Abstract
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 language | English |
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Pages (from-to) | 1157-1171 |
Number of pages | 15 |
Journal | Biochemical Pharmacology |
Volume | 73 |
Issue number | 8 |
DOIs | |
Publication status | Published - 2007 Apr 15 |
Externally published | Yes |
Keywords
- 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