & McGinty, D. (2005). Effects on sleep of microdialysis of adenosine A(1) and A(2a) receptor analogs into the lateral preoptic area of rats. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 289(6), R1715–R1723. Mizoguchi, A., Eguchi, N., Kimura, K., Kiyohara, Y., Qu, W. M., Huang, Z. L., et al. (2001). Dominant localization of prostaglandin D receptors on arachnoid trabecular cells in mouse basal forebrain and their involvement in the regulation of non-rapid eye movement sleep. Proceedings of the National Academy of Sciences of the United States of America, 98(20), 11674–11679. Monopoli, A., Lozza, G., Forlani, A., Mattavelli, A., & Ongini, E. (1998). Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats. Neuroreport, 9(17), 3955–3959. Moore, J. T., Chen, J. Q., Han, B., Meng, Q. C., Veasey, S. C., Beck, S. G., et al. (2012). Direct activation of sleep-promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis. Current Biology, 22(21), 2008–2016. Narumiya, S., Ogorochi, T., Nakao, K., & Hayaishi, O. (1982). Prostaglandin D2 in rat brain, spinal cord and pituitary: basal level and regional distribution. Life Sciences, 31(19), 2093–2103. Ogorochi, T., Narumiya, S., Mizuno, N., Yamashita, K., Miyazaki, H., & Hayaishi, O. (1984). Regional distribution of prostaglandins D2, E2, and F2 alpha and related enzymes in postmortem human brain. Journal of Neurochemistry, 43(1), 71–82. Oishi, Y., Huang, Z. L., Fredholm, B. B., Urade, Y., & Hayaishi, O. (2008). Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep. Proceedings of the National Academy of Sciences of the United States of America, 105(50), 19992–19997.

Oishi, Y., Suzuki, Y., Takahashi, K., Yonezawa, T., Kanda, T., Takata, Y., et al. (2017). Activation of ventral tegmental area dopamine neurons produces wakefulness through dopamine D-2-like receptors in mice. Brain Structure & Function, 222(6), 2907–2915. Oishi, Y., Xu, Q., Wang, L., Zhang, B. J., Takahashi, K., Takata, Y., et al. (2017). Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice. Nature Communications, 8(1), 734. Okada, T., Mochizuki, T., Huang, Z. L., Eguchi, N., Sugita, Y., Urade, Y., et al. (2003). Dominant localization of adenosine deaminase in leptomeninges and involvement of the enzyme in sleep. Biochemical and Biophysical Research Communications, 312(1), 29–34. Onoe, H., Ueno, R., Fujita, I., Nishino, H., Oomura, Y., & Hayaishi, O. (1988). Prostaglandin-D2, a cerebral sleep-inducing substance in monkeys. Proceedings of the National Academy of Sciences of the United States of America, 85(11), 4082–4086. Osaka, T., & Matsumura, H. (1995). Noradrenaline inhibits preoptic sleep-active neurons through alpha 2-receptors in the rat. Neuroscience Research, 21(4), 323–330. Paes-de-Carvalho, R. (2002). Adenosine as a signaling molecule in the retina: biochemical and developmental aspects. Anais da Academia Brasileira de Ci^encias, 74(3), 437–451. Parkinson, F. E., Damaraju, V. L., Graham, K., Yao, S. Y., Baldwin, S. A., Cass, C. E., et al. (2011). Molecular biology of nucleoside transporters and their distributions and functions in the brain. Current Topics in Medicinal Chemistry, 11(8), 948–972. Pascual, O., Casper, K. B., Kubera, C., Zhang, J., Revilla-Sanchez, R., Sul, J. Y., et al. (2005). Astrocytic purinergic signaling coordinates synaptic networks. Science, 310(5745), 113–116. Pentreath, V. W., Rees, K., Owolabi, O. A., Philip, K. A., & Doua, F. (1990). The somnogenic T lymphocyte suppressor prostaglandin D2 is selectively elevated in cerebrospinal fluid of advanced sleeping sickness patients. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84(6), 795–799. Petit, J. M., Burlet-Godinot, S., Magistretti, P. J., & Allaman, I. (2015). Glycogen metabolism and the homeostatic regulation of sleep. Metabolic Brain Disease, 30(1), 263–279. Porkka-Heiskanen, T., Strecker, R. E., & McCarley, R. W. (2000). Brain site-specificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study. Neuroscience, 99(3), 507–517. Porkka-Heiskanen, T., Strecker, R. E., Thakkar, M., Bjorkum, A. A., Greene, R. W., & McCarley, R. W. (1997). Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science, 276(5316), 1265–1268. Prediger, R. D. S., Batista, L. C., & Takahashi, R. N. (2005). Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats: involvement of adenosine A1 and A2A receptors. Neurobiology of Aging, 26(6), 957–964. Pull, I., & Mcilwain, H. (1972). Metabolism of [C-14] adenine and derivatives by cerebral tissues, superfused and electrically stimulated. The Biochemical Journal, 126(4), 965–973. Qu, W. M., Huang, Z. L., Xu, X. H., Aritake, K., Eguchi, N., Nambu, F., et al. (2006). Lipocalin-type prostaglandin D synthase produces prostaglandin D-2 involved in regulation of physiological sleep. Proceedings of the National Academy of Sciences of the United States of America, 103(47), 17949–17954. Radulovacki, M., Virus, R. M., Djuricicnedelson, M., & Green, R. D. (1983). Hypnotic effects of deoxycorformycin in rats. Brain Research, 271(2), 392–395. Radulovacki, M., Virus, R. M., Djuricicnedelson, M., & Green, R. D. (1984). Adenosine-analogs and sleep in rats. The Journal of Pharmacology and Experimental Therapeutics, 228(2), 268–274. Radulovacki, M., Virus, R. M., Rapoza, D., & Crane, R. A. (1985). A comparison of the dose-response effects of pyrimidine ribonucleosides and adenosine on sleep in rats. Psychopharmacology, 87(2), 136–140.

PART B. REGULATION OF WAKING AND SLEEPING

REFERENCES

Rai, S., Kumar, S., Alam, M. A., Szymusiak, R., McGinty, D., & Alam, M. N. (2010). A(1) receptor mediated adenosinergic regulation of perifornical-lateral hypothalamic area neurons in freely behaving rats. Neuroscience, 167(1), 40–48. Raingo, J., Khvotchev, M., Liu, P., Darios, F., Li, Y. C., Ramirez, D. M., et al. (2012). VAMP4 directs synaptic vesicles to a pool that selectively maintains asynchronous neurotransmission. Nature Neuroscience, 15(5), 738–745. Roberts, L. J., 2nd, Sweetman, B. J., Lewis, R. A., Austen, K. F., & Oates, J. A. (1980). Increased production of prostaglandin D2 in patients with systemic mastocytosis. The New England Journal of Medicine, 303(24), 1400–1404. Rosin, D. L., Robeva, A., Woodard, R. L., Guyenet, P. G., & Linden, J. (1998). Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system. The Journal of Comparative Neurology, 401(2), 163–186. Roth, T. (2007). Insomnia: definition, prevalence, etiology, and consequences. Journal of Clinical Sleep Medicine, 3(5 Suppl), S7–S10. Russo, S. J., & Nestler, E. J. (2013). The brain reward circuitry in mood disorders. Nature Reviews Neuroscience, 14(9), 609–625. Salvatore, C. A., Jacobson, M. A., Taylor, H. E., Linden, J., & Johnson, R. G. (1993). Molecular cloning and characterization of the human A3 adenosine receptor. Proceedings of the National Academy of Sciences of the United States of America, 90(21), 10365–10369. Saper, C. B., Scammell, T. E., & Lu, J. (2005). Hypothalamic regulation of sleep and circadian rhythms. Nature, 437(7063), 1257–1263. Satoh, S., Matsumura, H., & Hayaishi, O. (1998). Involvement of adenosine A(2A) receptor in sleep promotion. European Journal of Pharmacology, 351(2), 155–162. Satoh, S., Matsumura, H., Koike, N., Tokunaga, Y., Maeda, T., & Hayaishi, O. (1999). Region-dependent difference in the sleeppromoting potency of an adenosine A2A receptor agonist. The European Journal of Neuroscience, 11(5), 1587–1597. Satoh, S., Matsumura, H., Suzuki, F., & Hayaishi, O. (1996). Promotion of sleep mediated by the A2a-adenosine receptor and possible involvement of this receptor in the sleep induced by prostaglandin D2 in rats. Proceedings of the National Academy of Sciences of the United States of America, 93(12), 5980–5984. Scammell, T. E., Gerashchenko, D. Y., Mochizuki, T., McCarthy, M. T., Estabrooke, I. V., Sears, C. A., et al. (2001). An adenosine A2a agonist increases sleep and induces Fos in ventrolateral preoptic neurons. Neuroscience, 107(4), 653–663. Scharbarg, E., Daenens, M., Lemaitre, F., Geoffroy, H., GuilleCollignon, M., Gallopin, T., et al. (2016). Astrocyte-derived adenosine is central to the hypnogenic effect of glucose. Scientific Reports, 6, 19107. Scharf, M. T., Naidoo, N., Zimmerman, J. E., & Pack, A. I. (2008). The energy hypothesis of sleep revisited. Progress in Neurobiology, 86(3), 264–280. Schrader, J. (1983). Metabolism of adenosine and sites of production in the heart. In R. Berne, T. Rall, & R. Rubio (Eds.), Vol. 2. Regulatory function of adenosine (pp. 133–156). US: Springer. Schultz, W., Carelli, R. M., & Wightman, R. M. (2015). Phasic dopamine signals: from subjective reward value to formal economic utility. Current Opinion in Behavioral Sciences, 5, 147–154. Seow, L. S. E., Abdin, E., Chang, S., Chong, S. A., & Subramaniam, M. (2018). Identifying the best sleep measure to screen clinical insomnia in a psychiatric population. Sleep Medicine, 41, 86–93. Sherin, J. E., Elmquist, J. K., Torrealba, F., & Saper, C. B. (1998). Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. The Journal of Neuroscience, 18(12), 4705–4721. Sherin, J. E., Shiromani, P. J., McCarley, R. W., & Saper, C. B. (1996). Activation of ventrolateral preoptic neurons during sleep. Science, 271(5246), 216–219.

135

Shneyvays, V., Zinman, T., & Shainberg, A. (2004). Analysis of calcium responses mediated by the A3 adenosine receptor in cultured newborn rat cardiac myocytes. Cell Calcium, 36(5), 387–396. Sitkovsky, M. V., Lukashev, D., Apasov, S., Kojima, H., Koshiba, M., Caldwell, C., et al. (2004). Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annual Review of Immunology, 22, 657–682. Stiasny-Kolster, K., Clever, S. C., Moller, J. C., Oertel, W. H., & Mayer, G. (2007). Olfactory dysfunction in patients with narcolepsy with and without REM sleep behaviour disorder. Brain, 130(Pt 2), 442–449. Strecker, R. E., Morairty, S., Thakkar, M. M., Porkka-Heiskanen, T., Basheer, R., Dauphin, L. J., et al. (2000). Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state. Behavioural Brain Research, 115(2), 183–204. Svenningsson, P., Fourreau, L., Bloch, B., Fredholm, B. B., Gonon, F., & Le Moine, C. (1999). Opposite tonic modulation of dopamine and adenosine on c-fos gene expression in striatopallidal neurons. Neuroscience, 89(3), 827–837. Tellez, L. A., Perez, I. O., Simon, S. A., & Gutierrez, R. (2012). Transitions between sleep and feeding states in rat ventral striatum neurons. Journal of Neurophysiology, 108(6), 1739–1751. Thakkar, M. M., Engemann, S. C., Walsh, K. M., & Sahota, P. K. (2008). Adenosine and the homeostatic control of sleep: effects of A1 receptor blockade in the perifornical lateral hypothalamus on sleep–wakefulness. Neuroscience, 153(4), 875–880. Thakkar, M. M., Winston, S., & McCarley, R. W. (2002). Orexin neurons of the hypothalamus express adenosine Al receptors. Brain Research, 944(1–2), 190–194. Ticho, S. R., & Radulovacki, M. (1991). Role of adenosine in sleep and temperature regulation in the preoptic area of rats. Pharmacology Biochemistry and Behavior, 40(1), 33–40. Tobler, I., & Scherschlicht, R. (1990). Sleep and eeg slow-wave activity in the domestic cat—effect of sleep-deprivation. Behavioural Brain Research, 37(2), 109–118. Tracey, W. R., Magee, W., Masamune, H., Oleynek, J. J., & Hill, R. J. (1998). Selective activation of adenosine A3 receptors with N6-(3chlorobenzyl)-5’-N-methylcarboxamidoadenosine (CB-MECA) provides cardioprotection via KATP channel activation. Cardiovascular Research, 40(1), 138–145. Urade, Y., Eguchi, N., Qu, W. M., Sakata, M., Huang, Z. L., Chen, J. F., et al. (2003). Sleep regulation in adenosine A2A receptor-deficient mice. Neurology, 61(11 Suppl. 6), S94–S96. Vanwylen, D. G. L., Park, T. S., Rubio, R., & Berne, R. M. (1986). Increases in cerebral interstitial fluid adenosine concentration during hypoxia, local potassium infusion, and ischemia. Journal of Cerebral Blood Flow and Metabolism, 6(5), 522–528. Varin, C., Rancillac, A., Geoffroy, H., Arthaud, S., Fort, P., & Gallopin, T. (2015). Glucose induces slow-wave sleep by exciting the sleeppromoting neurons in the ventrolateral preoptic nucleus: a new link between sleep and metabolism. The Journal of Neuroscience, 35(27), 9900–9911. Villablanca, J. (1972). Permanent reduction in sleep after removal of cerebral-cortex and striatum in cats. Brain Research, 36(2), 463–468. Virus, R. M., Ticho, S., Pilditch, M., & Radulovacki, M. (1990). A comparison of the effects of caffeine, 8-cyclopentyltheophylline, and alloxazine on sleep in rats. Possible roles of central nervous system adenosine receptors. Neuropsychopharmacology, 3(4), 243–249. Volkow, N. D., & Morales, M. (2015). The brain on drugs: from reward to addiction. Cell, 162(4), 712–725. Wang, Y. Q., Tu, Z. C., Xu, X. Y., Li, R., Qu, W. M., Urade, Y., et al. (2012). Acute administration of fluoxetine normalizes rapid eye movement sleep abnormality, but not depressive behaviors in olfactory bulbectomized rats. Journal of Neurochemistry, 120(2), 314–324.

PART B. REGULATION OF WAKING AND SLEEPING

136

8. ADENOSINERGIC CONTROL OF SLEEP/WAKE BEHAVIOR

Wise, R. A. (2004). Dopamine, learning and motivation. Nature Reviews Neuroscience, 5(6), 483–494. Wu, W. P., Hao, J. X., Halldner, L., Lovdahl, C., DeLander, G. E., Wiesenfeld-Hallin, Z., et al. (2005). Increased nociceptive response in mice lacking the adenosine A1 receptor. Pain, 113(3), 395–404. Xu, K., Bastia, E., & Schwarzschild, M. (2005). Therapeutic potential of adenosine A(2A) receptor antagonists in parkinson’s disease. Pharmacology & Therapeutics, 105(3), 267–310. Yang, C., Franciosi, S., & Brown, R. E. (2013). Adenosine inhibits the excitatory synaptic inputs to basal forebrain cholinergic, GABAergic and parvalbumin neurons in mice. Frontiers in Neurology, 4, 77. Yegutkin, G. G. (2008). Nucleotide- and nucleoside-converting ectoenzymes: important modulators of purinergic signalling cascade. Biochimica et Biophysica Acta, 1783(5), 673–694. Yuan, X. S., Wang, L., Dong, H., Qu, W. M., Yang, S. R., Cherasse, Y., et al. (2017). Striatal adenosine A(2A) receptor neurons control active-period sleep via parvalbumin neurons in external globus pallidus. eLife, 6, e29055. Zablocki, J. A., Wu, L., Shryock, J., & Belardinelli, L. (2004). Partial A(1) adenosine receptor agonists from a molecular perspective and their potential use as chronic ventricular rate control agents during atrial fibrillation (AF). Current Topics in Medicinal Chemistry, 4(8), 839–854.

Zaborszky, L., Pang, K., Somogyi, J., Nadasdy, Z., & Kallo, I. (1999). The basal forebrain corticopetal system revisited. Annals of the New York Academy of Sciences, 877, 339–367. Zhang, B. J., Huang, Z. L., Chen, J. F., Urade, Y., & Qu, W. M. (2017). Adenosine A(2A) receptor deficiency attenuates the somnogenic effect of prostaglandin D-2 in mice. Acta Pharmacologica Sinica, 38(4), 469–476. Zhang, J. P., Xu, Q., Yuan, X. S., Cherasse, Y., Schiffmann, S. N., de Kerchove d’Exaerde, A., et al. (2013). Projections of nucleus accumbens adenosine A(2A) receptor neurons in the mouse brain and their implications in mediating sleep-wake regulation. Frontiers in Neuroanatomy, 7, 43. Zimmermann, H. (2000). Extracellular metabolism of ATP and other nucleotides. Naunyn-Schmiedeberg’s Archives of Pharmacology, 362(4–5), 299–309. Zimmermann, H. (2006). Ectonucleotidases in the nervous system. Novartis Foundation Symposium, 276, 113–128. discussion 128–130, 233–237, 275–281.

PART B. REGULATION OF WAKING AND SLEEPING