Methylxanthines and Sleep

  • Tarja Porkka-HeiskanenEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 200)


Caffeine is widely used to promote wakefulness and counteract fatigue induced by restriction of sleep, but also to counteract the effects of caffeine abstinence. Adenosine is a physiological molecule, which in the central nervous system acts predominantly as an inhibitory neuromodulator. Adenosine is also a sleep-promoting molecule. Caffeine binds to adenosine receptors, and the antagonism of the adenosinergic system is believed to be the mechanism through which caffeine counteracts sleep in humans as well as in other species. The sensitivity for caffeine varies markedly among individuals. Recently, genetic variations in genes related to adenosine metabolism have provided at least a partial explanation for this variability. The main effects of caffeine on sleep are decreased sleep latency, shortened total sleep time, decrease in power in the delta range, and sleep fragmentation. Caffeine may also decrease the accumulation of sleep propensity during waking, thus inducing long-term harmful effects on sleep quality.


Adenosine Adenosine receptors Caffeine Sleep Sleep deprivation 


  1. Alsene K, Deckert J, Sand P, de Wit H (2003) Association between A2A receptor gene polymorphism and caffeine-induced anxiety. Neuropharmacology 28:1694–1702Google Scholar
  2. Basheer R, Bauer A, Elmenhorst D, Ramesh V, McCarley RW (2007) Sleep deprivation upregulates A1 adenosine receptors in the rat basal forebrain. Neuroreport 18:1895–1859PubMedCrossRefGoogle Scholar
  3. Basheer R, Strecker RE, Thakkar MM, McCarley RW (2004) Adenosine and sleep-wake regulation. Prog Neurobiol 73:379–396PubMedCrossRefGoogle Scholar
  4. Battistuzzi G, Iudicone P, Santolamazza P, Petrucci R (1981) Activity of adenosine deaminase allelic forms in intact erythrocytes and in lymphocytes. Ann Hum Genet 45:15–19PubMedCrossRefGoogle Scholar
  5. Benington JH, Heller HC (1995) Restoration of brain energy metabolism as the function of sleep. Prog Neurobiol 45:347–360PubMedCrossRefGoogle Scholar
  6. Benington JH, Kodali SK, Heller HC (1995) Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation. Brain Res 692:79–85PubMedCrossRefGoogle Scholar
  7. Birkett DJ, Miners JO (1991) Caffeine renal clearance and urine caffeine concentrations during steady state dosing. Implications for monitoring caffeine intake during sports events. Br J Clin Pharmacol 31:405–408PubMedCrossRefGoogle Scholar
  8. Bonnet MH (1991) The effect of varying prophylactic naps on performance, alertness and mood throughout a 52-hour sustained operation. Sleep 14:307–315PubMedGoogle Scholar
  9. Bonnet MH, Arand DL (1992) Caffeine use as a model of acute and chronic insomnia. Sleep 15:526–536PubMedGoogle Scholar
  10. Bonnet MH, Arand DL (1996) Metabolic rate and the restorative function of sleep. Physiol Behav 59:777–782PubMedCrossRefGoogle Scholar
  11. Bonnet MH, Balkin TJ, Dinges DF, Roehrs T, Rogers NL, Wesenten NJ (2005) The use of stimulants to modify performance during sleep loss: a review by the sleep deprivation and stimulant task force of the American Academy of Sleep Medicine. Sleep 28:1163–1187PubMedGoogle Scholar
  12. Bonnet MH, Gomez S, Wirth O, Arand DL (1995) The use of caffeine versus prophylactic naps in sustained performance. Sleep 18:97–104PubMedGoogle Scholar
  13. Borbely AA (1982) A two process model of sleep regulation. Hum Neurobiol 1:195–204PubMedGoogle Scholar
  14. Carter AJ, O′Connor CMJ, Ungerstedt U (1995) Caffeine enhances acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A1 receptors. J Pharmacol Exp Ther 273:637–642PubMedGoogle Scholar
  15. Chagoya de Sanchez V, Hernandez Munoz R, Suarez J, Vidrio S, Yanez L, Diaz Munoz M (1993) Day-night variations of adenosine and its metabolizing enzymes in the brain cortex of the rat–possible physiological significance for the energetic homeostasis and the sleep-wake cycle. Brain Res 612:115–121PubMedCrossRefGoogle Scholar
  16. Colton T, Gosselin RE, Smith RP (1968) The tolerance of coffee drinkers to caffeine. Clin Pharmacol Ther 9:31–39PubMedGoogle Scholar
  17. Curatolo PW, Robertson D (1983) The health consequences of caffeine. Ann Intern Med 98: 641–653PubMedGoogle Scholar
  18. Dunwiddie TV (1985) The physiological role of adenosine in the central nervous system. Int Rev Neurobiol 27:63–139PubMedCrossRefGoogle Scholar
  19. Dunwiddie TV, Hoffer BJ, Fredholm BB (1981) Alkylxanthines elevate hippocampal excitability. Evident role of endogenous adenosine. Naunyn Schmiedebergs Arch Pharmacol 316:326–330PubMedCrossRefGoogle Scholar
  20. Elmenhorst D, Meyer PT, Winz OH, Matusch A, Ermert J, Coenen HH, Basheer R, Haas HL, Zilles K, Bauer A (2009) Sleep deprivation increases A1 adenosine receptor binding in the human brain: a positron emission tomography study. J Neurosci 27:2410–2415CrossRefGoogle Scholar
  21. Fernstrom MH, Bazil CW, Fernstrom JD (1984) Caffeine injection raises brain tryptophan level, but does not stimulate the rate of serotonin synthesis in rat brain. Life Sci 35:1241–1247PubMedCrossRefGoogle Scholar
  22. Finelli LA, Baumann H, Borbely AA, Achermann P (2000) Dual electroencephalogram markers of human sleep homeostasis: correlation between theta activity in waking and slow-wave activity in sleep. Neuroscience 101:523–529PubMedCrossRefGoogle Scholar
  23. Fredholm BB, Dunwiddie TV (1988) How does adenosine inhibit transmitter release? Trends Pharmacol Sci 9:130–134PubMedCrossRefGoogle Scholar
  24. Fredholm BB, Bättig K, Holmén J, Nehling 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
  25. Fredholm BB, Jonzon B, Lindgren E (1984) Changes in noradrenaline release and in beta receptor number in rat hippocampus following long-term treatment with theophylline or l-phenylisopropyladenosine. Acta Physiol Scand 122:55–59PubMedCrossRefGoogle Scholar
  26. Gass N, Porkka-Heiskanen T, Kalinchuk AV (2009) The role of the basal forebrain adenosine receptors in sleep homeostasis. Neuroreport 20:1013–1018PubMedCrossRefGoogle Scholar
  27. Greene RW, Haas HL, Hermann A (1985) Effects of caffeine on hippocampal pyramidal cells in vitro. Br J Pharmacol 85:163–169PubMedCrossRefGoogle Scholar
  28. Haavisto M-L, Porkka-Heiskanen T, Hublin C, Härmä M, Mutanen P, Muller K, Virkkala J, Sallinen M (2010) Sleep restriction for the duration of a work week impairs multitasking performance. J Sleep Res (epub ahead of printing)Google Scholar
  29. Hadfield MG, Milio C (1989) Caffeine and regional brain monoamine utilization in mice. Life Sci 45:2637–2644PubMedCrossRefGoogle Scholar
  30. Hayaishi O (1988) Sleep-wake regulation of prostaglandin-D2 and prostaglandin-E2. J Biol Chem 2630:19758Google Scholar
  31. Hayaishi O (2002) Molecular genetic studies on sleep-wake regulation, with special emphasis on the prostaglandin D2 system. J Appl Physiol 92:863–868PubMedGoogle Scholar
  32. Hotta H, Kagitani F, Kondo M, Uchida S (2009) Basal forebrain stimulation induces NGF secretion in ipsilateral parietal cortex via nicotinic receptor activation in adult, but not aged rats. Neurosci Res 63:122–8PubMedCrossRefGoogle Scholar
  33. Huang ZL, Qu WM, Eguchi N, Chen JF, Schwarzschild MA, Fredholm BB, Urade Y, Hayaishi O (2005) Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci 8:858–859PubMedCrossRefGoogle Scholar
  34. Huston JP, Haas HL, Pfister M, Decking U, Schrader J, Schwarting RK (1996) Extracellular adenosine levels in neostriatum and hippocampus during rest and activity periods of rats. Neuroscience 73:99–107PubMedCrossRefGoogle Scholar
  35. Höfer I, Bättig K (1994) Cardiovascular, behavioral, and subjective effects of caffeine under field conditions. Pharmacol Biochem Behav 48:899–908PubMedCrossRefGoogle Scholar
  36. James JE (1998) Acute and chronic effects of caffeine on performance, mood, headache, and sleep. Neuropsychobiology 38:32–41PubMedCrossRefGoogle Scholar
  37. James JE, Keane MA (2007) Caffeine, sleep and wakefulness: implications of new understanding about withdrawal reversal. Hum Psychopharmacol 22:549–558PubMedCrossRefGoogle Scholar
  38. Juliano LM, Griffiths RR (2004) A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity and associated features. Psychopharmacology 176:1–29PubMedCrossRefGoogle Scholar
  39. Kalinchuk AV, McCarley RW, Stenberg D, Porkka-Heiskanen T, Basheer R (2008) The role of cholinergic basal forebrain neurons in adenosine-mediated homeostatic corntol of sleep: lessons from 192 IgG-saporin lesions. Neuroscience 157:238–253PubMedCrossRefGoogle Scholar
  40. Kalinchuk AV, Stenberg D, Rosenberg PA, Porkka-Heiskanen T (2006) Inducible and neuronal nitric oxide synthases (NOS) have complementary roles in recovery sleep induction. Eur J Neurosci 24:1–14CrossRefGoogle Scholar
  41. Karacan I, Thornby JI, Anch M, Booth GH, Williams RL, Salis PJ (1976) Dose-related sleep disturbances induced by coffee and caffeine. Clin Pharm Ther 20:682–689Google Scholar
  42. Krueger JM, Fang J (1997) Cytokines in sleep regulation. In: Hayaishi O, Inoue S (eds) Sleep and sleep disorders: from molecule to behavior. Academic/Harcourt Brace, TokyoGoogle Scholar
  43. Landolt HP (2008) Sleep homeostasis: a role for adenosine in humans. Biochem Pharmacol 75:2070–2079PubMedCrossRefGoogle Scholar
  44. Landolt HP, Dijk DJ, Gaus SE, Borbely AA (1995a) Caffeine reduces low-frequency delta activity in the human sleep EEG. Neuropsychopharmacology 12:229–238PubMedCrossRefGoogle Scholar
  45. Landolt HP, Retey J, Tönz K, Gottselig JM, Khatami R, Buckelmuller I, Achermann P (2004) Caffeine attenuates waking and sleep electroencephalographic markers of sleep homeostasis in humans. Neuropsychopharmacology 29:1933–1939PubMedCrossRefGoogle Scholar
  46. Landolt HP, Werth E, Borbely AA, Dijk DJ (1995b) Caffeine intake (200 mg) in the morning affects human sleep and EEG power spectra at night. Brain Res 675:67–74PubMedCrossRefGoogle Scholar
  47. McGinty DJ, Szymusiak RS (2000) The sleep-wake switch: a neuronal alarm clock. Nat Med 6:510–511PubMedCrossRefGoogle Scholar
  48. Murillo-Rodriguez E, Blanco-Centurion C et al (2004) The diurnal rhythm of adenosine levels in the basal forebrain of young and old rats. Neuroscience 123:361–370PubMedCrossRefGoogle Scholar
  49. Murray TF, Blaker WD, Cheney DL, Costa E (1982) Inhibition of acetylcholine turnover rate in rat hippocampus and cortex by intraventricular injection of adenosine analogs. J Pharmacol Exp Ther 222:550–554PubMedGoogle Scholar
  50. Nicholson AN, Stone BM (1980) Heterocyclic amphetamine derivative and caffeine on sleep in man. Br J Clin Pharmacol 9:195–203PubMedCrossRefGoogle Scholar
  51. Oishi Y, Huang ZL, Fredholm BB, Urade Y, Hayaishi O (2008) Adenosine in the tuberomamillary nucleus suppresses the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep. Proc Natl Acad Sci USA 105:19992–19997PubMedCrossRefGoogle Scholar
  52. Okuma T, Matsuoka H, Yosihihiko M, Toyomura K (1982) Model insomnia by methylphenidate and caffeine and use in the evaluation of temazepam. Psychopharmacology 76:201–208PubMedCrossRefGoogle Scholar
  53. Phillis JW, Edstrom JP (1976) Effects of adenosine analogs on rat cerebral cortical neurons. Life Sci 19:1041–1053PubMedCrossRefGoogle Scholar
  54. Phillis JW, Wu PH (1981) The role of adenosine and its nucleotides in central synaptic transmission. Prog Neurobiol 16:187–293PubMedCrossRefGoogle Scholar
  55. Popoli P, Sagratella S, Scotti De Carolis A (1987) An EEG and behavioural study on the excitatory properties of caffeine in rabbits. Arch Int Pharmacodyn Ther 290:5–15PubMedGoogle Scholar
  56. Porkka-Heiskanen T, Strecker RE, Bjorkum AA, Thakkar M, Greene RW, McCarley RW (1997) Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 276:1265–1268PubMedCrossRefGoogle Scholar
  57. Porkka-Heiskanen T, Strecker RE, McCarley RW (2000) Brain site specificity of extracellular concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study. Neuroscience 99:507–517PubMedCrossRefGoogle Scholar
  58. Rainnie DG, Grunze HC, McCarley RW, Greene RW (1994) Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal. Science 263:689–692PubMedCrossRefGoogle Scholar
  59. Ram A, Pandey HP, Matsumura H, Kasahara-Orita K, Nakajima T, Takahata R, Satoh S, Terao A, Hayaishi O (1997) CSF levels of prostaglandins, especially the level of prostaglandin D2, are correlated with increasing propensity towards sleep in rats. Brain Res 751:81–89PubMedCrossRefGoogle Scholar
  60. Retey JV, Adam M, Honegger E, Khatami R, Luhmann UFO, Jung HH, Landolt HP (2005) A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proc Natl Acad Sci USA 102:15676–15681PubMedCrossRefGoogle Scholar
  61. Retey JV, Adam M, Khatami R, Luhmann UFO, Jung HH, Berger W, Landolt HP (2007) A genetic variation in adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. Clin Pharm Ther 81:692–698CrossRefGoogle Scholar
  62. Roehrs T, Roth T (2008) Caffeine: sleep and daytime sleepiness. Sleep Med Rev 12:153–162PubMedCrossRefGoogle Scholar
  63. Saper CB, Chou TC, Scammell TE (2001) The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 24:726–731PubMedCrossRefGoogle Scholar
  64. Satoh S, Matsamura 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 USA 93:5980–5984PubMedCrossRefGoogle Scholar
  65. 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 11:1587–1597PubMedCrossRefGoogle Scholar
  66. Schweitzer PK, Randazzo AC, Stone K, Erman M, Walsh JK (2006) Laboratory and field studies of naps and caffeine as practical countermeasures for sleep-wake problems associated with night work. Sleep 29:39–50PubMedGoogle Scholar
  67. Schwierin B, Borbely AA, Tobler I (1996) Effects of N6-cyclopentyladenosine and caffeine on sleep regulation in the rat. Eur J Pharmacol 300:163–171PubMedCrossRefGoogle Scholar
  68. Shaw PJ, Cirelli C, Greenspan RJ, Tononi G (2000) Correlates of sleep and waking in Drosophila melanogaster. Science 287:1834–1837PubMedCrossRefGoogle Scholar
  69. Sinton CM, Petitjean F (1989) The influence of cronic caffeine administration on sleep parameters in the cat. Pharmacol Biochem Behav 32:459–462PubMedCrossRefGoogle Scholar
  70. Stenberg D (2007) Neuroanatomy and neurochemistry of sleep. Cell Mol Life Sci 64:1187–1204PubMedCrossRefGoogle Scholar
  71. Stenberg D, Litonius E, Halldner L, Johansson B, Fredholm BB, Porkka-Heiskanen T (2003) Sleep and its homeostatic regulation in mice lacking adenosine A1 receptor. J Sleep Res 12:283–290PubMedCrossRefGoogle Scholar
  72. Strecker RE, Morairty SR, Thakkar MM, Porkka-Heiskanen T, Basheer R, Dauphin LJ, Rainnie DG, Greene RW, McCarley RW (2000) Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state. Behav Brain Res 115:183–204PubMedCrossRefGoogle Scholar
  73. Thakkar MM, Winston S, McCarley RW (2003) A1 receptor and adenosinergic homeostatic regulation of sleep-wakefulness: effects of antisense to the A1 receptor in the cholinergic basal forebrain. J Neurosci 23:4278–4287PubMedGoogle Scholar
  74. Ticho SR, Radulovacki M (1991) Role of adenosine in sleep and temperature regulation in the preoptic area of rats. Pharmacol Biochem Behav 40:33–40PubMedCrossRefGoogle Scholar
  75. Urade Y, Hayaishi O (1999) Prostaglandin D2 and sleep regulation. Biochim Biophys Acta 1436:606–615PubMedCrossRefGoogle Scholar
  76. Vyazovskiy VV, Tobler I (2005) Theta activity in the waking EEG is a marker of sleep propensity in the rat. Brain Res 1050:64–71PubMedCrossRefGoogle Scholar
  77. Wigren H-K, Rytkönen K-M, Porkka-Heiskanen T (2009) Basal forebrain lactate release and promotion of cortical arousal during prolonged waking is attenuated in aging. J Neurosci 29:11698–11707Google Scholar
  78. Wu MN, Ho K, Crocker A, Yue Z, Seghal A (2009) The effects of caffeine on sleep in Drosophila require PKA activity, but not the adenosine receptor. J Neurosci 29:11029–11037PubMedCrossRefGoogle Scholar
  79. Wurts SW, Edgar DM (2000) Caffeine during sleep deprivation: sleep tendency and dynamics of recovery sleep in rats. Pharmacol Biochem Behav 65:155–162PubMedCrossRefGoogle Scholar
  80. Yanik G, Glaum S, Radulovacki M (1987) The dose-response effects of caffeine on sleep in rats. Brain Res 403:177–180PubMedCrossRefGoogle Scholar
  81. Yokogawa T, Marin W, Faraco J, Pezeron G, Appelbaum L, Zhang J, Rosa F, Mourrain P, Mignot E (2007) Characterization of sleep in zebrafish and insomnia in hypocretin mutants. PLoS Biol 5:e277PubMedCrossRefGoogle Scholar
  82. Zhdanova IV, Wang SY, Leclair OU, Danilova NP (2001) Melatonin promotes sleep-like state in zebrafish. Brain Res 903:263–268PubMedCrossRefGoogle Scholar

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© Springer Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Institute of Biomedicine/PhysiologyUniversity of HelsinkiHelsinkiFinland

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