[Regulation of the phases of the sleep-wakefulness cycle with histamine]

Distributed neural networks in the brain sustain generation of wakefulness and two sleep states: non-REM sleep and REM sleep. These three behavioral states are jointly ingrained in a rhythmic sequence that constitutes the sleep-wakefulness cycle. This paper reviews and updates knowledge about the involvement of the histaminergic system in sleep-wakefulness cycle organization. Histaminergic neurons are exclusively located in the hypothalamic tuberomammillary nucleus, but are the source of a widespread projection system to many brain regions. Histamine neurons are active during waking, especially with high attention need, and remain silent in both non-REM and REM sleep. There have been described four metabotropic histamine receptors, of which H1R, H2R and H3R are present in the nervous system. H1R and H2R are mainly postsynaptic heteroreceptors, whereas H3R is thought to be mostly a presynaptic auto- and hetero-receptor. Histaminergic neurons are excited by hypocretinergic neurons and most of the arousing hypocretin effects are thought to depend on histaminergic actions. Interactions among histaminergic axons and cholinergic nuclei within forebrain and brainstem are particularly important for cortical activation. In contrast, histaminergic tuberomammillary neurons, similarly to other aminergic neurons in locus coeruleus or dorsal raphe nucleus, are inhibited by non-REM sleep-promoting neurons of the preoptic region. Further inhibitory actions on histamine neurons come from adenosine release on tuberomammillary region. Finally, histaminergic neurons inhibit REM-on hypothalamic neurons containing melanine-concentrating hormone, thus supporting a permissive role of tuberomammillary nucleus in REM sleep. Actually, knockout mice for histidine decarboxylase, the enzyme synthetizing histamine, show a significant REM sleep increase.