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, Suengmok Cho

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 partialmodulator at the BZDbinding 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.

Original languageEnglish
Pages (from-to)530-539
Number of pages10
JournalMolecular Pharmacology
Volume90
Issue number5
DOIs
Publication statusPublished - 2016 Nov

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Yang, H., Woo, J., Pae, A. N., Um, M. Y., Cho, N. C., Park, K. D., Yoon, M., Kim, J., Lee, C. J., & Cho, S. (2016). α-pinene, a major constituent of pine tree oils, enhances non-rapid eye movement sleep in mice through GABAA-benzodiazepine receptors. Molecular Pharmacology, 90(5), 530-539. https://doi.org/10.1124/mol.116.105080