Histaminergic Control of Sleep-Wake Cycles: Recent Therapeutic Advances for Sleep and Wake Disorders

The role of histaminergic neurotransmission in the promotion of waking has been extensively studied in preclinical species. Appreciation for the role of histamine continues to expand with increasing understanding of the interaction of histamine within the broad network of neuromodulators that regulate sleep and wake. The effects of histamine on waking are transduced through the H1 and the H3 receptors in the central nervous system. Brain penetrant over-the-counter antihistamines comprised of antagonist actions at H1 receptors as well as varying degrees of antimuscarinic properties are marketed as sleep aids, based on their well-known daytime drowsiness side effects. The data supporting their use as sedatives, however, are not consistent. H3 receptors are presynaptic receptors that limit histamine release as well as that of monoamine neurotransmitters thought to participate in the maintenance of waking. In this review, we discuss the existing studies on various antihistamines and antagonists of the H1 receptor in the regulation of sleep in preclinical studies, normal subjects and in subjects with sleep disorders. In addition, we review the current data available on the use of ligands at H3 receptors for the modulation of sleep and wake.