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

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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 [1-3], 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 [5-9].

Histaminergic perikarya occur exclusively in the tuberomammillary nucleus (TMn) and adjacent areas of the posterior hypothalamus [10-13], a heterogeneous area crucial for waking as its destruction or inactivation induces hypersomnia [4-6]. 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 [2-4; 10-13]. 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 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 a-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 [25-28] 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 [7-9].

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.