title: α-Pinene, a Major Constituent of Pine Tree Oils, Enhances Non-Rapid Eye Movement Sleep in Mice through GABAA-benzodiazepine Receptors.
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 GABAAreceptor-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 GABAAreceptor.
authors: 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.).
authors: Hyejin
authors: H
authors: Yang
authors: 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.).
authors: Junsung
authors: J
authors: Woo
authors: 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.).
authors: Ae Nim
authors: AN
authors: Pae
authors: 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.).
authors: Min Young
authors: MY
authors: Um
authors: 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.).
authors: Nam-Chul
authors: NC
authors: Cho
authors: 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.).
authors: Ki Duk
authors: KD
authors: Park
authors: 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.).
authors: Minseok
authors: M
authors: Yoon
authors: 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.).
authors: Jiyoung
authors: J
authors: Kim
authors: 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.) cjl@kist.re.kr smcho@kfri.re.kr.
authors: C Justin
authors: CJ
authors: Lee
authors: 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.) cjl@kist.re.kr smcho@kfri.re.kr.
authors: Suengmok
authors: S
authors: Cho
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism*; D000081008:Bicyclic Monoterpenes; D001665:Binding Sites; D005133:Eye Movements / Q000187:drug effects*; D005442:Flumazenil / Q000737:chemistry / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D039821:Monoterpenes / Q000737:chemistry / Q000494:pharmacology*; D010424:Pentobarbital; D028223:Pinus / Q000737:chemistry*; D010938:Plant Oils / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects*; D012895:Sleep, REM / Q000187:drug effects; D013997:Time Factors; D014851:Wakefulness / Q000187:drug effects; D000077334:Zolpidem
chemical_list: D000081008:Bicyclic Monoterpenes; D039821:Monoterpenes; D010938:Plant Oils; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D000077334:Zolpidem; D010424:Pentobarbital; C005451:alpha-pinene