Caffeine is known to disrupt sleep and its administration to human subjects has been used to model sleep disruption. We previously showed that its effects on sleep onset latency are comparable between rats and humans. This study evaluated the potential use of caffeine as a model of sleep disruption in the rat, by assessing its effects on sleep architecture and electroencephalogram (EEG) frequency spectrum, and using sleep-promoting drugs to reverse these effects. Rats were implanted with radiotelemetry devices for body temperature, EEG, electromyogram and locomotor activity. Following recovery, animals were dosed with caffeine (10 mg/kg) alone or in combination with zolpidem (10 mg/kg) or trazodone (20 mg/kg). Sleep was scored for the subsequent 12 h using automated analysis software. Caffeine dose-dependently disrupted sleep: it increased WAKE time, decreased NREM (non-REM) sleep time and NREM bout duration (but not bout number), and decreased delta activity in NREM sleep. It also dose-dependently increased locomotor activity and body temperature. When given alone, zolpidem suppressed REM whilst trazodone increased NREM sleep time at the expense of WAKE, increased NREM bout duration, increased delta activity in NREM sleep and reduced body temperature. In combination, zolpidem attenuated caffeine’s effects on WAKE, whilst trazodone attenuated its effects on NREM sleep, NREM bout duration, delta activity, body temperature and locomotor activity. Caffeine administration produced many of the signs of insomnia that were improved by two of its most successful current treatments. This model may therefore be useful in the study of new drugs for the treatment of sleep disturbance.
Adam K Tomeny M Oswald I (1986) Physiological and psychological differences between good and poor sleepers. J Psychiatr Res20: 301–316.
2.
Anderson NJ Reynolds DS Stendsbol TB (2006) Effects of the 5HT-2A antagonist MDL100907 on rat sleep parameters. J Sleep Res15: P211.
3.
Antoniou K Papadopoulou-Daifoti Z Hyphantis T Papathanasiou G Bekris E Marselos M (2005) A detailed behavioral analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A1 and A2A receptors. Psychopharmacology183: 154–162.
4.
Bonnet MH Arand DL (1992) Caffeine use as a model of acute and chronic insomnia. Sleep15: 526–536.
5.
Bonnet MH Arand DL (2001) Impact of activity and arousal upon spectral EEG parameters. Physiol Behav74: 291–298.
6.
Borbely AA Baumann F Brandeis D Strauch I Lehmann D (1981) Sleep deprivation: effect on sleep stages and EEG power density in man. Electroencephalogr Clin Neurophysiol51: 483–495.
7.
Borbely AA Trachsel L Tobler I (1988) Effect of ritanserin on sleep stages and sleep EEG in the rat. Eur J Pharmacol156: 275–278.
8.
Boutrel B Koob GF (2004) What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications. Sleep27: 1181–1194.
9.
Brocco M Dekeyne A Veiga S Girardon S Millan MJ (2002) Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake. A pharmacological characterization of diverse classes of antidepressant agents. Pharmacol Biochem Behav71: 667–680.
10.
Brunner DP Dijk DJ Munch M Borbely AA (1991) Effect of zolpidem on sleep and sleep EEG spectra in healthy young men. Psychopharmacology104: 1–5.
11.
Caccia S Ballabio M Fanelli R Guiso G Zanini MG (1981) Determination of plasma and brain concentrations of trazodone and its metabolite, 1-m-chlorophenylpiperazine, by gas-liquid chromatography. J Chromatogr210: 311–318.
12.
Carter AJ O’Connor WT Carter MJ Ungerstedt U (1995) Caffeine enhances acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A1 receptors. J Pharmacol Exp Ther273: 637–642.
13.
Cysneiros RM Farkas D Harmatz JS von Moltke LL Greenblatt DJ (2007) Pharmacokinetic and pharmacodynamic interactions between zolpidem and caffeine. Clin Pharmacol Ther82: 54–62.
14.
Deboer T (1998) Brain temperature dependent changes in the electroencephalogram power spectrum of humans and animals. J Sleep Res7: 254–262.
15.
Depoortere H Zivkovic B Lloyd KG Sanger DJ Perrault G Langer SZ (1986) Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. J Pharmacol Exp Ther237: 649–658.
16.
Dijk DJ Brunner DP Borbely AA (1990) Time course of EEG power density during long sleep in humans. Am J Physiol258: R650–R661.
17.
Drapeau C Hamel-Hebert I Robillard R Selmaoui B Filipini D Carrier J (2006) Challenging sleep in aging: the effects of 200 mg of caffeine during the evening in young and middle-aged moderate caffeine consumers. J Sleep Res15: 133–141.
18.
El Yacoubi M Ledent C Parmentier M Costentin J Vaugeois JM (2003) Caffeine reduces hypnotic effects of alcohol through adenosine A2A receptor blockade. Neuropharmacology45: 977–985.
19.
Erman MK Erwin CW Gengo FM Jamieson AO Lemmi H Mahowald MW (2001) Comparative efficacy of zolpidem and temazepam in transient insomnia. Hum Psychopharmacol16: 169–176.
20.
Fish LR Gilligan MT Humphries AC Ivarsson M Ladduwahetty T Merchant KJ (2005) 4-Fluorosulfonylpiperidines: selective 5-HT2A ligands for the treatment of insomnia. Bioorg Med Chem Lett15: 3665–3669.
21.
Fredholm BB Battig K Holmen J Nehlig A Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev51: 83–133.
22.
Garrigou-Gadenne D Burke JT Durand A Depoortere H Thenot JP Morselli PL (1989) Pharmacokinetics, brain distribution and pharmaco-electrocorticographic profile of zolpidem, a new hypnotic, in the rat. J Pharmacol Exp Ther248: 1283–1288.
23.
Gottesmann C Gandolfo G Arnaud C Gauthier P (1998) The intermediate stage and paradoxical sleep in the rat: influence of three generations of hypnotics. Eur J Neurosci10: 409–414.
24.
Haffmans PM Vos MS (1999) The effects of trazodone on sleep disturbances induced by brofaromine. Eur Psychiatry14: 167–171.
25.
Hicks JA Argyropoulos SV Rich AS Nash JR Bell CJ Edwards C (2002) Randomised controlled study of sleep after nefazodone or paroxetine treatment in out-patients with depression. Br J Psychiatry180: 528–535.
26.
Hindmarch I Rigney U Stanley N Quinlan P Rycroft J Lane J (2000) A naturalistic investigation of the effects of day-long consumption of tea, coffee and water on alertness, sleep onset and sleep quality. Psychopharmacology149: 203–216.
27.
Ivarsson M Paterson LM Hutson PH (2005) Antidepressants and REM sleep in Wistar-Kyoto and Sprague-Dawley rats. Eur J Pharmacol522: 63–71.
28.
Kantor S Jakus R Bodizs R Halasz P Bagdy G (2002) Acute and long-term effects of the 5-HT2 receptor antagonist ritanserin on EEG power spectra, motor activity, and sleep: changes at the light-dark phase shift. Brain Res943: 105–111.
29.
Landolt HP (2008) Sleep homeostasis: a role for adenosine in humans? Biochem Pharmacol75: 2070–2079.
30.
Landolt HP Dijk DJ Gaus SE Borbely AA (1995) Caffeine reduces low-frequency delta activity in the human sleep EEG. Neuropsychopharmacology12: 229–238.
31.
Landolt HP Meier V Burgess HJ Finelli LA Cattelin F Achermann P (1999) Serotonin-2 receptors and human sleep: effect of a selective antagonist on EEG power spectra. Neuropsychopharmacology21: 455–466.
32.
Landolt HP Retey JV Tonz K Gottselig JM Khatami R Buckelmuller I (2004) Caffeine attenuates waking and sleep electroencephalographic markers of sleep homeostasis in humans. Neuropsychopharmacology29: 1933–1939.
33.
Lelkes Z Obal F Alfoldi P Erdos A Rubicsek G Benedek G (1994) Effects of acute and chronic treatment with trazodone, an antidepressant, on the sleep-wake activity in rats. Pharmacol Res30: 105–115.
34.
Lu J Greco MA (2006) Sleep circuitry and the hypnotic mechanism of GABAA drugs. J Clin Sleep Med2: S19–S26.
35.
Mailliet F Galloux P Poisson D (2001) Comparative effects of melatonin, zolpidem and diazepam on sleep, body temperature, blood pressure and heart rate measured by radiotelemetry in Wistar rats. Psychopharmacology156: 417–426.
36.
Marek GJ McDougle CJ Price LH Seiden LS (1992) A comparison of trazodone and fluoxetine: implications for a serotonergic mechanism of antidepressant action. Psychopharmacology (Berl)109: 2–11.
37.
Mendelson WB (2005) A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry66: 469–476.
38.
Montgomery I Oswald I Morgan K Adam K (1983) Trazodone enhances sleep in subjective quality but not in objective duration. Br J Clin Pharmacol16: 139–144.
39.
Morairty SR Hedley L Flores J Martin R Kilduff TS (2008) Selective 5HT2A and 5HT6 receptor antagonists promote sleep in rats. Sleep31: 34–44.
40.
Owens MJ Morgan WN Plott SJ Nemeroff CB (1997) Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther283: 1305–1322.
41.
Paterson LM Nutt DJ Ivarsson M Hutson PH Wilson SJ (2009) Effects on sleep stages and microarchitecture of caffeine and its combination with zolpidem or trazodone in healthy volunteers. J Psychopharmacol23: 487–494.
42.
Paterson LM Wilson SJ Nutt DJ Hutson PH Ivarsson M (2007) A translational, caffeine-induced model of onset insomnia in rats and healthy volunteers. Psychopharmacology191: 943–950.
43.
Popa D Lena C Fabre V Prenat C Gingrich J Escourrou P (2005) Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors. J Neurosci25: 11231–11238.
44.
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. Science276: 1265–1268.
45.
Retey JV Adam M Khatami R Luhmann UF Jung HH Berger W (2007) A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. Clin Pharmacol Ther81: 692–698.
46.
Saletu-Zyhlarz G Anderer P Brandstatter N Dantendorfer K Gruber G Mandl M (2000) Placebo-controlled sleep laboratory studies on the acute effects of zolpidem on objective and subjective sleep and awakening quality in nonorganic insomnia related to neurotic and stress-related disorder. Neuropsychobiology41: 139–148.
47.
Saletu-Zyhlarz GM Abu-Bakr MH Anderer P Gruber G Mandl M Strobl R (2002) Insomnia in depression: differences in objective and subjective sleep and awakening quality to normal controls and acute effects of trazodone. Prog Neuropsychopharmacol Biol Psychiatry26: 249–260.
48.
Schlosberg AJ (1983) Temperature responses in rats after acute and chronic administrations of caffeine. Pharmacol Biochem Behav18: 935–942.
49.
Schwierin B Borbely AA Tobler I (1996) Effects of N6-cyclopentyladenosine and caffeine on sleep regulation in the rat. Eur J Pharmacol300: 163–171.
50.
Sharpley AL Solomon RA Fernando AI da Roza Davis JM Cowen PJ (1990) Dose-related effects of selective 5-HT2 receptor antagonists on slow wave sleep in humans. Psychopharmacology101: 568–569.
51.
Shinomiya K Omichi J Ohnishi R Ito H Yoshida T Kamei C (2004) Effects of chlorogenic acid and its metabolites on the sleep-wakefulness cycle in rats. Eur J Pharmacol504: 185–189.
52.
Strecker RE Morairty S Thakkar MM Porkka-Heiskanen T Basheer R Dauphin LJ (2000) Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state. Behav Brain Res115: 183–204.
53.
Suzuki H Yamadera H Nakamura S Endo S (2002) Effects of trazodone and imipramine on the biological rhythm: an analysis of sleep EEG and body core temperature. J Nippon Med Sch69: 333–341.
54.
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. Neuroscience153: 875–880.
55.
Van Bemmel AL Beersma DG Van den Hoofdakker RH (1995) Changes in EEG power density of non-REM sleep in depressed patients during treatment with trazodone. J Affect Disord35: 11–19.
56.
Varkevisser M Van Dongen HP Kerkhof GA (2005) Physiologic indexes in chronic insomnia during a constant routine: evidence for general hyperarousal? Sleep28: 1588–1596.
57.
Wang Y Lau CE (1998) Caffeine has similar pharmacokinetics and behavioral effects via the i.p. and p.o. routes of administration. Pharmacol Biochem Behav60: 271–278.
58.
Yamadera H Nakamura S Suzuki H Endo S (1998) Effects of trazodone hydrochloride and imipramine on polysomnography in healthy subjects. Psychiatry Clin Neurosci52: 439–443.
