title: Doxepin and diphenhydramine increased non-rapid eye movement sleep through blockade of histamine H1 receptors.
abstract: Histaminergic neurons have been reported to play an important role in the regulation of sleep-wake behavior through the histamine H1 receptor (R, H1R). First generation H1R antagonists, such as doxepin and diphenhydramine, produce drowsiness in humans, and are occasionally used to treat insomnia. However, if H1R antagonists function via physically blocking the H1R remains unclear. In the current study, we used H1R knockout (KO) mice to investigate if the sleep-promoting effects of doxepin and diphenhydramine are dependent on blockade of the H1R. When doxepin was administered, non-rapid eye movement (NREM) sleep in wild type (WT) mice increased for 4h, with an increase in the numbers of NREM sleep bouts of 256-512 s and 512-1024 s. These effects were not observed in the H1R KO mice. Furthermore, diphenhydramine increased NREM sleep for 6h in WT, and not in the H1R KO mice after the injection. These results indicate that both doxepin at 15 mg/kg and diphenhydramine at 10 mg/kg induce NREM sleep through blockade of H1R.
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Yi-Qun
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Yohko
authors.initials: Y
authors.lastname: Takata
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, Fudan University, Shanghai, China; The Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Ze
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Meng-Qi
authors.initials: MQ
authors.lastname: Zhang
authors.affiliation: Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, Fudan University, Shanghai, China; The Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: quweimin@fudan.edu.cn.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Qu
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, Fudan University, Shanghai, China; The Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: huangzl@fudan.edu.cn.
authors.forename: Zhi-Li
authors.initials: ZL
authors.lastname: Huang
mesh_terms: D000818:Animals; D004155:Diphenhydramine / Q000494:pharmacology*; D004316:Doxepin / Q000494:pharmacology*; D004569:Electroencephalography; D004576:Electromyography; D005133:Eye Movements / Q000187:drug effects*; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017286:Polysomnography; D012890:Sleep / Q000187:drug effects*
chemical_list: D006634:Histamine H1 Antagonists; D004316:Doxepin; D004155:Diphenhydramine
keywords: H(1) receptor; Knockout mice; NREM sleep; Wakefulness