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

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.