Although HA was suggested to be a waking substance in the brain many years ago (Monnier et al. 1970), it is now clear that histaminergic neurones and brain H1 receptors are essential for normal regulation of sleep-wake cycles. Findings in support of this conclusion have been summarized (Leurs et al. 1998; Brown et al. 2001): (1) CNS HA injections induce electrographic arousal, effects which are blocked by H1 antagonists (2) pharmacological or surgical manipulation of the histaminergic tuberomammillary system induces hypersomno-lence, and (3) histaminergic neurone activity and brain HA turnover rates follow sleep-wake cycles, with highest activity during wakeful periods. Current thought is that histaminergic neurones function within hypothalamic sleep-wake circuits, with inputs from orexin A— containing (wake-promoting) neurones and preoptic sleep regulatory centres, and outputs to several critical areas (Brown et al. 2001; Eriksson et al. 2001; Saper et al. 2001). Thus, the sedative profile of brain-penetrating H1 antagonists (which accounts for their clinical utility as over-the-counter sleep aids) is believed to be due to blockade of brain H1 receptors. In addition, the wake-promoting drug modafinil, whose mechanism remains elusive, was recently shown to activate histaminergic neurones (Scammell et al. 2000). H3 receptor modulation of the histaminergic system shows the expected effects on wakefulness. Thus, H3 antagonists, which act on pre-synaptic H3 receptors to increase the release of neuronal HA, promote wakefulness and decrease rapid eye movement (REM) and slow-wave sleep, whereas H3 agonists reduce neuronal HA release and increase slow-wave sleep (Lin et al. 1990; Leurs et al. 1998). Recent studies suggest that sleep disorders may have a histaminergic component; most interesting are results showing: (1) animal models of narcolepsy (in which the orexin [hypocretin] Hcrtr-2 receptor is mutated) have defective histaminergic transmission (Nishino et al. 2001), and (2) orexin A—induced arousal is abolished in H1 receptor-deficient mice (Huang etal. 2001).
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