title: Role of histamine H1-receptor on behavioral states and wake maintenance during deficiency of a brain activating system: A study using a knockout mouse model.
abstract: Using knockout (KO) mice lacking the histamine (HA)-synthesizing enzyme (histidine decarboxylase, HDC), we have previously shown the importance of histaminergic neurons in maintaining wakefulness (W) under behavioral challenges. Since the central actions of HA are mediated by several receptor subtypes, it remains to be determined which one(s) could be responsible for such a role. We have therefore compared the cortical-EEG, sleep and W under baseline conditions or behavioral/pharmacological stimuli in littermate wild-type (WT) and H1-receptor KO (H1-/-) mice. We found that H1-/- mice shared several characteristics with HDC KO mice, i.e. 1) a decrease in W after lights-off despite its normal baseline daily amount; 2) a decreased EEG slow wave sleep (SWS)/W power ratio; 3) inability to maintain W in response to behavioral challenges demonstrated by a decreased sleep latency when facing various stimuli. These effects were mediated by central H1-receptors. Indeed, in WT mice, injection of triprolidine, a brain-penetrating H1-receptor antagonist increased SWS, whereas ciproxifan (H3-receptor antagonist/inverse agonist) elicited W; all these injections had no effect in H1-/- mice. Finally, H1-/- mice showed markedly greater changes in EEG power (notably in the 0.8-5 Hz band) and sleep-wake cycle than in WT mice after application of a cholinergic antagonist or an indirect agonist, i.e., scopolamine or physostigmine. Hence, the role of HA in wake-promotion is largely ensured by H1-receptors. An upregulated cholinergic system may account for a quasi-normal daily amount of W in HDC or H1-receptor KO mice and likely constitutes a major compensatory mechanism when the brain is facing deficiency of an activating system. This article is part of the Special Issue entitled 'Histamine Receptors'.
authors.affiliation: Waking Team, Integrative Physiology of the Brain Arousal Systems, CRNL, INSERM-U1028, CNRS UMR5292, School of Medicine, Claude Bernard University, Lyon, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Parmentier
authors.affiliation: Waking Team, Integrative Physiology of the Brain Arousal Systems, CRNL, INSERM-U1028, CNRS UMR5292, School of Medicine, Claude Bernard University, Lyon, France; Department of Physiology, Zhongshan Medical College, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Waking Team, Integrative Physiology of the Brain Arousal Systems, CRNL, INSERM-U1028, CNRS UMR5292, School of Medicine, Claude Bernard University, Lyon, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Perier
authors.affiliation: Waking Team, Integrative Physiology of the Brain Arousal Systems, CRNL, INSERM-U1028, CNRS UMR5292, School of Medicine, Claude Bernard University, Lyon, France.
authors.forename: Hideo
authors.initials: H
authors.lastname: Akaoka
authors.affiliation: Department of Anatomy and Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Minnamaija
authors.initials: M
authors.lastname: Lintunen
authors.affiliation: Department of Neuroscience, Anatomy, Histology & Embryology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Anatomy and Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Pertti
authors.initials: P
authors.lastname: Panula
authors.affiliation: Unit for Immune Surveillance Research, Research Center for Allergy and Immunology, RIKEN Institute, Tsurumi-ku, Yokohama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Waking Team, Integrative Physiology of the Brain Arousal Systems, CRNL, INSERM-U1028, CNRS UMR5292, School of Medicine, Claude Bernard University, Lyon, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Franco
authors.affiliation: Waking Team, Integrative Physiology of the Brain Arousal Systems, CRNL, INSERM-U1028, CNRS UMR5292, School of Medicine, Claude Bernard University, Lyon, France. Electronic address: lin@univ-lyonl.fr.
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Lin
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018680:Cholinergic Antagonists / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010830:Physostigmine / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism; D012601:Scopolamine / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D014311:Triprolidine / Q000494:pharmacology; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology*
chemical_list: D018680:Cholinergic Antagonists; D002800:Cholinesterase Inhibitors; D006634:Histamine H1 Antagonists; D054828:Histamine H3 Antagonists; D007093:Imidazoles; D011969:Receptors, Histamine H1; D018100:Receptors, Histamine H3; D014311:Triprolidine; C115705:ciproxifan; D010830:Physostigmine; D012601:Scopolamine
keywords: Arousal; Behavior; Cholinergic transmission; Compensation; Cortical activation; EEG; H1-receptor; Histamine; Knockout mice; Sleep; Wakefulness