The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders

R. Parmentier, C. Anaclet, C. Guhennec, E. Brousseau, D. Bricout, T. Giboulot, D. Bozyczko-Coyne, K. Spiegel, H. Ohtsu, M. Williams, J. S. Lin

Research output: Contribution to journalArticlepeer-review

149 Citations (Scopus)


Brain histaminergic neurons play a prominent role in arousal and maintenance of wakefulness (W). H3-receptors control the activity of histaminergic neurons through presynaptic autoinhibition. The role of H3-receptor antagonists/inverse agonists (H3R-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 H3R-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 (H3R-agonist) enhanced slow wave sleep and dose-dependently attenuated ciproxifan-induced W, indicating that the effects of both ligands involve H3-receptor mechanisms. Additional studies using knockout (KO) mice confirmed the essential role of H3-receptors and histamine-mediated transmission in the wake properties of H3R-antagonists. Thus ciproxifan produced no increase in W in either histidine-decarboxylase (HDC, histamine-synthesizing enzyme) or H1- or H3-receptor KO-mice whereas its waking effects persisted in H2-receptor KO-mice. These data validate the hypothesis that H3R-antagonists, through disinhibition of H3-autoreceptors, enhancing synaptic histamine that in turn activates postsynaptic H1-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 H3-receptors as potentially novel therapeutic targets for vigilance and sleep-wake disorders.

Original languageEnglish
Pages (from-to)1157-1171
Number of pages15
JournalBiochemical Pharmacology
Issue number8
Publication statusPublished - 2007 Apr 15
Externally publishedYes


  • Arousal
  • Cortical EEG
  • H-receptor
  • Histamine
  • Knockout mice
  • Modafinil
  • Narcolepsy
  • Psychostimulant
  • Sleep-wake cycle
  • Sleep-wake disorders
  • Somnolence
  • Vigilance

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


Dive into the research topics of 'The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders'. Together they form a unique fingerprint.

Cite this