pp 1-23 | Cite as

Adenosine and Sleep

  • Michael LazarusEmail author
  • Jiang-Fan Chen
  • Zhi-Li Huang
  • Yoshihiro Urade
  • Bertil B. Fredholm
Part of the Handbook of Experimental Pharmacology book series


The classic endogenous somnogen adenosine promotes sleep via A1 and A2A receptors. In this chapter, we present an overview of the current knowledge regarding the regulation of adenosine levels, adenosine receptors, and available pharmacologic and genetic tools to manipulate the adenosine system. This is followed by a summary of current knowledge of the role of adenosine and its receptors in the regulation of sleep and wakefulness. Despite strong data implicating numerous brain areas, including the basal forebrain, the tuberomammillary nucleus, the lateral hypothalamus, and the nucleus accumbens, in the adenosinergic control of sleep, the complete neural circuitry in the brain involved in the sleep-promoting effects of adenosine remains unclear. Moreover, the popular demand for natural sleep aids has led to a search for natural compounds that can promote sleep via adenosine receptor activation. Finally, we discuss the effects of caffeine in man and the possible use of more selective adenosine receptor drugs for the treatment of sleep disorders.


Adeno-associated virus Astrocytes CGS 21680 DREADD Istradefylline Modafinil Non-rapid eye movement sleep Optogenetics Prostaglandin D2 Slow-wave sleep 


  1. Adler CH, Thorpy MJ (2005) Sleep issues in Parkinson’s disease. Neurology 64:S12–S20PubMedCrossRefGoogle Scholar
  2. Alam MN, Szymusiak R, Gong H, King J, McGinty D (1999) Adenosinergic modulation of rat basal forebrain neurons during sleep and waking: neuronal recording with microdialysis. J Physiol 521:679–690. doi: 10.1111/j.1469-7793.1999.00679.x PubMedPubMedCentralCrossRefGoogle Scholar
  3. Alsene K, Deckert J, Sand P, de Wit H (2003) Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 28:1694–1702. doi: 10.1038/sj.npp.1300232 PubMedCrossRefGoogle Scholar
  4. Aoyama S, Kase H, Borrelli E (2000) Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist. J Neurosci 20:5848–5852PubMedGoogle Scholar
  5. Arnaud MJ (2011) Pharmacokinetics and metabolism of natural methylxanthines in animal and man. Handb Exp Pharmacol 200:33–91. doi: 10.1007/978-3-642-13443-2_3 CrossRefGoogle Scholar
  6. Atack JR et al (2014) JNJ-40255293, a novel adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson’s disease. ACS Chem Neurosci 5:1005–1019. doi: 10.1021/cn5001606 PubMedCrossRefGoogle Scholar
  7. Augusto E et al (2013) Ecto-5′-nucleotidase (CD73)-mediated formation of adenosine is critical for the striatal adenosine A2A receptor functions. J Neurosci 33:11390–11399. doi: 10.1523/jneurosci.5817-12.2013 PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bachmann V et al (2012) Functional ADA polymorphism increases sleep depth and reduces vigilant attention in humans. Cereb Cortex 22:962–970. doi: 10.1093/cercor/bhr173 PubMedCrossRefGoogle Scholar
  9. Ballarin M, Fredholm BB, Ambrosio S, Mahy N (1991) Extracellular levels of adenosine and its metabolites in the striatum of awake rats: inhibition of uptake and metabolism. Acta Physiol Scand 142:97–103. doi: 10.1111/j.1748-1716.1991.tb09133.x PubMedCrossRefGoogle Scholar
  10. Basheer R, Strecker RE, Thakkar MM, McCarley RW (2004) Adenosine and sleep–wake regulation. Prog Neurobiol 73:379–396. doi: 10.1016/j.pneurobio.2004.06.004 PubMedCrossRefGoogle Scholar
  11. Bastia E, Xu YH, Scibelli AC, Day YJ, Linden J, Chen JF, Schwarzschild MA (2005) A crucial role for forebrain adenosine A(2A) receptors in amphetamine sensitization. Neuropsychopharmacology 30:891–900. doi: 10.1038/sj.npp.1300630 PubMedCrossRefGoogle Scholar
  12. Benington JH, Kodali SK, Heller HC (1995) Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation. Brain Res 692:79–85. doi: 10.1016/0006-8993(95)00590-m PubMedCrossRefGoogle Scholar
  13. Benveniste H, Hansen AJ, Ottosen NS (1989) Determination of brain interstitial concentrations by microdialysis. J Neurochem 52:1741–1750. doi: 10.1111/j.1471-4159.1989.tb07252.x PubMedCrossRefGoogle Scholar
  14. Bodenmann S, Hohoff C, Freitag C, Deckert J, Rétey JV, Bachmann V, Landolt HP (2012) Polymorphisms of ADORA2A modulate psychomotor vigilance and the effects of caffeine on neurobehavioural performance and sleep EEG after sleep deprivation. Br J Pharmacol 165:1904–1913. doi: 10.1111/j.1476-5381.2011.01689.x PubMedPubMedCentralCrossRefGoogle Scholar
  15. Bodin P, Burnstock G (1998) Increased release of ATP from endothelial cells during acute inflammation. Inflamm Res 47:351–354PubMedCrossRefGoogle Scholar
  16. Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K (2005) Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci 8:1263–1268. doi: 10.1038/nn1525 PubMedCrossRefGoogle Scholar
  17. Burke TM et al (2015) Effects of caffeine on the human circadian clock in vivo and in vitro. Sci Transl Med 7:146–305. doi: 10.1126/scitranslmed.aac5125 CrossRefGoogle Scholar
  18. Burnstock G, Verkhratsky A (2012) Mechanisms of ATP release and inactivation. In: Purinergic signalling and the nervous system. Springer, Berlin Heidelberg, pp 79–118. doi: 10.1007/978-3-642-28863-0_4 CrossRefGoogle Scholar
  19. Byrne EM, Johnson J, McRae AF, Nyholt DR, Medland SE, Gehrman PR, Heath AC, Madden PA, Montgomery GW, Chenevix-Trench G, Martin NG (2012) A genome-wide association study of caffeine-related sleep disturbance: confirmation of a role for a common variant in the adenosine receptor. Sleep 35:967–975. doi: 10.5665/sleep.1962 PubMedPubMedCentralCrossRefGoogle Scholar
  20. Chait LD (1992) Factors influencing the subjective response to caffeine. Behav Pharmacol 3:219–228PubMedGoogle Scholar
  21. Chekeni FB et al (2010) Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature 467:863–867. doi: 10.1038/nature09413 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  22. Chen J-F et al (2001) The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice. Proc Natl Acad Sci U S A 98:1970–1975. doi: 10.1073/pnas.98.4.1970 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  23. Chen Y et al (2006) ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314:1792–1795. doi: 10.1126/science.1132559 ADSPubMedCrossRefGoogle Scholar
  24. Chen C et al (2015) Paeoniflorin promotes non-rapid eye movement sleep via adenosine A1 receptors. J Pharmacol Exp Ther 356:64–73. doi: 10.1124/jpet.115.227819 PubMedCrossRefGoogle Scholar
  25. Clark I, Landolt HP (2017) Coffee, caffeine, and sleep: a systematic review of epidemiological studies and randomized controlled trials. Sleep Med Rev 31:70–78. doi: 10.1016/j.smrv.2016.01.006 PubMedCrossRefGoogle Scholar
  26. Dale N, Frenguelli BG (2012) Measurement of purine release with microelectrode biosensors. Purinergic Signal 8:27–40. doi: 10.1007/s11302-011-9273-4 PubMedCrossRefGoogle Scholar
  27. Dale RC et al (2004) Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity. Brain 127:21–33. doi: 10.1093/brain/awh008 PubMedCrossRefGoogle Scholar
  28. Deisseroth K (2014) Circuit dynamics of adaptive and maladaptive behaviour. Nature 505:309–317. doi: 10.1038/nature12982 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  29. Elliott MR et al (2009) Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461:282–286. doi: 10.1038/nature08296 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  30. Eltzschig HK (2009) Adenosine: an old drug newly discovered. Anesthesiology 111:904–915. doi: 10.1097/ALN.0b013e3181b060f2 PubMedPubMedCentralCrossRefGoogle Scholar
  31. Ena SL, De Backer J-F, Schiffmann SN, de Kerchove d’Exaerde A (2013) FACS array profiling identifies Ecto-5′ nucleotidase as a striatopallidal neuron-specific Gene involved in striatal-dependent learning. J Neurosci 33:8794–8809. doi: 10.1523/jneurosci.2989-12.2013 PubMedCrossRefGoogle Scholar
  32. Evans SM, Griffiths RR (1991) Dose-related caffeine discrimination in normal volunteers: individual differences in subjective effects and self-reported cues. Behav Pharmacol 2:345–356PubMedGoogle Scholar
  33. Faigle M, Seessle J, Zug S, El Kasmi KC, Eltzschig HK (2008) ATP release from vascular endothelia occurs across Cx43 hemichannels and is attenuated during hypoxia. PLoS One 3:e2801. doi: 10.1371/journal.pone.0002801 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  34. Farrell MS et al (2013) A Galphas DREADD mouse for selective modulation of cAMP production in striatopallidal neurons. Neuropsychopharmacology 38:854–862. doi: 10.1038/npp.2012.251 PubMedPubMedCentralCrossRefGoogle Scholar
  35. Feldberg W, Sherwood SL (1954) Injections of drugs into the lateral ventricle of the cat. J Physiol 123:148–167PubMedPubMedCentralCrossRefGoogle Scholar
  36. Fields RD, Stevens B (2000) ATP: an extracellular signaling molecule between neurons and glia. Trends Neurosci 23:625–633. doi: 10.1016/S0166-2236(00)01674-X PubMedCrossRefGoogle Scholar
  37. Fredholm BB (2007) Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 14:1315–1323PubMedCrossRefGoogle Scholar
  38. Fredholm BB (2014) Adenosine – a physiological or pathophysiological agent? J Mol Med 92:201–206. doi: 10.1007/s00109-013-1101-6 PubMedCrossRefGoogle Scholar
  39. Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133PubMedGoogle Scholar
  40. Fredholm BB, Chen J-F, Cunha RA, Svenningsson P, Vaugeois J-M (2005a) Adenosine and brain function. Int Rev Neurobiol 63:191–270. doi: 10.1016/S0074-7742(05)63007-3 PubMedCrossRefGoogle Scholar
  41. Fredholm BB, Chen JF, Masino SA, Vaugeois JM (2005b) Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs. Annu Rev Pharmacol Toxicol 45:385–412. doi: 10.1146/annurev.pharmtox.45.120403.095731 PubMedCrossRefGoogle Scholar
  42. Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Muller CE (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors – an update. Pharmacol Rev 63:1–34. doi: 10.1124/pr.110.003285 PubMedPubMedCentralCrossRefGoogle Scholar
  43. Fuller PM, Yamanaka A, Lazarus M (2015) How genetically engineered systems are helping to define, and in some cases redefine, the neurobiological basis of sleep and wake. Temperature 2:406–417. doi: 10.1080/23328940.2015.1075095 CrossRefGoogle Scholar
  44. Fuxe K et al (2003) Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson’s disease. Neurology 61:S19–S23PubMedCrossRefGoogle Scholar
  45. Gallopin T et al (2005) The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus. Neuroscience 134:1377–1390PubMedCrossRefGoogle Scholar
  46. Garcia-Garcia F, Acosta-Pena E, Venebra-Munoz A, Murillo-Rodriguez E (2009) Sleep-inducing factors. CNS Neurol Disord Drug Targets 8:235–244PubMedCrossRefGoogle Scholar
  47. Geiger JD, Fyda DM (1991) Adenosine transport in nervous system tissues. In: Stone TW (ed) Adenosine in the nervous system. Academic Press, London, pp 1–23. doi: 10.1016/B978-0-12-672640-4.50007-8 Google Scholar
  48. Giguere PM, Kroeze WK, Roth BL (2014) Tuning up the right signal: chemical and genetic approaches to study GPCR functions. Curr Opin Cell Biol 27:51–55. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  49. Giros B, Caron MG (1993) Molecular characterization of the dopamine transporter. Trends Pharmacol Sci 14:43–49. doi: 10.1016/0165-6147(93)90029-J PubMedCrossRefGoogle Scholar
  50. Goodman A, Barker R (2010) How vital is sleep in Huntington’s disease? J Neurol 257:882–897. doi: 10.1007/s00415-010-5517-4 PubMedCrossRefGoogle Scholar
  51. Guthrie PB, Knappenberger J, Segal M, Bennett MVL, Charles AC, Kater SB (1999) ATP released from astrocytes mediates glial calcium waves. J Neurosci 19:520–528PubMedGoogle Scholar
  52. Halassa MM, Fellin T, Haydon PG (2007) The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med 13:54–63. doi: 10.1016/j.molmed.2006.12.005 PubMedCrossRefGoogle Scholar
  53. Halassa MM et al (2009) Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron 61:213–219PubMedPubMedCentralCrossRefGoogle Scholar
  54. Hauser RA et al (2011) Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol 10:221–229. doi: 10.1016/s1474-4422(11)70012-6 PubMedCrossRefGoogle Scholar
  55. Hogl B et al (2002) Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 25:905–909PubMedCrossRefGoogle Scholar
  56. Hollopeter G et al (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409:202–207. doi: 10.1038/35051599 ADSPubMedCrossRefGoogle Scholar
  57. Holst SC, Landolt H-P (2015) Sleep homeostasis, metabolism, and adenosine. Curr Sleep Med Rep 1:27–37. doi: 10.1007/s40675-014-0007-3 CrossRefGoogle Scholar
  58. Hong Z-Y, Huang Z-L, Qu W-M, Eguchi N, Urade Y, Hayaishi O (2005) An adenosine A2A receptor agonist induces sleep by increasing GABA release in the tuberomammillary nucleus to inhibit histaminergic systems in rats. J Neurochem 92:1542–1549. doi: 10.1111/j.1471-4159.2004.02991.x PubMedCrossRefGoogle Scholar
  59. Hu Z et al (2013) Cordycepin increases nonrapid eye movement sleep via adenosine receptors in rats. Evid Based Complement Alternat Med 2013:8. doi: 10.1155/2013/840134 Google Scholar
  60. Huang Z-L et al (2005) Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci 8:858–859. PubMedCrossRefGoogle Scholar
  61. Huang Z-L, Urade Y, Hayaishi O (2007) Prostaglandins and adenosine in the regulation of sleep and wakefulness. Curr Opin Pharmacol 7:33–38. doi: 10.1016/j.coph.2006.09.004 PubMedCrossRefGoogle Scholar
  62. Huang ZL, Urade Y, Hayaishi O (2011) The role of adenosine in the regulation of sleep. Curr Top Med Chem 11:1047–1057PubMedCrossRefGoogle Scholar
  63. Huitron-Resendiz S et al (2005) Urotensin II modulates rapid eye movement sleep through activation of brainstem cholinergic neurons. J Neurosci 25:5465–5474. doi: 10.1523/jneurosci.4501-04.2005 PubMedCrossRefGoogle Scholar
  64. Inoué S, Honda K, Komoda Y (1995) Sleep as neuronal detoxification and restitution. Behav Brain Res 69:91–96. doi: 10.1016/0166-4328(95)00014-k PubMedCrossRefGoogle Scholar
  65. Ishimori K (1909) True cause of sleep: a hypnogenic substance as evidenced in the brain of sleep-deprived animals. Tokyo Igakkai Zasshi 23:429–457Google Scholar
  66. Jenner P, Mori A, Hauser R, Morelli M, Fredholm BB, Chen JF (2009) Adenosine, adenosine A2A antagonists, and Parkinson’s disease. Parkinsonism Relat Disord 15:406–413. doi: 10.1016/j.parkreldis.2008.12.006 PubMedCrossRefGoogle Scholar
  67. Kalinchuk AV et al (2003) Local energy depletion in the basal forebrain increases sleep. Eur J Neurosci 17:863–869. doi: 10.1046/j.1460-9568.2003.02532.x PubMedCrossRefGoogle Scholar
  68. Krueger JM, Majde JA (2003) Humoral links between sleep and the immune system: research issues. Ann N Y Acad Sci 992:9–20ADSPubMedCrossRefGoogle Scholar
  69. Krueger JM, Walter J, Dinarello CA, Wolff SM, Chedid L (1984) Sleep-promoting effects of endogenous pyrogen (interleukin-1). Am J Phys 246:R994–R999Google Scholar
  70. Krueger JM, Obal F Jr, Fang J, Kubota T, Taishi P (2001) The role of cytokines in physiological sleep regulation. Ann N Y Acad Sci 933:211–221ADSPubMedCrossRefGoogle Scholar
  71. Krueger JM, Clinton JM, Winters BD, Zielinski MR, Taishi P, Jewett KA, Davis CJ (2011) Involvement of cytokines in slow wave sleep. Prog Brain Res 193:39–47. doi: 10.1016/b978-0-444-53839-0.00003-x PubMedPubMedCentralCrossRefGoogle Scholar
  72. Kubota K (1989) Kuniomi Ishimori and the first discovery of sleep-inducing substances in the brain. Neurosci Res 6:497–518PubMedCrossRefGoogle Scholar
  73. Lazarus M, Yoshida K, Coppari R, Bass CE, Mochizuki T, Lowell BB, Saper CB (2007) EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses. Nat Neurosci 10:1131–1133. PubMedCrossRefGoogle Scholar
  74. Lazarus M et al (2011) Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens. J Neurosci 31:10067–10075. doi: 10.1523/jneurosci.6730-10.2011 PubMedPubMedCentralCrossRefGoogle Scholar
  75. Lazarus M, Huang Z-L, Lu J, Urade Y, Chen J-F (2012) How do the basal ganglia regulate sleep–wake behavior? Trends Neurosci 35:723–732. doi: 10.1016/j.tins.2012.07.001 PubMedCrossRefGoogle Scholar
  76. Lazarus M, Chen J-F, Urade Y, Huang Z-L (2013) Role of the basal ganglia in the control of sleep and wakefulness. Curr Opin Neurobiol 23:780–785. doi: 10.1016/j.conb.2013.02.001 PubMedPubMedCentralCrossRefGoogle Scholar
  77. Legendre R, Pieron H (1913) Recherches sur le besoin de sommeil consécutif à une veille prolongée. Z Allegem Physiol 14:235–262Google Scholar
  78. Li Y et al (2015) Optogenetic activation of adenosine a receptor signaling in the dorsomedial striatopallidal neurons suppresses goal-directed behavior. Neuropsychopharmacology 41:1003–1013. doi: 10.1038/npp.2015.227 PubMedPubMedCentralCrossRefGoogle Scholar
  79. Linden J (2006) Purinergic chemotaxis. Science 314:1689–1690. doi: 10.1126/science.1137190 PubMedCrossRefGoogle Scholar
  80. Lovatt D et al (2012) Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity. Proc Natl Acad Sci U S A 109:6265–6270. doi: 10.1073/pnas.1120997109 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  81. MacDonald PE, Braun M, Galvanovskis J, Rorsman P (2006) Release of small transmitters through kiss-and-run fusion pores in rat pancreatic beta cells. Cell Metab 4:283–290. doi: 10.1016/j.cmet.2006.08.011 PubMedCrossRefGoogle Scholar
  82. Matsuura K, Tomimoto H (2015) Istradefylline is recommended for morning use: a report of 4 cases. Intern Med 54:509–511. doi: 10.2169/internalmedicine.54.3522 PubMedCrossRefGoogle Scholar
  83. Mazzotti DR, Guindalini C, de Souza AAL, Sato JR, Santos-Silva R, Bittencourt LRA, Tufik S (2012) Adenosine deaminase polymorphism affects sleep EEG spectral power in a large epidemiological sample. PLoS One 7:e44154. doi: 10.1371/journal.pone.0044154 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  84. Methippara MM, Kumar S, Alam MN, Szymusiak R, McGinty D (2005) Effects on sleep of microdialysis of adenosine A1 and A2a receptor analogs into the lateral preoptic area of rats. Am J Physiol Regul Integr Comp Physiol 289:R1715–R1723. doi: 10.1152/ajpregu.00247.2005 PubMedCrossRefGoogle Scholar
  85. Minzenberg MJ, Carter CS (2007) Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 33:1477–1502PubMedCrossRefGoogle Scholar
  86. Monoi N et al (2016) Japanese sake yeast supplementation improves the quality of sleep: a double-blind randomised controlled clinical trial. J Sleep Res 25:116–123. doi: 10.1111/jsr.12336 PubMedCrossRefGoogle Scholar
  87. Müller CE, Jacobson KA (2011) Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta 1808:1290–1308. doi: 10.1016/j.bbamem.2010.12.017 PubMedCrossRefGoogle Scholar
  88. Mullington J, Korth C, Hermann DM, Orth A, Galanos C, Holsboer F, Pollmächer T (2000) Dose-dependent effects of endotoxin on human sleep. Am J Physiol Regul Integr Comp Physiol 278:R947–R955PubMedGoogle Scholar
  89. Mullington JM, Hinze-Selch D, Pollmacher T (2001) Mediators of inflammation and their interaction with sleep: relevance for chronic fatigue syndrome and related conditions. Ann N Y Acad Sci 933:201–210ADSPubMedCrossRefGoogle Scholar
  90. Nakamura Y, Midorikawa T, Monoi N, Kimura E, Murata-Matsuno A, Sano T, Oka K, Sugafuji T, Uchiyama A, Murakoshi M, Sugiyama K, Nishino H, Urade Y (2016) Oral administration of Japanese sake yeast (Saccharomyces cerevisiae sake) promotes non-rapid eye movement sleep in mice via adenosine A2A receptors. J Sleep Res 25:746–753. doi: 10.1111/jsr.12434 PubMedCrossRefGoogle Scholar
  91. Obeso JA et al (2000) Pathophysiologic basis of surgery for Parkinson’s disease. Neurology 55:S7–12PubMedCrossRefGoogle Scholar
  92. Ochiishi T et al (1999a) Cellular localization of adenosine A1 receptors in rat forebrain: immunohistochemical analysis using adenosine A1 receptor-specific monoclonal antibody. J Comp Neurol 411:301–316PubMedCrossRefGoogle Scholar
  93. Ochiishi T et al (1999b) High level of adenosine A1 receptor-like immunoreactivity in the CA2/CA3a region of the adult rat hippocampus. Neuroscience 93:955–967PubMedCrossRefGoogle Scholar
  94. Oishi Y, Huang Z-L, Fredholm BB, Urade Y, Hayaishi O (2008) Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep. Proc Natl Acad Sci U S A 105:19992–19997. doi: 10.1073/pnas.0810926105 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  95. Oishi Y, Yoshida K, Scammell TE, Urade Y, Lazarus M, Saper CB (2015) The roles of prostaglandin E2 and D2 in lipopolysaccharide-mediated changes in sleep. Brain Behav Immun 47:172–177. doi: 10.1016/j.bbi.2014.11.019 PubMedCrossRefGoogle Scholar
  96. Pascual O et al (2005) Astrocytic purinergic signaling coordinates synaptic networks. Science 310:113–116. doi: 10.1126/science.1116916 ADSPubMedCrossRefGoogle Scholar
  97. Porkka-Heiskanen T, Strecker RE, Thakkar M, Bjorkum AA, Greene RW, McCarley RW (1997) Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 276:1265–1268PubMedPubMedCentralCrossRefGoogle Scholar
  98. Porkka-Heiskanen T, Strecker RE, McCarley RW (2000) Brain site-specificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study. Neuroscience 99:507–517. doi: 10.1016/S0306-4522(00)00220-7 PubMedCrossRefGoogle Scholar
  99. Prediger RDS, Batista LC, Takahashi RN (2005) Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats: involvement of adenosine A1 and A2A receptors. Neurobiol Aging 26:957–964. doi: 10.1016/j.neurobiolaging.2004.08.012 PubMedCrossRefGoogle Scholar
  100. Qiu M-H, Vetrivelan R, Fuller PM, Lu J (2010) Basal ganglia control of sleep–wake behavior and cortical activation. Eur J Neurosci 31:499–507. doi: 10.1111/j.1460-9568.2009.07062.x PubMedPubMedCentralCrossRefGoogle Scholar
  101. Qu W-M et al (2006) Lipocalin-type prostaglandin D synthase produces prostaglandin D2 involved in regulation of physiological sleep. Proc Natl Acad Sci U S A 103:17949–17954ADSPubMedPubMedCentralCrossRefGoogle Scholar
  102. Qu W-M, Huang Z-L, Xu X-H, Matsumoto N, Urade Y (2008) Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil. J Neurosci 28:8462–8469. doi: 10.1523/jneurosci.1819-08.2008 PubMedCrossRefGoogle Scholar
  103. Qu W-M, Xu X-H, Yan M-M, Wang Y-Q, Urade Y, Huang Z-L (2010) Essential role of dopamine D2 receptor in the maintenance of wakefulness, but not in homeostatic regulation of sleep, in mice. J Neurosci 30:4382–4389. doi: 10.1523/jneurosci.4936-09.2010 PubMedCrossRefGoogle Scholar
  104. Radulovacki M, Virus RM, Djuricic-Nedelson M, Green RD (1983) Hypnotic effects of deoxycorformycin in rats. Brain Res 271:392–395PubMedCrossRefGoogle Scholar
  105. Reppert SM, Weaver DR, Stehle JH, Rivkees SA (1991) Molecular cloning and characterization of a rat A1-adenosine receptor that is widely expressed in brain and spinal cord. Mol Endocrinol 5:1037–1048. doi: 10.1210/mend-5-8-1037 PubMedCrossRefGoogle Scholar
  106. Resta R, Yamashita Y, Thompson LF (1998) Ecto-enzyme and signaling functions of lymphocyte CD73. Immunol Rev 161:95–109PubMedCrossRefGoogle Scholar
  107. Rétey JV et al (2005) A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proc Natl Acad Sci U S A 102:15676–15681. doi: 10.1073/pnas.0505414102 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  108. Rétey JV, Adam M, Khatami R, Luhmann UF, Jung HH, Berger W, Landolt HP (2007) A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. Clin Pharmacol Ther 81:692–698PubMedCrossRefGoogle Scholar
  109. Rivkees SA, Price SL, Zhou FC (1995) Immunohistochemical detection of A1 adenosine receptors in rat brain with emphasis on localization in the hippocampal formation, cerebral cortex, cerebellum, and basal ganglia. Brain Res 677:193–203PubMedCrossRefGoogle Scholar
  110. Rosenbaum E (1892) Warum müssen wir schlafen?: eine neue Theorie des Schlafes. August Hirschwald, BerlinGoogle Scholar
  111. Rosin DL, Robeva A, Woodard RL, Guyenet PG, Linden J (1998) Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system. J Comp Neurol 401:163–186PubMedCrossRefGoogle Scholar
  112. Saper CB, Scammell TE, Lu J (2005) Hypothalamic regulation of sleep and circadian rhythms. Nature 437:1257–1263ADSPubMedCrossRefGoogle Scholar
  113. Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE (2010) Sleep state switching. Neuron 68:1023–1042PubMedPubMedCentralCrossRefGoogle Scholar
  114. 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. Proc Natl Acad Sci U S A 93:5980–5984ADSPubMedPubMedCentralCrossRefGoogle Scholar
  115. Satoh S, Matsumura H, Koike N, Tokunaga Y, Maeda T, Hayaishi O (1999) Region-dependent difference in the sleep-promoting potency of an adenosine A2A receptor agonist. Eur J Neurosci 11:1587–1597. doi: 10.1046/j.1460-9568.1999.00569.x PubMedCrossRefGoogle Scholar
  116. Scammell TE et al (2001) An adenosine A2a agonist increases sleep and induces Fos in ventrolateral preoptic neurons. Neuroscience 107:653–663. doi: 10.1016/s0306-4522(01)00383-9 PubMedCrossRefGoogle Scholar
  117. Scammell TE, Arrigoni E, Thompson MA, Ronan PJ, Saper CB, Greene RW (2003) Focal deletion of the adenosine A1 receptor in adult mice using an adeno-associated viral vector. J Neurosci 23:5762–5770PubMedGoogle Scholar
  118. Schrader J (1983) Metabolism of adenosine and sites of production in the heart. In: Berne R, Rall T, Rubio R (eds) Regulatory function of adenosine, Developments in pharmacology, vol 2. Springer US, New York, pp 133–156. doi: 10.1007/978-1-4613-3909-0_9 CrossRefGoogle Scholar
  119. Shen HY et al (2008) A critical role of the adenosine A2A receptor in extrastriatal neurons in modulating psychomotor activity as revealed by opposite phenotypes of striatum and forebrain A2A receptor knock-outs. J Neurosci 28:2970–2975PubMedCrossRefGoogle Scholar
  120. Sherin JE, Shiromani PJ, McCarley RW, Saper CB (1996) Activation of ventrolateral preoptic neurons during sleep. Science 271:216–219ADSPubMedCrossRefGoogle Scholar
  121. Sherin JE, Elmquist JK, Torrealba F, Saper CB (1998) Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci 18:4705–4721PubMedGoogle Scholar
  122. Stiasny-Kolster K, Clever SC, Moller JC, Oertel WH, Mayer G (2007) Olfactory dysfunction in patients with narcolepsy with and without REM sleep behaviour disorder. Brain 130:442–449. doi: 10.1093/brain/awl343 PubMedCrossRefGoogle Scholar
  123. Strecker RE et al (2000) Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state. Behav Brain Res 115:183–204. doi: 10.1016/s0166-4328(00)00258-8 PubMedCrossRefGoogle Scholar
  124. Svenningsson P, Fourreau L, Bloch B, Fredholm BB, Gonon F, Le Moine C (1999) Opposite tonic modulation of dopamine and adenosine on c-fos gene expression in striatopallidal neurons. Neuroscience 89:827–837PubMedCrossRefGoogle Scholar
  125. Thakkar MM, Engemann SC, Walsh KM, Sahota PK (2008) Adenosine and the homeostatic control of sleep: effects of A1 receptor blockade in the perifornical lateral hypothalamus on sleep–wakefulness. Neuroscience 153:875–880. doi: 10.1016/j.neuroscience.2008.01.017 PubMedCrossRefGoogle Scholar
  126. Ueno R, Ishikawa Y, Nakayama T, Hayaishi O (1982) Prostaglandin D2 induces sleep when microinjected into the preoptic area of conscious rats. Biochem Biophys Res Commun 109:576–582. doi: 10.1016/0006-291x(82)91760-0 PubMedCrossRefGoogle Scholar
  127. Urade Y, Hayaishi O (2011) Prostaglandin D2 and sleep/wake regulation. Sleep Med Rev 15:411–418. doi: 10.1016/j.smrv.2011.08.003 PubMedCrossRefGoogle Scholar
  128. Urade Y, Lazarus M (2013) Prostaglandin D2 in the regulation of sleep. In: Shaw PJ, Tafti M, Thorpy MJ (eds) The genetic basis of sleep and sleep disorders. Cambridge University Press, New York, pp 73–83CrossRefGoogle Scholar
  129. Urade Y et al (2003) Sleep regulation in adenosine A2A receptor-deficient mice. Neurology 61:S94–S96PubMedCrossRefGoogle Scholar
  130. Ushikubi F et al (1998) Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 395:281–284ADSPubMedCrossRefGoogle Scholar
  131. van Diepen HC, Lucassen EA, Yasenkov R, Groenen I, Ijzerman AP, Meijer JH, Deboer T (2014) Caffeine increases light responsiveness of the mouse circadian pacemaker. Eur J Neurosci 40:3504–3511. doi: 10.1111/ejn.12715 PubMedCrossRefGoogle Scholar
  132. Virus RM, 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 3:243–249PubMedGoogle Scholar
  133. Wall MJ, Dale N (2013) Neuronal transporter and astrocytic ATP exocytosis underlie activity-dependent adenosine release in the hippocampus. J Physiol 591:3853–3871. doi: 10.1113/jphysiol.2013.253450 PubMedPubMedCentralCrossRefGoogle Scholar
  134. Wang Y-Q et al (2016) Adenosine A2A receptors in the olfactory bulb suppress rapid eye movement sleep in rodents. Brain Struct Funct. doi: 10.1007/s00429-016-1281-2
  135. Wei CJ, Li W, Chen JF (2011) Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies. Biochim Biophys Acta 1808:1358–1379. doi: 10.1016/j.bbamem.2010.12.018 PubMedCrossRefGoogle Scholar
  136. Wetter TC, Collado-Seidel V, Pollmacher T, Yassouridis A, Trenkwalder C (2000) Sleep and periodic leg movement patterns in drug-free patients with Parkinson’s disease and multiple system atrophy. Sleep 23:361–367PubMedCrossRefGoogle Scholar
  137. Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM (2001) Dopaminergic role in stimulant-induced wakefulness. J Neurosci 21:1787–1794PubMedGoogle Scholar
  138. Yamaguchi H, Maruyama T, Urade Y, Nagata S (2014) Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells. Elife 3:e02172. doi: 10.7554/eLife.02172 PubMedPubMedCentralCrossRefGoogle Scholar
  139. Yang C, Franciosi S, Brown RE (2013) Adenosine inhibits the excitatory synaptic inputs to basal forebrain cholinergic, GABAergic and parvalbumin neurons in mice. Front Neurol 4:77. doi: 10.3389/fneur.2013.00077 PubMedPubMedCentralCrossRefGoogle Scholar
  140. Yegutkin GG (2008) Nucleotide- and nucleoside-converting ectoenzymes: important modulators of purinergic signalling cascade. Biochim Biophys Acta 1783:673–694. doi: 10.1016/j.bbamcr.2008.01.024 PubMedCrossRefGoogle Scholar
  141. Yin D et al (2015) Paeoniflorin exerts analgesic and hypnotic effects via adenosine A1 receptors in a mouse neuropathic pain model. Psychopharmacology 233:281–293. doi: 10.1007/s00213-015-4108-6 PubMedCrossRefGoogle Scholar
  142. Yizhar O, Fenno LE, Davidson TJ, Mogri M, Deisseroth K (2011) Optogenetics in neural systems. Neuron 71:9–34. doi: 10.1016/j.neuron.2011.06.004 PubMedCrossRefGoogle Scholar
  143. Yu L et al (2008) Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms. Ann Neurol 63:338–346. doi: 10.1002/ana.21313 PubMedCrossRefGoogle Scholar
  144. Zetterstrom T, Vernet L, Ungerstedt U, Tossman U, Jonzon B, Fredholm BB (1982) Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre. Neurosci Lett 29:111–115PubMedCrossRefGoogle Scholar
  145. Zhang Z et al (2007) Regulated ATP release from astrocytes through lysosome exocytosis. Nat Cell Biol 9:945–953PubMedCrossRefGoogle Scholar
  146. Zhang Y, Li M, Kang R-X, Shi J-G, Liu G-T, Zhang J-J (2012) NHBA isolated from Gastrodia elata exerts sedative and hypnotic effects in sodium pentobarbital-treated mice. Pharmacol Biochem Behav 102:450–457. doi: 10.1016/j.pbb.2012.06.002 PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Michael Lazarus
    • 1
    Email author
  • Jiang-Fan Chen
    • 2
    • 3
  • Zhi-Li Huang
    • 4
  • Yoshihiro Urade
    • 1
  • Bertil B. Fredholm
    • 5
  1. 1.International Institute for Integrative Sleep Medicine (WPI-IIIS), University of TsukubaTsukubaJapan
  2. 2.Department of NeurologyBoston University School of MedicineBostonUSA
  3. 3.Molecular Medicine Institute, Wenzhou Medical UniversityZhejiangChina
  4. 4.State Key Laboratory of Medical Neurobiology, Department of PharmacologyInstitutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College of Fudan UniversityShanghaiChina
  5. 5.Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden

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