Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 23 May 1997:
Vol. 276. no. 5316, pp. 1265 - 1268
DOI: 10.1126/science.276.5316.1265
Prev | Table of Contents | Next

Reports

Adenosine: A Mediator of the Sleep-Inducing Effects of Prolonged Wakefulness

Tarja Porkka-Heiskanen, Robert E. Strecker, Mahesh Thakkar, Alvhild A. Bjørkum, Robert W. Greene, Robert W. McCarley *

Both subjective and electroencephalographic arousal diminish as a function of the duration of prior wakefulness. Data reported here suggest that the major criteria for a neural sleep factor mediating the somnogenic effects of prolonged wakefulness are satisfied by adenosine, a neuromodulator whose extracellular concentration increases with brain metabolism and which, in vitro, inhibits basal forebrain cholinergic neurons. In vivo microdialysis measurements in freely behaving cats showed that adenosine extracellular concentrations in the basal forebrain cholinergic region increased during spontaneous wakefulness as contrasted with slow wave sleep; exhibited progressive increases during sustained, prolonged wakefulness; and declined slowly during recovery sleep. Furthermore, the sleep-wakefulness profile occurring after prolonged wakefulness was mimicked by increased extracellular adenosine induced by microdialysis perfusion of an adenosine transport inhibitor in the cholinergic basal forebrain but not by perfusion in a control noncholinergic region.

T. Porkka-Heiskanen, Department of Psychiatry, Harvard Medical School, Brockton Veterans Administration Medical Center (VAMC), 116 A, 940 Belmont Street, Brockton, MA 02401, USA, and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
R. E. Strecker, M. Thakkar, A. A. Bjørkum, R. W. Greene, R. W. McCarley, Department of Psychiatry, Harvard Medical School, Brockton VAMC, 116 A, 940 Belmont Street, Brockton, MA 02401, USA.
*   To whom correspondence should be addressed. E-mail: mccarley{at}warren.med.harvard.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Effects on sleep stages and microarchitecture of caffeine and its combination with zolpidem or trazodone in healthy volunteers.
L. Paterson, D. Nutt, M Ivarsson, P. Hutson, and S. Wilson (2009)
J Psychopharmacol 23, 487-494
   Abstract »    PDF »
Characterisation of the effects of caffeine on sleep in the rat: a potential model of sleep disruption.
L. Paterson, S. Wilson, D. Nutt, P. Hutson, and M Ivarsson (2009)
J Psychopharmacol 23, 475-486
   Abstract »    PDF »
Control and Function of the Homeostatic Sleep Response by Adenosine A1 Receptors.
T. E. Bjorness, C. L. Kelly, T. Gao, V. Poffenberger, and R. W. Greene (2009)
J. Neurosci. 29, 1267-1276
   Abstract »    Full Text »    PDF »
Adenosine A1 and A2A Receptors in Mouse Prefrontal Cortex Modulate Acetylcholine Release and Behavioral Arousal.
C. J. Van Dort, H. A. Baghdoyan, and R. Lydic (2009)
J. Neurosci. 29, 871-881
   Abstract »    Full Text »    PDF »
Sleep fragmentation impairs ventilatory long-term facilitation via adenosine A1 receptors.
M. McGuire, J. L. Tartar, Y. Cao, R. W. McCarley, D. P. White, R. E. Strecker, and L. Ling (2008)
J. Physiol. 586, 5215-5229
   Abstract »    Full Text »    PDF »
Sleep Loss and Sleepiness: Current Issues.
T. J. Balkin, T. Rupp, D. Picchioni, and N. J. Wesensten (2008)
Chest 134, 653-660
   Abstract »    Full Text »    PDF »
Identification of a population of sleep-active cerebral cortex neurons.
D. Gerashchenko, J. P. Wisor, D. Burns, R. K. Reh, P. J. Shiromani, T. Sakurai, H. O. de la Iglesia, and T. S. Kilduff (2008)
PNAS 105, 10227-10232
   Abstract »    Full Text »    PDF »
Histamine in the Nervous System.
H. L. Haas, O. A. Sergeeva, and O. Selbach (2008)
Physiol Rev 88, 1183-1241
   Abstract »    Full Text »    PDF »
Temporal distributions of seizure occurrence from various epileptogenic regions.
T. S. Durazzo, S. S. Spencer, R. B. Duckrow, E. J. Novotny, D. D. Spencer, and H. P. Zaveri (2008)
Neurology 70, 1265-1271
   Abstract »    Full Text »    PDF »
An emerging link between general anesthesia and sleep.
R. Allada (2008)
PNAS 105, 2257-2258
   Full Text »    PDF »
Effects of Ibotenate and 192IgG-Saporin Lesions of the Nucleus Basalis Magnocellularis/Substantia Innominata on Spontaneous Sleep and Wake States and on Recovery Sleep after Sleep Deprivation in Rats.
S. Kaur, A. Junek, M. A. Black, and K. Semba (2008)
J. Neurosci. 28, 491-504
   Abstract »    Full Text »    PDF »
Mathematical Model of Network Dynamics Governing Mouse Sleep-Wake Behavior.
C. G. D. Behn, E. N. Brown, T. E. Scammell, and N. J. Kopell (2007)
J Neurophysiol 97, 3828-3840
   Abstract »    Full Text »    PDF »
The Neuropharmacology of Sleep Disorders: Better Sleeping Through Chemistry?.
J. Suhl (2007)
Journal of Pharmacy Practice 20, 181-191
   Abstract »    PDF »
Physiology and Pathophysiology of Purinergic Neurotransmission.
G. Burnstock (2007)
Physiol Rev 87, 659-797
   Abstract »    Full Text »    PDF »
Sleep Deprivation Increases A1 Adenosine Receptor Binding in the Human Brain: A Positron Emission Tomography Study.
D. Elmenhorst, P. T. Meyer, O. H. Winz, A. Matusch, J. Ermert, H. H. Coenen, R. Basheer, H. L. Haas, K. Zilles, and A. Bauer (2007)
J. Neurosci. 27, 2410-2415
   Abstract »    Full Text »    PDF »
Adenosine Inhibits Activity of Hypocretin/Orexin Neurons by the A1 Receptor in the Lateral Hypothalamus: A Possible Sleep-Promoting Effect.
Z.-W. Liu and X.-B. Gao (2007)
J Neurophysiol 97, 837-848
   Abstract »    Full Text »    PDF »
Neurobiology of the Sleep-Wake Cycle: Sleep Architecture, Circadian Regulation, and Regulatory Feedback.
P. M. Fuller, J. J. Gooley, and C. B. Saper (2006)
J Biol Rhythms 21, 482-493
   Abstract »    PDF »
Adenosine and Sleep Homeostasis in the Basal Forebrain.
C. Blanco-Centurion, M. Xu, E. Murillo-Rodriguez, D. Gerashchenko, A. M. Shiromani, R. J. Salin-Pascual, P. R. Hof, and P. J. Shiromani (2006)
J. Neurosci. 26, 8092-8100
   Abstract »    Full Text »    PDF »
Neuron-glia metabolic coupling and plasticity.
P. J. Magistretti (2006)
J. Exp. Biol. 209, 2304-2311
   Abstract »    Full Text »    PDF »
Neuronal metabolism governs cortical network response state.
M. O. Cunningham, D. D. Pervouchine, C. Racca, N. J. Kopell, C. H. Davies, R. S. G. Jones, R. D. Traub, and M. A. Whittington (2006)
PNAS 103, 5597-5601
   Abstract »    Full Text »    PDF »
Altered sleep-wake characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 receptor knockout mice.
Z.-L. Huang, T. Mochizuki, W.-M. Qu, Z.-Y. Hong, T. Watanabe, Y. Urade, and O. Hayaishi (2006)
PNAS 103, 4687-4692
   Abstract »    Full Text »    PDF »
The Pathogenesis of Obstructive Sleep Apnea: Advances in the Past 100 Years.
D. P. White (2006)
Am. J. Respir. Cell Mol. Biol. 34, 1-6
   Full Text »    PDF »
Effects on sleep of microdialysis of adenosine A1 and A2a receptor analogs into the lateral preoptic area of rats.
M. M. Methippara, S. Kumar, Md. N. Alam, R. Szymusiak, and D. McGinty (2005)
Am J Physiol Regulatory Integrative Comp Physiol 289, R1715-R1723
   Abstract »    Full Text »    PDF »
Timing and Consolidation of Human Sleep, Wakefulness, and Performance by a Symphony of Oscillators.
D.-J. Dijk and M. von Schantz (2005)
J Biol Rhythms 20, 279-290
   Abstract »    PDF »
Locus Ceruleus Control of Slow-Wave Homeostasis.
C. Cirelli, R. Huber, A. Gopalakrishnan, T. L. Southard, and G. Tononi (2005)
J. Neurosci. 25, 4503-4511
   Abstract »    Full Text »    PDF »
Syndromic patent ductus arteriosus: Evidence for haploinsufficient TFAP2B mutations and identification of a linked sleep disorder.
A. Mani, J. Radhakrishnan, A. Farhi, K. S. Carew, C. A. Warnes, C. Nelson-Williams, R. W. Day, B. Pober, M. W. State, and R. P. Lifton (2005)
PNAS 102, 2975-2979
   Abstract »    Full Text »    PDF »
A Circadian Clock and Light/Dark Adaptation Differentially Regulate Adenosine in the Mammalian Retina.
C. Ribelayga and S. C. Mangel (2005)
J. Neurosci. 25, 215-222
   Abstract »    Full Text »    PDF »
Mutant mice: sleep starved and chronologically clueless.
C. R. Jones (2004)
Am J Physiol Regulatory Integrative Comp Physiol 287, R10-R11
   Full Text »    PDF »
Modulation of the excitability of cholinergic basal forebrain neurones by KATP channels.
T. G. J. Allen and D. A. Brown (2004)
J. Physiol. 554, 353-370
   Abstract »    Full Text »    PDF »
Minireview: Sleep regulation in adenosine A2A receptor-deficient mice.
Y. Urade, N. Eguchi, W.-M. Qu, M. Sakata, Z.-L. Huang, J.-F. Chen, M. A. Schwarzschild, J. S. Fink, and O. Hayaishi (2003)
Neurology 61, S94-96
   Full Text »
Sleep deprivation reduces proliferation of cells in the dentate gyrus of the hippocampus in rats.
R. guzman-marin, N. Suntsova, D. R Stewart, H. Gong, R. Szymusiak, and D. McGinty (2003)
J. Physiol. 549, 563-571
   Abstract »    Full Text »    PDF »
A1 Receptor and Adenosinergic Homeostatic Regulation of Sleep-Wakefulness: Effects of Antisense to the A1 Receptor in the Cholinergic Basal Forebrain.
M. M. Thakkar, S. Winston, and R. W. McCarley (2003)
J. Neurosci. 23, 4278-4287
   Abstract »    Full Text »    PDF »
Resetting Intrinsic Purinergic Modulation of Neural Activity: An Associative Mechanism?.
N. Dale (2002)
J. Neurosci. 22, 10461-10469
   Abstract »    Full Text »    PDF »
Adenosine Induces Inositol 1,4,5-Trisphosphate Receptor-Mediated Mobilization of Intracellular Calcium Stores in Basal Forebrain Cholinergic Neurons.
R. Basheer, E. Arrigoni, H. S. Thatte, R. W. Greene, I. S. Ambudkar, and R. W. McCarley (2002)
J. Neurosci. 22, 7680-7686
   Abstract »    Full Text »    PDF »
Differential Modulation of Nucleus Accumbens Synapses.
J. M. Brundege and J. T. Williams (2002)
J Neurophysiol 88, 142-151
   Abstract »    Full Text »    PDF »
Brain Glycogen Decreases with Increased Periods of Wakefulness: Implications for Homeostatic Drive to Sleep.
J. Kong, P. N. Shepel, C. P. Holden, M. Mackiewicz, A. I. Pack, and J. D. Geiger (2002)
J. Neurosci. 22, 5581-5587
   Abstract »    Full Text »    PDF »
Sleep deprivation decreases glycogen in the cerebellum but not in the cortex of young rats.
P. Gip, G. Hagiwara, N. F. Ruby, and H. C. Heller (2002)
Am J Physiol Regulatory Integrative Comp Physiol 283, R54-R59
   Abstract »    Full Text »    PDF »
Pharmacological Protection of Synaptic Function, Spatial Learning, and Memory from Transient Hypoxia in Rats.
M.-K. Sun, H. Xu, and D. L. Alkon (2002)
J. Pharmacol. Exp. Ther. 300, 408-416
   Abstract »    Full Text »    PDF »
International Union of Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors.
B. B. Fredholm, A. P. IJzerman, K. A. Jacobson, K.-N. Klotz, and J. Linden (2001)
Pharmacol. Rev. 53, 527-552
   Abstract »    Full Text »    PDF »
Hibernation, a Model of Neuroprotection.
F. Zhou, X. Zhu, R. J. Castellani, R. Stimmelmayr, G. Perry, M. A. Smith, and K. L. Drew (2001)
Am. J. Pathol. 158, 2145-2151
   Abstract »    Full Text »    PDF »
Dopaminergic Role in Stimulant-Induced Wakefulness.
J. P. Wisor, S. Nishino, I. Sora, G. H. Uhl, E. Mignot, and D. M. Edgar (2001)
J. Neurosci. 21, 1787-1794
   Abstract »    Full Text »    PDF »
Adenosine-Mediated Presynaptic Modulation of Glutamatergic Transmission in the Laterodorsal Tegmentum.
E. Arrigoni, D. G. Rainnie, R. W. McCarley, and R. W. Greene (2001)
J. Neurosci. 21, 1076-1085
   Abstract »    Full Text »    PDF »
Nitric Oxide-Stimulated Increase in Extracellular Adenosine Accumulation in Rat Forebrain Neurons in Culture Is Associated with ATP Hydrolysis and Inhibition of Adenosine Kinase Activity.
P. A. Rosenberg, Y. Li, M. Le, and Y. Zhang (2000)
J. Neurosci. 20, 6294-6301
   Abstract »    Full Text »    PDF »
Relief of G-Protein Inhibition of Calcium Channels and Short-Term Synaptic Facilitation in Cultured Hippocampal Neurons.
D. L. Brody and D. T. Yue (2000)
J. Neurosci. 20, 889-898
   Abstract »    Full Text »    PDF »
Compensatory sleep response to 12 h wakefulness in young and old rats.
P. J. Shiromani, J. Lu, D. Wagner, J. Thakkar, M. A. Greco, R. Basheer, and M. Thakkar (2000)
Am J Physiol Regulatory Integrative Comp Physiol 278, R125-R133
   Abstract »    Full Text »    PDF »
Adenosinergic modulation of rat basal forebrain neurons during sleep and waking: neuronal recording with microdialysis.
M. N. Alam, R. Szymusiak, H. Gong, J. King, and D. McGinty (1999)
J. Physiol. 521, 679-690
   Abstract »    Full Text »    PDF »
Nocturnal Increase in Plasma cGMP Levels in Humans.
I. V. Zhdanova, M. Simmons, J. N. Marcus, A. C. Busza, O. U. Leclair, and J. A. Taylor (1999)
J Biol Rhythms 14, 307-313
   Abstract »    PDF »
Adenosine: a Mediator of Interleukin-1beta -Induced Hippocampal Synaptic Inhibition.
W. P. Luk, Y. Zhang, T. D. White, F. A. Lue, C. Wu, C.-G. Jiang, L. Zhang, and H. Moldofsky (1999)
J. Neurosci. 19, 4238-4244
   Abstract »    Full Text »    PDF »
Temperature-Dependent Modulation of Excitatory Transmission in Hippocampal Slices Is Mediated by Extracellular Adenosine.
S. A. Masino and T. V. Dunwiddie (1999)
J. Neurosci. 19, 1932-1939
   Abstract »    Full Text »    PDF »
Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use.
B. B. Fredholm, K. Battig, J. Holmen, A. Nehlig, and E. E. Zvartau (1999)
Pharmacol. Rev. 51, 83-133
   Abstract »    Full Text »    PDF »
Caffeine Intake, Tolerance, and Withdrawal in Women: A Population-Based Twin Study.
K. S. Kendler and C. A. Prescott (1999)
Am J Psychiatry 156, 223-228
   Abstract »    Full Text »
Dissimilarity of slow-wave activity enhancement by torpor and sleep deprivation in a hibernator.
A. M. Strijkstra and S. Daan (1998)
Am J Physiol Regulatory Integrative Comp Physiol 275, R1110-R1117
   Abstract »    Full Text »    PDF »
Effects of sleep deprivation in neonatal rats.
M. G. Frank, R. Morrissette, and H. C. Heller (1998)
Am J Physiol Regulatory Integrative Comp Physiol 275, R148-R157
   Abstract »    Full Text »    PDF »
Compensatory Sleep Responses to Wakefulness Induced by the Dopamine Autoreceptor Antagonist (-)DS121.
M. F. Olive, W. F. Seidel, and D. M. Edgar (1998)
J. Pharmacol. Exp. Ther. 285, 1073-1083
   Abstract »    Full Text »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)