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

Biochem Pharmacol. 2007 Apr 15;73(8):1157-71. doi: 10.1016/j.bcp.2007.01.002. Epub 2007 Jan 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds / pharmacology*
  • Benzhydryl Compounds / therapeutic use
  • Brain / drug effects
  • Brain / physiology
  • Electroencephalography / drug effects
  • Histamine / metabolism*
  • Histamine Agonists / pharmacology*
  • Histamine Agonists / therapeutic use
  • Histamine Antagonists / pharmacology*
  • Histamine Antagonists / therapeutic use
  • Mice
  • Mice, Knockout
  • Modafinil
  • Models, Animal
  • Receptors, Histamine H3 / physiology*
  • Sleep / drug effects
  • Sleep / physiology
  • Sleep Wake Disorders / drug therapy
  • Wakefulness / drug effects
  • Wakefulness / physiology


  • Benzhydryl Compounds
  • Histamine Agonists
  • Histamine Antagonists
  • Receptors, Histamine H3
  • Histamine
  • Modafinil