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Research ArticleArticle

α-Pinene, a Major Constituent of Pine Tree Oils, Enhances Non-Rapid Eye Movement Sleep in Mice through GABAA-benzodiazepine Receptors

Hyejin Yang, Junsung Woo, Ae Nim Pae, Min Young Um, Nam-Chul Cho, Ki Duk Park, Minseok Yoon, Jiyoung Kim, C. Justin Lee and Suengmok Cho
Molecular Pharmacology November 2016, 90 (5) 530-539; DOI: https://doi.org/10.1124/mol.116.105080
Hyejin Yang
Division of Functional Food Research, Korea Food Research Institute, Seongnam, Republic of Korea (H.Y., M.Y.U., M.Y., J.K., S.C.); Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, Republic of Korea (J.W., C.J.L.); Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Seoul, Republic of Korea (A.N.P. ,N.-C.C., K.D.P.); and KU-KIST Graduate School of Converging Sciences and Technologies, Korea University, Seoul, Republic of Korea (C.J.L.)
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Junsung Woo
Division of Functional Food Research, Korea Food Research Institute, Seongnam, Republic of Korea (H.Y., M.Y.U., M.Y., J.K., S.C.); Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, Republic of Korea (J.W., C.J.L.); Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Seoul, Republic of Korea (A.N.P. ,N.-C.C., K.D.P.); and KU-KIST Graduate School of Converging Sciences and Technologies, Korea University, Seoul, Republic of Korea (C.J.L.)
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Ae Nim Pae
Division of Functional Food Research, Korea Food Research Institute, Seongnam, Republic of Korea (H.Y., M.Y.U., M.Y., J.K., S.C.); Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, Republic of Korea (J.W., C.J.L.); Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Seoul, Republic of Korea (A.N.P. ,N.-C.C., K.D.P.); and KU-KIST Graduate School of Converging Sciences and Technologies, Korea University, Seoul, Republic of Korea (C.J.L.)
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Min Young Um
Division of Functional Food Research, Korea Food Research Institute, Seongnam, Republic of Korea (H.Y., M.Y.U., M.Y., J.K., S.C.); Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, Republic of Korea (J.W., C.J.L.); Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Seoul, Republic of Korea (A.N.P. ,N.-C.C., K.D.P.); and KU-KIST Graduate School of Converging Sciences and Technologies, Korea University, Seoul, Republic of Korea (C.J.L.)
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Nam-Chul Cho
Division of Functional Food Research, Korea Food Research Institute, Seongnam, Republic of Korea (H.Y., M.Y.U., M.Y., J.K., S.C.); Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, Republic of Korea (J.W., C.J.L.); Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Seoul, Republic of Korea (A.N.P. ,N.-C.C., K.D.P.); and KU-KIST Graduate School of Converging Sciences and Technologies, Korea University, Seoul, Republic of Korea (C.J.L.)
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Ki Duk Park
Division of Functional Food Research, Korea Food Research Institute, Seongnam, Republic of Korea (H.Y., M.Y.U., M.Y., J.K., S.C.); Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, Republic of Korea (J.W., C.J.L.); Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Seoul, Republic of Korea (A.N.P. ,N.-C.C., K.D.P.); and KU-KIST Graduate School of Converging Sciences and Technologies, Korea University, Seoul, Republic of Korea (C.J.L.)
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Minseok Yoon
Division of Functional Food Research, Korea Food Research Institute, Seongnam, Republic of Korea (H.Y., M.Y.U., M.Y., J.K., S.C.); Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, Republic of Korea (J.W., C.J.L.); Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Seoul, Republic of Korea (A.N.P. ,N.-C.C., K.D.P.); and KU-KIST Graduate School of Converging Sciences and Technologies, Korea University, Seoul, Republic of Korea (C.J.L.)
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Jiyoung Kim
Division of Functional Food Research, Korea Food Research Institute, Seongnam, Republic of Korea (H.Y., M.Y.U., M.Y., J.K., S.C.); Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, Republic of Korea (J.W., C.J.L.); Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Seoul, Republic of Korea (A.N.P. ,N.-C.C., K.D.P.); and KU-KIST Graduate School of Converging Sciences and Technologies, Korea University, Seoul, Republic of Korea (C.J.L.)
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C. Justin Lee
Division of Functional Food Research, Korea Food Research Institute, Seongnam, Republic of Korea (H.Y., M.Y.U., M.Y., J.K., S.C.); Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, Republic of Korea (J.W., C.J.L.); Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Seoul, Republic of Korea (A.N.P. ,N.-C.C., K.D.P.); and KU-KIST Graduate School of Converging Sciences and Technologies, Korea University, Seoul, Republic of Korea (C.J.L.)
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Suengmok Cho
Division of Functional Food Research, Korea Food Research Institute, Seongnam, Republic of Korea (H.Y., M.Y.U., M.Y., J.K., S.C.); Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, Republic of Korea (J.W., C.J.L.); Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Seoul, Republic of Korea (A.N.P. ,N.-C.C., K.D.P.); and KU-KIST Graduate School of Converging Sciences and Technologies, Korea University, Seoul, Republic of Korea (C.J.L.)
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Abstract

α-Pinene is a major monoterpene of the pine tree essential oils. It has been reported that α-pinene shows anxiolytic and hypnotic effects upon inhaled administration. However, hypnotic effect by oral supplementation and the molecular mechanism of α-pinene have not been determined yet. By combining in vivo sleep behavior, ex vivo electrophysiological recording from brain slices, and in silico molecular modeling, we demonstrate that (−)-α-pinene shows sleep enhancing property through a direct binding to GABAA-benzodiazepine (BZD) receptors by acting as a partial modulator at the BZD binding site. The effect of (−)-α-pinene on sleep-wake profiles was evaluated by recording electroencephalogram and electromyogram. The molecular mechanism of (−)-α-pinene was investigated by electrophysiology and molecular docking study. (−)-α-pinene significantly increased the duration of non-rapid eye movement sleep (NREMS) and reduced the sleep latency by oral administration without affecting duration of rapid eye movement sleep and delta activity. (−)-α-pinene potentiated the GABAA receptor-mediated synaptic response by increasing the decay time constant of sIPSCs in hippocampal CA1 pyramidal neurons. These effects of (−)-α-pinene on sleep and inhibitory synaptic response were mimicked by zolpidem, acting as a modulator for GABAA-BZD receptors, and fully antagonized by flumazenil, an antagonist for GABAA-BZD receptor. (−)-α-pinene was found to bind to aromatic residues of α1- and -γ2 subunits of GABAA-BZD receptors in the molecular model. We conclude that (−)-α-pinene enhances the quantity of NREMS without affecting the intensity of NREMS by prolonging GABAergic synaptic transmission, acting as a partial modulator of GABAA-BZD receptors and directly binding to the BZD binding site of GABAA receptor.

Footnotes

    • Received May 9, 2016.
    • Accepted August 19, 2016.
  • H.Y. and J.W. contributed equally to this work.

  • This study was supported by grants from the Korea Food Research Institute [Grant E0164503-01], Creative Research Initiative Program, Korean National Research Foundation [Grant 2015R1A3A2066619], Korea Institute of Science and Technology [Grant 2E26662], KU-KIST Graduate School of Science and Technology program [Grant R1435281], and National Research Council of Science and Technology (NST) grant by the Korea government (MSIP) [Grant CRC-15-04-KIST].

  • dx.doi.org/10.1124/mol.116.105080.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 90 (5)
Molecular Pharmacology
Vol. 90, Issue 5
1 Nov 2016
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Research ArticleArticle

Sleep-enhancing Effect of α-Pinene through GABAA Receptor

Hyejin Yang, Junsung Woo, Ae Nim Pae, Min Young Um, Nam-Chul Cho, Ki Duk Park, Minseok Yoon, Jiyoung Kim, C. Justin Lee and Suengmok Cho
Molecular Pharmacology November 1, 2016, 90 (5) 530-539; DOI: https://doi.org/10.1124/mol.116.105080

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Research ArticleArticle

Sleep-enhancing Effect of α-Pinene through GABAA Receptor

Hyejin Yang, Junsung Woo, Ae Nim Pae, Min Young Um, Nam-Chul Cho, Ki Duk Park, Minseok Yoon, Jiyoung Kim, C. Justin Lee and Suengmok Cho
Molecular Pharmacology November 1, 2016, 90 (5) 530-539; DOI: https://doi.org/10.1124/mol.116.105080
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