Elsevier

Biochemical Pharmacology

Volume 73, Issue 8, 15 April 2007, Pages 1157-1171
Biochemical Pharmacology

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

https://doi.org/10.1016/j.bcp.2007.01.002Get rights and content

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.

Introduction

The functional importance of histamine (HA) in sleep–wake regulation dates back to the 1930s when the prototypical anti-histamine drugs were discovered. Now identified as H1-receptor antagonists, the use of this class of drugs in the treatment of allergic diseases is frequently associated with sedation, drowsiness and slowed reaction time in humans. With the discovery, in the early 1980s, that histamine is a central neurotransmitter [1], [2], [3], it was hypothesized that blockade of histamine-mediated transmission could be responsible for these side-effects. Recent experimental data support the hypothesis that histaminergic neurons constitute a major wake-promoting system [4] within the brain arousal networks [5], [6], [7], [8], [9].

Histaminergic perikarya occur exclusively in the tuberomammillary nucleus (TMn) and adjacent areas of the posterior hypothalamus [10], [11], [12], [13], a heterogeneous area crucial for waking as its destruction or inactivation induces hypersomnia [4], [5], [6]. TM neurons send inputs to various brain regions, notably those that control the sleep–wake cycle, such as the cortex, thalamus, preoptic and anterior hypothalamus, brainstem and forebrain cholinergic and monoaminergic structures [2], [3], [4], [10], [11], [12], [13]. Identified histaminergic neurons in the mouse [14] as well as presumed histaminergic cells in the cat [6], [15], discharge tonically and specifically during wakefulness; this pattern of activity being the most wake-selective pattern identified in the brain to date. Histaminergic neurons stimulate or facilitate target neurons in large brain areas through postsynaptic H1 and H2 receptors [2], [3], thus contributing to cortical activation [4]. Indeed, treatments that impair HA-mediated neurotransmission, e.g., blockade of HA synthesis or postsynaptic H1 receptors, increase cortical slow waves and enhance sleep. In contrast, enhancement of histaminergic neurotransmission promotes waking [4], [13], [16], [17]. Finally, Long-term abolition of HA synthesis in knockout (KO) mice impairs the cortical electroencephalogram (EEG) and has deleterious effect on both sleep and wake quality, thus causing permanent somnolence and behavioral deficits. Consequently, mice that lack brain HA are unable to remain awake when high vigilance is required, e.g. at lights off or placed in a new environment [16]. Together, these results indicate that HA-containing neurons have a key role in maintaining the brain awake under normal conditions and in the presence of behavioral challenges.

Since H3-receptors control the release, synthesis and turnover of HA and the neuronal activity of histaminergic cells [15], [18], [19], it was hypothesized that the cortical activity and sleep–wake cycle could be modulated through H3-receptor and consequently their ligands [20]. Consistent with this assumption, early studies in cats showed that sleep increased or decreased following, respectively, administration of H3-receptor agonists or antagonist/inverse agonists. Thioperamide, an imidazole H3R-antagonist, promoted cortical activation and waking while α-methylhistamine, a chiral H3R-agonist and BP2-94, another H3-receptor agonist, enhanced cortical slow activity and increased slow wave sleep [4], [20]. Similar results were obtained using H3R-agonists or antagonists in mice, rats and guinea pigs [16], [21], [22], although the effect of H3R-agonists appeared to be compound- and species-dependent [23], [24].

The robust effects of H3-receptor ligands in sleep–wake control in animals supports a potential role in treating human sleep–wake disorders, notably the use of H3R-antagonists to improve somnolence and vigilance deficiency of diverse pathophysiological origin. However, several important fundamental questions arise as regards to the characterization of their effects. For example, what are their effects on sleep–wake parameters as compared to those induced by the current wake-promoting compound modafinil [25], [26], [27], [28] or classical psychostimulants? Is their waking effect mediated specifically by H3-receptors and through HA-mediated neurotransmission? The latter question is particularly important as H3-receptors also function as heteroreceptors that control the release and synthesis of other neurotransmitters in addition to HA including acetylcholine, dopamine, norepinephrine, serotonin and galanin [3], [29], also involved in sleep–wake control [7], [8], [9].

In the present study, therefore, the effects of the H3R-antagonists, thioperamide and ciproxifan, were studied on the cortical EEG and sleep–wake cycle in mouse, a species in which the effects of H3R-ligands are less well documented, but of great interest in basic and preclinical investigations particularly because of increasing use of knockout (KO) models. The waking effects of H3R-antagonists were compared with those induced by the atypical stimulant, modafinil and the classical psychostimulants, amphetamine and caffeine. Additionally, the pharmacological profile of ciproxifan was evaluated using pharmacological antagonism with the H3R-agonist, imetit and in several KO mouse models in which HA-mediated neurotransmission was altered either in terms of synthesis or receptors.

Section snippets

Effects of modafinil, psychostimulants and H3-receptor antagonists on the mouse cortical EEG and sleep–wake cycle

To compare the wake promoting effects of H3R-antagonists versus modafinil and classical psychostimulants, C57/Black6/J genetic background mice (n = 22, Charles River, France) were implanted with electrodes to monitor the cortical EEG and sleep–wake cycle according to previously described methods [16]. Briefly, All mouse strains used in this study were housed individually in transparent barrels (Ø 20 cm, height 30 cm) in an insulated sound-proofed recording room maintained at an ambient temperature

Effects of the H3-receptor agonist, imetit on the mouse cortical EEG and sleep–wake cycle and ciproxifan-induced waking

From this and other studies, it is clearly established that H3R-antagonists promote waking and improve vigilance. An important corollary question is whether H3R-agonists induce or facilitate sleep. It was also important to verify if the waking effect of H3R-antagonists could be reversed by H3R-agonists. To this aim, the effects of imetit (a potent and selective H3R-agonist) were examined in the same mouse model (n = 8) during lights-off phase, when the animals spent most of the time awake at

Characterization of the wake-promoting agents with reference to histamine-mediated transmission using knockout mouse models

As HA neurons are thought to play a crucial role in maintaining cortical activation and waking, one may ask whether modafinil induces sustained wakefulness via activation of histaminergic neurons. The same question may be addressed regarding psychostimulants even though a predominant dopaminergic mechanism exists. The question has become more intriguing since reports in the rat of a c-fos expression in histaminergic tuberomammillary nucleus [41] and an increase in hypothalamic HA outflow [42],

Conclusions

Sleep–wake disorders constitute a major challenge of public health due to their high prevalence (19–37%) in the general population. Somnolence is associated with various pathological conditions including sleep apnea, excessive daytime sleepiness due to nocturnal insomnia, Parkinson's disease and narcolepsy or circumstances related to lifestyle, including daytime sleepiness due to voluntary sleep restriction or sleep deprivation resulting from night shift work, overwork or jet-lag. Novel, safe,

Acknowledgments

The authors wish to thank Colette Buda, Jean-Pierre Sastre and Gerard Guidon for their experimental and technical contributions, Pr H. Watanabe (Kyushu Univ. Fukuka, Japan) for providing the H1- and H2-receptor knockout mouse strains and Dr. H. Kotani (Banyu Pharmaceutical Co. Ltd, Japan) for providing the H3-receptor knockout mouse strain and Dr. J.M. Lecomte (Bioprojet, Paris, France) for the kind gift of ciproxifan to JSL This work was supported by (1) INSERM U52, U480 and U628, Lyon,

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