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

Molecular pharmacology, 2016-11, Vol.90 (5), p.530-539 [Peer Reviewed Journal]

Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics. ;EISSN: 1521-0111 ;DOI: 10.1124/mol.116.105080 ;PMID: 27573669

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Title:
α-Pinene, a Major Constituent of Pine Tree Oils, Enhances Non-Rapid Eye Movement Sleep in Mice through GABAA-benzodiazepine Receptors
Author: Yang, Hyejin ; Woo, Junsung ; Pae, Ae Nim ; Um, Min Young ; Cho, Nam-Chul ; Park, Ki Duk ; Yoon, Minseok ; Kim, Jiyoung ; Lee, C Justin ; Cho, Suengmok
Subjects: Animals ; Benzodiazepines - metabolism ; Binding Sites ; Eye Movements - drug effects ; Flumazenil - chemistry ; Flumazenil - pharmacology ; Inhibitory Postsynaptic Potentials - drug effects ; Male ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Models, Molecular ; Monoterpenes - chemistry ; Monoterpenes - pharmacology ; Pentobarbital ; Pinus - chemistry ; Plant Oils - pharmacology ; Pyridines - chemistry ; Pyridines - pharmacology ; Receptors, GABA-A - metabolism ; Sleep - drug effects ; Sleep, REM - drug effects ; Time Factors ; Wakefulness - drug effects
Is Part Of: Molecular pharmacology, 2016-11, Vol.90 (5), p.530-539
Description: 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 GABA -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 GABA 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 GABA -BZD receptors, and fully antagonized by flumazenil, an antagonist for GABA -BZD receptor. (-)-α-pinene was found to bind to aromatic residues of α1- and -γ2 subunits of GABA -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 GABA -BZD receptors and directly binding to the BZD binding site of GABA receptor.
Publisher: United States
Language: English
Identifier: EISSN: 1521-0111
DOI: 10.1124/mol.116.105080
PMID: 27573669
Source: Geneva Foundation Free Medical Journals
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α-Pinene, a Major Constituent of Pine Tree Oils, Enhances Non-Rapid Eye Movement Sleep in Mice through GABAA-benzodiazepine Receptors

Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics. ;EISSN: 1521-0111 ;DOI: 10.1124/mol.116.105080 ;PMID: 27573669

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