The brain H 3-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 3R-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 3R-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 3R-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 3R-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 3R-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.