title: The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders.
abstract: Brain histaminergic neurons play a prominent role in arousal and maintenance of wakefulness (W). H(3)-receptors control the activity of histaminergic neurons through presynaptic autoinhibition. The role of H(3)-receptor antagonists/inverse agonists (H(3)R-antagonists) in the potential therapy of vigilance deficiency and sleep-wake disorders were studied by assessing their effects on the mouse cortical EEG and sleep-wake cycle in comparison to modafinil and classical psychostimulants. The H(3)R-antagonists, thioperamide and ciproxifan increased W and cortical EEG fast rhythms and, like modafinil, but unlike amphetamine and caffeine, their waking effects were not accompanied by sleep rebound. Conversely, imetit (H(3)R-agonist) enhanced slow wave sleep and dose-dependently attenuated ciproxifan-induced W, indicating that the effects of both ligands involve H(3)-receptor mechanisms. Additional studies using knockout (KO) mice confirmed the essential role of H(3)-receptors and histamine-mediated transmission in the wake properties of H(3)R-antagonists. Thus ciproxifan produced no increase in W in either histidine-decarboxylase (HDC, histamine-synthesizing enzyme) or H(1)- or H(3)-receptor KO-mice whereas its waking effects persisted in H(2)-receptor KO-mice. These data validate the hypothesis that H(3)R-antagonists, through disinhibition of H(3)-autoreceptors, enhancing synaptic histamine that in turn activates postsynaptic H(1)-receptors promoting W. Interestingly amphetamine and modafinil, despite their potent arousal effects, appear unlikely to depend on histaminergic mechanism as their effects still occurred in HDC KO-mice. The present study thus distinguishes two classes of wake-improving agents: the first acting through non-histaminergic mechanisms and the second acting via histamine and supports brain H(3)-receptors as potentially novel therapeutic targets for vigilance and sleep-wake disorders.
authors.affiliation: INSERM-U628, Department of Experimental Medicine, Faculty of Medicine, Claude Bernard University, 69373 Lyon, France.
authors.forename: R
authors.initials: R
authors.lastname: Parmentier
authors.forename: C
authors.initials: C
authors.lastname: Anaclet
authors.forename: C
authors.initials: C
authors.lastname: Guhennec
authors.forename: E
authors.initials: E
authors.lastname: Brousseau
authors.forename: D
authors.initials: D
authors.lastname: Bricout
authors.forename: T
authors.initials: T
authors.lastname: Giboulot
authors.forename: D
authors.initials: D
authors.lastname: Bozyczko-Coyne
authors.forename: K
authors.initials: K
authors.lastname: Spiegel
authors.forename: H
authors.initials: H
authors.lastname: Ohtsu
authors.forename: M
authors.initials: M
authors.lastname: Williams
authors.forename: J S
authors.initials: JS
authors.lastname: Lin
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000502:physiology; D004569:Electroencephalography / Q000187:drug effects; D006632:Histamine / Q000378:metabolism*; D017442:Histamine Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D006633:Histamine Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D000077408:Modafinil; D023421:Models, Animal; D018100:Receptors, Histamine H3 / Q000502:physiology*; D012890:Sleep / Q000187:drug effects / Q000502:physiology; D012893:Sleep Wake Disorders / Q000188:drug therapy; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
chemical_list: D001559:Benzhydryl Compounds; D017442:Histamine Agonists; D006633:Histamine Antagonists; D018100:Receptors, Histamine H3; D006632:Histamine; D000077408:Modafinil