Molecular Mechanism of Sleep–Wake Regulation: From Basic to Translational Research

  • Yoshihiro UradeEmail author


Sleep gives our body its needed rest, which prepares us for the next day’s activities. In our modern society, people suffer from sleep deprivation, which leads to an inability to concentrate, to a loss of judgment, and to an increased risk of accidents. It is reported that 1 in 4–5 Japanese has a sleep problem and that 1 in 9 Japanese uses sleeping pills regularly. Hypnotic drugs are prescribed for insomnia patients. The current sleeping pills developed from tranquilizers are much safer than the ones used in the past, as the latter were developed from anesthetic agents, which brought death in case too many pills were taken. However, the current type of sleeping pills causes a coma in case of an overdose. Such pills are sometimes used in crimes such as coma robbery cases.


NREM Sleep Extracellular Adenosine Physiological Sleep Increase NREM Sleep Somnogenic Effect 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Drs. Michael Lazarus and Zhi-Li Huang for helpful comments on this manuscript. This work was supported by grants from the Japan Society for the Promotion of Science, Japan Science and Technology Agency, Takeda Science Foundation, Sankyo Foundation, the Program of Basic and Applied Researches for Innovations in Bio-oriented Industry of Japan, Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd, and Osaka City.


  1. 1.
    Narumiya, S., Ogorochi, T., Nakao, K., et al. (1982). Prostaglandin D2 in rat brain, spinal cord and pituitary: Basal level and regional distribution. Life Sciences, 31, 2093–2103.PubMedCrossRefGoogle Scholar
  2. 2.
    Ogorochi, T., Narumiya, S., Mizuno, N., et al. (1984). Regional distribution of prostaglandins D2, E2, and F2 alpha and related enzymes in postmortem human brain. Journal of Neurochemistry, 43, 71–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Ueno, R., Ishikawa, Y., Nakayama, T., et al. (1982). Prostaglandin D2 induces sleep when microinjected into the preoptic area of conscious rats. Biochemical and Biophysical Research Communications, 109, 576–582.PubMedCrossRefGoogle Scholar
  4. 4.
    Onoe, H., Ueno, R., Fujita, I., et al. (1988). Prostaglandin D2, a cerebral sleep-inducing substance in monkeys. Proceedings of the National Academy of Sciences of the United States of America, 85, 4082–4086.PubMedCrossRefGoogle Scholar
  5. 5.
    Roberts, L. J., Sweetman, B. J., Lewis, R. A., et al. (1980). Increased production of prostaglandin D2 in patients with systemic mastocytosis. The New England Journal of Medicine, 303, 1400–1404.PubMedCrossRefGoogle Scholar
  6. 6.
    Pentreath, V. W., Rees, K., Owolabi, O. A., et al. (1990). The somnogenic T lymphocyte suppressor prostaglandin D2 is selectively elevated in cerebrospinal fluid of advanced sleeping sickness patients. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84, 795–799.PubMedCrossRefGoogle Scholar
  7. 7.
    Kohtoh, S., Taguchi, Y., Matsumoto, N., et al. (2008). Algorithm for sleep scoring in experimental animals based on fast Fourier transform power spectrum analysis of the electroencephalogram. Sleep and Biological Rhythms, 6, 163–171.CrossRefGoogle Scholar
  8. 8.
    Mizoguchi, A., Eguchi, N., Kimura, K., et al. (2001). Dominant localization of prostaglandin D receptors on arachnoid trabecular cells in mouse basal forebrain and their involvement in the regulation of non-rapid eye movement sleep. Proceedings of the National Academy of Sciences of the United States of America, 98, 11674–11679.PubMedCrossRefGoogle Scholar
  9. 9.
    Qu, W. M., Huang, Z. L., Xu, X. H., et al. (2006). Lipocalin-type prostaglandin D synthase produces prostaglandin D2 involved in regulation of physiological sleep. Proceedings of the National Academy of Sciences of the United States of America, 103, 17949–17954.PubMedCrossRefGoogle Scholar
  10. 10.
    Huang, Z. L., Qu, W. M., Eguchi, N., et al. (2005). Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nature Neuroscience, 8, 858–859.PubMedCrossRefGoogle Scholar
  11. 11.
    Lazarus, M., Shen, H. Y., Cherasse, Y., et al. (2011). Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens. Journal of Neuroscience, 31, 10067–10075.PubMedCrossRefGoogle Scholar
  12. 12.
    Makino, Y., Kondo, S., Nishimura, Y., et al. (2009). Hastatoside and verbenalin are sleep-promoting components in Verbena officinalis. Sleep and Biological Rhythms, 7, 211–217.CrossRefGoogle Scholar
  13. 13.
    Qiu, M. H., Qu, W. M., Xu, X. H., et al. (2009). D1/D2 receptor-targeting L-stepholidine, an active ingredient of the Chinese herb Stephonia, induces non-rapid eye movement sleep in mice. Pharmacology, Biochemistry and Behavior, 94, 16–23.CrossRefGoogle Scholar
  14. 14.
    Omori, K., Kagami, Y., Yokoyama, C., et al. (2012). Promotion of non-rapid eye movement sleep in mice after oral administration of ornithine. Sleep and Biological Rhythms, 10, 38–45.CrossRefGoogle Scholar
  15. 15.
    Masaki, M., Aritake, K., Tanaka, H., et al. (2012). Crocin promotes non-rapid eye movement sleep in mice. Molecular Nutrition & Food Research, 56, 304–308.CrossRefGoogle Scholar
  16. 16.
    Liu, Z., Xu, X. H., Liu, T. Y., et al. (2012). Safranal enhances non-rapid eye movement sleep in pentobarbital-treated mice. CNS Neuroscience & Therapeutics. 18, 623–630.Google Scholar
  17. 17.
    Qu, W. M., Yue, X. F., Sun, Y., et al. (2012). Honokiol promotes non-rapid eye movement sleep via the benzodiazepine site of the GABAA receptor in mice. British Journal of Pharmacology. 167, 587–598.PubMedGoogle Scholar
  18. 18.
    Chen, C., Zhou, X., Luo, Y., et al. (2012). Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, induces sleep via the benzodiazepine site of GABAA receptor in mice. Neuropharmacology. 63, 1191–1199.Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Molecular Behavioral BiologyOsaka Bioscience InstituteSuita-shi, OsakaJapan

Personalised recommendations