Cardiovascular malfunction during sleep in adenosine A_<2A> receptor-deficient mice

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 15590217
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental physiology (including Physical medicine and Nutritional physiology)
• Research Institution: Osaka Bioscience Institute
• Principal Investigator: EGUCHI Naomi Osaka Bioscience Institute, Department of Molecular Behavioral Biology, Vice-Head, 分子行動生物学部門, 研究副部長 (10250086)
• Co-Investigator(Kenkyū-buntansha): SAKATA Mie Waseda University, Advanced Research Institute for Bioscience, Lecturer, 先端バイオ研究所, 講師 (10353525) ; URADE Yoshihiro Osaka Bioscience Institute, Department of Molecular Behavioral Biology, Head, 分子行動生物学部門, 研究部長 (10201360) ; SEI Hiroyoshi The University of Tokushima Graduate School, Institute of Health Biosciences, Department of Medical Informatics, Assistant Professor, 医学部・医学科・情報統合医学講座統合生理医学分野, 助教授 (40206602)
• Project Period (FY): 2003 – 2004
• Keywords: Rapid-eve movement sleep / Arterial pressure / Heart rate / Autonomic regulation / Adenosine / Dopamine / Adenosine A_<2A> receptor / ドーパミンD2受容体

Research Abstract

Autonomic function such as arterial pressure (AP), heart rate (HR), and respiration is quite stable and show the constant value during non-rapid eye movement (non-REM) sleep, but significantly fluctuates during REM sleep. However, the central mechanism for AP and HR changes associated with REM sleep remains unclear. Adenosine is an endogenous sleep substance. Dopamine serves as an AP regulator. An antagonistic interaction between adenosine A_<2A> receptor (A_<2A>R) and dopamine D_2 receptor has been well known. In this study, we simultaneously recorded electroencepharogram (EEG), electromyogram (EMG), AP, and HR in wild-type and the A_<2A>R gene-knockout (KO) mice to clarify the role of A_<2A>R in REM sleep-related cardiovascular function.
An A_<2A>R agonist (CGS-21680) induced sleep as judged by EEG and EMG recordings. In vivo microdialysis revealed that this agonist inhibited histamine release in both the frontal cortex and medial pre-optic area in a dose-dependent manner, and increased GABA release specifically in the histaminergic tuberomammillary nucleus but not in the frontal cortex. These results suggest that the A_<2A>R agonist induced sleep by inhibiting the histaminergic arousal system through increasing GABA release.
In wild-type mice, mean AP decreased during REM sleep, transiently dropped at REM sleep-offset, and then recovered to the basal level. HR also decreased during REM sleep, quickly increased at REM sleep-offset, and then recovered to the basal level. On the other hand, in A_<2A> KO mice, both mean AP and HR remarkably increased during REM sleep and then decreased quickly at REM sleep-offset. These results, taken together, indicate that A_<2A>R is involved in the autonomic regulation during REM sleep.

Research Products

• [Journal Article] Arterial pressure and heart rate increase during REM sleep in adenosine A_<2A>-receptor knockout mice, but not in wild-type mice. (2005)
  • Author(s): Sakata, M., Sei, H., Eguchi, N., Morita, Y., Urade, Y.
  • Journal Title: Neuropsychopharmacology (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Orexin A promotes histamine, but not norepinephrine or serotonin, release in frontal cortex of mice. (2005)
  • Author(s): Hong, Z.-Y., Huang, Z.-L., Qu, W.-M., Eguchi, N.
  • Journal Title: Acta Pharmacologica Sinica 26(2) Pages: 155-159
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] An adenosine A_<2A> receptor agonist induces sleep by increasing GABA release in the tuberomammillary nucleus to inhibit histaminergic systems in rats. (2005)
  • Author(s): Hong, Z.-Y., Huang, Z.-L., Qu, W.-M., Eguchi, N., Urade, Y., Hayaishi, O.
  • Journal Title: J. Neurochem. 92 Pages: 1542-1549
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] An adenosine A_<2A> receptor agonist induces sleep by increasing GABA release in the tuberomammillary nucleus to inhibit histaminergic systems in rats. (2005)
  • Author(s): Hong, Z.-Y., Huang, Z.-L., Qu, W.-M., Eguchi, N., Urade, Y, Hayaishi, O.
  • Journal Title: J.Neurochem. 92 Pages: 1542-1549
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Molecular mechanism of prostaglandin D_2-mediated non-REM sleep homeostasis studied by gene-knockout mice. (2004)
  • Author(s): Eguchi, N., Qu, W.-M., Huang, Z.-L., Sakata, M., Narumiya, S., Chen, J.-F., Urade, Y., Hayaishi, O.
  • Journal Title: Sleep and Biological Rhythms 2 Pages: S17-S18
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Histaminergic role in sleep-wake cycle of orexin, adenosine, and prostaglandin E_2 and D_2. (2004)
  • Author(s): Huang, Z.-L., Qu, W.-M., Eguchi, N., Chu, M., Okada, T., Sato, Y., Sakata, M., Mochizuki, T., Urade, Y., Hayaishi, O.
  • Journal Title: Sleep and Biological Rhythums 2 Pages: S21-S22
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adenosine A_<2A> receptor deficiency attenuates the somnogenic effect of prostaglandin D_2. (2004)
  • Author(s): Qu, W.-M., Huang, Z.-L., Mochizuki, T., Eguchi, N., Chen, J-F., Schwarzschild, M-A., Fink, S-J., Urade, Y., Hayaishi, O.
  • Journal Title: Sleep and Biological Rhythms 2 Pages: S55
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Lack of rebound of non-rapid eye movement sleep after sleep deprivation in adenosine A_<2A> receptor knockout mice. (2004)
  • Author(s): Sakata, M., Eguchim N., Qu, W.-M., Huang, Z.-L., Chen, J-F., Schwarzschild, M-A., Urade, Y., Hayaishi, O.
  • Journal Title: Sleep and Biological Rhythms 2 Pages: S56
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Extracellular histamine level in the frontal cortex is positively correlated with the amount of wakefulness in rats. (2004)
  • Author(s): Chu, M., Huang, Z-L., Qu, W-M., Eguchi, N., Yao, M-H., Urade, Y.
  • Journal Title: Neuroscience Research 49 Pages: 417-420
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genes for prostaglandin D synthase and receptor as well as adenosine A_<2A> Receptor are involved in the homeostatic regulation of NREM sleep. (2004)
  • Author(s): Hayaishi, O., Urade, Y., Eguchi, N., Huang, Zhi-Li.
  • Journal Title: Archives Italiennes de Biologie 142 Pages: 533-539
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Histaminergic role in sleep-wake cycle of orexin, adenosine, and prostaglandin E_2 and D_2. (2004)
  • Author(s): Huang, Z.-L., Qu, W.-M., Eguchi, N., Chu, M., Okada, T., Sato, Y., Sakata, M., Mochizuki, T., Urade, Y., Hayaishi, O.
  • Journal Title: Sleep and Biological Rhythms 2 Pages: S21-S22
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lack of rebound of non-rapid eye movement sleep after sleep deprivation in adenosine A_<2A> receptor knockout mice. (2004)
  • Author(s): Sakata, M., Eguchi, N., Qu, W.-M., Huang, Z.-L., Chen, J-F., Schwarzschild, M-A., Urade, Y., Hayaishi, O.
  • Journal Title: Sleep and Biological Rhythms 2 Pages: S56
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Extracellular histamine level in the frontal cortex is positively correlated with the amount of wakefulness in rats. (2004)
  • Author(s): Chu, M., Huang, Z-L, Qu, W-M, Eguchi, N., Yao, M-H., Urade, Y
  • Journal Title: Neuroscience Research 49 Pages: 417-420
  • Description: 「研究成果報告書概要(欧文)」より