Original Article | Published:

The Sleep-Promoting and Hypothermic Effects of Glycine are Mediated by NMDA Receptors in the Suprachiasmatic Nucleus

Neuropsychopharmacology volume 40, pages 14051416 (2015) | Download Citation

Abstract

The use of glycine as a therapeutic option for improving sleep quality is a novel and safe approach. However, despite clinical evidence of its efficacy, the details of its mechanism remain poorly understood. In this study, we investigated the site of action and sleep-promoting mechanisms of glycine in rats. In acute sleep disturbance, oral administration of glycine-induced non-rapid eye movement (REM) sleep and shortened NREM sleep latency with a simultaneous decrease in core temperature. Oral and intracerebroventricular injection of glycine elevated cutaneous blood flow (CBF) at the plantar surface in a dose-dependent manner, resulting in heat loss. Pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists AP5 and CGP78608 but not the glycine receptor antagonist strychnine inhibited the CBF increase caused by glycine injection into the brain. Induction of c-Fos expression was observed in the hypothalamic nuclei, including the medial preoptic area (MPO) and the suprachiasmatic nucleus (SCN) shell after glycine administration. Bilateral microinjection of glycine into the SCN elevated CBF in a dose-dependent manner, whereas no effect was observed when glycine was injected into the MPO and dorsal subparaventricular zone. In addition, microinjection of D-serine into the SCN also increased CBF, whereas these effects were blocked in the presence of L-701324. SCN ablation completely abolished the sleep-promoting and hypothermic effects of glycine. These data suggest that exogenous glycine promotes sleep via peripheral vasodilatation through the activation of NMDA receptors in the SCN shell.

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Acknowledgements

We thank Dr Yoichi Ueta and Dr Takashi Maruyama (University of Occupational and Environmental Health, Kitakyusyu, Japan) for their valuable comments.

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Author notes

    • Nobuhiro Kawai
    •  & Noriaki Sakai

    These authors contributed equally to the work.

Affiliations

  1. Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Japan

    • Nobuhiro Kawai
    • , Sachie Karakawa
    • , Yosuke Tsuneyoshi
    • , Noriko Kawasaki
    • , Tomoko Takeda
    •  & Makoto Bannai
  2. Sleep and Circadian Neurobiology laboratory, Stanford University School of Medicine, Stanford, CA, USA

    • Noriaki Sakai
    • , Masashi Okuro
    •  & Seiji Nishino
  3. Department of Geriatric Medicine, Kanazawa Medical University, Kanazawa, Japan

    • Masashi Okuro

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Correspondence to Makoto Bannai.

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DOI

https://doi.org/10.1038/npp.2014.326

Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)

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