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Methylxanthines and Sleep

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Methylxanthines

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 200))

Abstract

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.

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References

  • Alsene K, Deckert J, Sand P, de Wit H (2003) Association between A2A receptor gene polymorphism and caffeine-induced anxiety. Neuropharmacology 28:1694–1702

    CAS  Google Scholar 

  • Basheer R, Bauer A, Elmenhorst D, Ramesh V, McCarley RW (2007) Sleep deprivation upregulates A1 adenosine receptors in the rat basal forebrain. Neuroreport 18:1895–1859

    Article  PubMed  CAS  Google Scholar 

  • Basheer R, Strecker RE, Thakkar MM, McCarley RW (2004) Adenosine and sleep-wake regulation. Prog Neurobiol 73:379–396

    Article  PubMed  CAS  Google Scholar 

  • Battistuzzi G, Iudicone P, Santolamazza P, Petrucci R (1981) Activity of adenosine deaminase allelic forms in intact erythrocytes and in lymphocytes. Ann Hum Genet 45:15–19

    Article  PubMed  CAS  Google Scholar 

  • Benington JH, Heller HC (1995) Restoration of brain energy metabolism as the function of sleep. Prog Neurobiol 45:347–360

    Article  PubMed  CAS  Google Scholar 

  • Benington JH, Kodali SK, Heller HC (1995) Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation. Brain Res 692:79–85

    Article  PubMed  CAS  Google Scholar 

  • 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 31:405–408

    Article  PubMed  CAS  Google Scholar 

  • Bonnet MH (1991) The effect of varying prophylactic naps on performance, alertness and mood throughout a 52-hour sustained operation. Sleep 14:307–315

    PubMed  CAS  Google Scholar 

  • Bonnet MH, Arand DL (1992) Caffeine use as a model of acute and chronic insomnia. Sleep 15:526–536

    PubMed  CAS  Google Scholar 

  • Bonnet MH, Arand DL (1996) Metabolic rate and the restorative function of sleep. Physiol Behav 59:777–782

    Article  PubMed  CAS  Google Scholar 

  • 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 28:1163–1187

    PubMed  Google Scholar 

  • Bonnet MH, Gomez S, Wirth O, Arand DL (1995) The use of caffeine versus prophylactic naps in sustained performance. Sleep 18:97–104

    PubMed  CAS  Google Scholar 

  • Borbely AA (1982) A two process model of sleep regulation. Hum Neurobiol 1:195–204

    PubMed  CAS  Google Scholar 

  • 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 273:637–642

    PubMed  CAS  Google Scholar 

  • 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 612:115–121

    Article  PubMed  CAS  Google Scholar 

  • Colton T, Gosselin RE, Smith RP (1968) The tolerance of coffee drinkers to caffeine. Clin Pharmacol Ther 9:31–39

    PubMed  CAS  Google Scholar 

  • Curatolo PW, Robertson D (1983) The health consequences of caffeine. Ann Intern Med 98: 641–653

    PubMed  CAS  Google Scholar 

  • Dunwiddie TV (1985) The physiological role of adenosine in the central nervous system. Int Rev Neurobiol 27:63–139

    Article  PubMed  CAS  Google Scholar 

  • Dunwiddie TV, Hoffer BJ, Fredholm BB (1981) Alkylxanthines elevate hippocampal excitability. Evident role of endogenous adenosine. Naunyn Schmiedebergs Arch Pharmacol 316:326–330

    Article  PubMed  CAS  Google Scholar 

  • 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 27:2410–2415

    Article  Google Scholar 

  • 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 35:1241–1247

    Article  PubMed  CAS  Google Scholar 

  • 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 101:523–529

    Article  PubMed  CAS  Google Scholar 

  • Fredholm BB, Dunwiddie TV (1988) How does adenosine inhibit transmitter release? Trends Pharmacol Sci 9:130–134

    Article  PubMed  CAS  Google Scholar 

  • 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 51:83–133

    PubMed  CAS  Google Scholar 

  • 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 122:55–59

    Article  PubMed  CAS  Google Scholar 

  • Gass N, Porkka-Heiskanen T, Kalinchuk AV (2009) The role of the basal forebrain adenosine receptors in sleep homeostasis. Neuroreport 20:1013–1018

    Article  PubMed  CAS  Google Scholar 

  • Greene RW, Haas HL, Hermann A (1985) Effects of caffeine on hippocampal pyramidal cells in vitro. Br J Pharmacol 85:163–169

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Hadfield MG, Milio C (1989) Caffeine and regional brain monoamine utilization in mice. Life Sci 45:2637–2644

    Article  PubMed  CAS  Google Scholar 

  • Hayaishi O (1988) Sleep-wake regulation of prostaglandin-D2 and prostaglandin-E2. J Biol Chem 2630:19758

    Google Scholar 

  • Hayaishi O (2002) Molecular genetic studies on sleep-wake regulation, with special emphasis on the prostaglandin D2 system. J Appl Physiol 92:863–868

    PubMed  CAS  Google Scholar 

  • 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 63:122–8

    Article  PubMed  CAS  Google Scholar 

  • 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 8:858–859

    Article  PubMed  CAS  Google Scholar 

  • 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 73:99–107

    Article  PubMed  CAS  Google Scholar 

  • Höfer I, Bättig K (1994) Cardiovascular, behavioral, and subjective effects of caffeine under field conditions. Pharmacol Biochem Behav 48:899–908

    Article  PubMed  Google Scholar 

  • James JE (1998) Acute and chronic effects of caffeine on performance, mood, headache, and sleep. Neuropsychobiology 38:32–41

    Article  PubMed  CAS  Google Scholar 

  • James JE, Keane MA (2007) Caffeine, sleep and wakefulness: implications of new understanding about withdrawal reversal. Hum Psychopharmacol 22:549–558

    Article  PubMed  Google Scholar 

  • Juliano LM, Griffiths RR (2004) A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity and associated features. Psychopharmacology 176:1–29

    Article  PubMed  CAS  Google Scholar 

  • 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 157:238–253

    Article  PubMed  CAS  Google Scholar 

  • 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 24:1–14

    Article  Google Scholar 

  • 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 20:682–689

    CAS  Google Scholar 

  • 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, Tokyo

    Google Scholar 

  • Landolt HP (2008) Sleep homeostasis: a role for adenosine in humans. Biochem Pharmacol 75:2070–2079

    Article  PubMed  CAS  Google Scholar 

  • Landolt HP, Dijk DJ, Gaus SE, Borbely AA (1995a) Caffeine reduces low-frequency delta activity in the human sleep EEG. Neuropsychopharmacology 12:229–238

    Article  PubMed  CAS  Google Scholar 

  • 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 29:1933–1939

    Article  PubMed  CAS  Google Scholar 

  • 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 675:67–74

    Article  PubMed  CAS  Google Scholar 

  • McGinty DJ, Szymusiak RS (2000) The sleep-wake switch: a neuronal alarm clock. Nat Med 6:510–511

    Article  PubMed  CAS  Google Scholar 

  • 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 123:361–370

    Article  PubMed  CAS  Google Scholar 

  • 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 222:550–554

    PubMed  CAS  Google Scholar 

  • Nicholson AN, Stone BM (1980) Heterocyclic amphetamine derivative and caffeine on sleep in man. Br J Clin Pharmacol 9:195–203

    Article  PubMed  CAS  Google Scholar 

  • 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 105:19992–19997

    Article  PubMed  CAS  Google Scholar 

  • Okuma T, Matsuoka H, Yosihihiko M, Toyomura K (1982) Model insomnia by methylphenidate and caffeine and use in the evaluation of temazepam. Psychopharmacology 76:201–208

    Article  PubMed  CAS  Google Scholar 

  • Phillis JW, Edstrom JP (1976) Effects of adenosine analogs on rat cerebral cortical neurons. Life Sci 19:1041–1053

    Article  PubMed  CAS  Google Scholar 

  • Phillis JW, Wu PH (1981) The role of adenosine and its nucleotides in central synaptic transmission. Prog Neurobiol 16:187–293

    Article  PubMed  CAS  Google Scholar 

  • 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 290:5–15

    PubMed  CAS  Google Scholar 

  • 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 276:1265–1268

    Article  PubMed  CAS  Google Scholar 

  • 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 99:507–517

    Article  PubMed  CAS  Google Scholar 

  • Rainnie DG, Grunze HC, McCarley RW, Greene RW (1994) Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal. Science 263:689–692

    Article  PubMed  CAS  Google Scholar 

  • 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 751:81–89

    Article  PubMed  CAS  Google Scholar 

  • 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 102:15676–15681

    Article  PubMed  CAS  Google Scholar 

  • 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 81:692–698

    Article  CAS  Google Scholar 

  • Roehrs T, Roth T (2008) Caffeine: sleep and daytime sleepiness. Sleep Med Rev 12:153–162

    Article  PubMed  Google Scholar 

  • Saper CB, Chou TC, Scammell TE (2001) The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 24:726–731

    Article  PubMed  CAS  Google Scholar 

  • 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 93:5980–5984

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 29:39–50

    PubMed  Google Scholar 

  • Schwierin B, Borbely AA, Tobler I (1996) Effects of N6-cyclopentyladenosine and caffeine on sleep regulation in the rat. Eur J Pharmacol 300:163–171

    Article  PubMed  CAS  Google Scholar 

  • Shaw PJ, Cirelli C, Greenspan RJ, Tononi G (2000) Correlates of sleep and waking in Drosophila melanogaster. Science 287:1834–1837

    Article  PubMed  CAS  Google Scholar 

  • Sinton CM, Petitjean F (1989) The influence of cronic caffeine administration on sleep parameters in the cat. Pharmacol Biochem Behav 32:459–462

    Article  PubMed  CAS  Google Scholar 

  • Stenberg D (2007) Neuroanatomy and neurochemistry of sleep. Cell Mol Life Sci 64:1187–1204

    Article  PubMed  CAS  Google Scholar 

  • 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 12:283–290

    Article  PubMed  Google Scholar 

  • 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 115:183–204

    Article  PubMed  CAS  Google Scholar 

  • 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 23:4278–4287

    PubMed  CAS  Google Scholar 

  • Ticho SR, Radulovacki M (1991) Role of adenosine in sleep and temperature regulation in the preoptic area of rats. Pharmacol Biochem Behav 40:33–40

    Article  PubMed  CAS  Google Scholar 

  • Urade Y, Hayaishi O (1999) Prostaglandin D2 and sleep regulation. Biochim Biophys Acta 1436:606–615

    Article  PubMed  CAS  Google Scholar 

  • Vyazovskiy VV, Tobler I (2005) Theta activity in the waking EEG is a marker of sleep propensity in the rat. Brain Res 1050:64–71

    Article  PubMed  CAS  Google Scholar 

  • 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 29:11698–11707

    Google Scholar 

  • 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 29:11029–11037

    Article  PubMed  CAS  Google Scholar 

  • Wurts SW, Edgar DM (2000) Caffeine during sleep deprivation: sleep tendency and dynamics of recovery sleep in rats. Pharmacol Biochem Behav 65:155–162

    Article  PubMed  CAS  Google Scholar 

  • Yanik G, Glaum S, Radulovacki M (1987) The dose-response effects of caffeine on sleep in rats. Brain Res 403:177–180

    Article  PubMed  CAS  Google Scholar 

  • 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:e277

    Article  PubMed  Google Scholar 

  • Zhdanova IV, Wang SY, Leclair OU, Danilova NP (2001) Melatonin promotes sleep-like state in zebrafish. Brain Res 903:263–268

    Article  PubMed  CAS  Google Scholar 

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  1. Institute of Biomedicine/Physiology, University of Helsinki, 63, Haartmaninkatu 8, 00014, Helsinki, Finland

    Tarja Porkka-Heiskanen

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Porkka-Heiskanen, T. (2011). Methylxanthines and Sleep. In: Methylxanthines. Handbook of Experimental Pharmacology, vol 200. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-13443-2_12

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