Histamine in the regulation of wakefulness

Abstract

The histaminergic system is exclusively localized within the posterior hypothalamus with projection to almost all the major regions of the central nervous system. Strong and consistent evidence exist to suggest that histamine, acting via H₁ and/or H₃ receptor has a pivotal role in the regulation of sleep-wakefulness. Administration of histamine or H₁ receptor agonists induces wakefulness, whereas administration of H₁ receptor antagonists promotes sleep. The H₃ receptor functions as an auto-receptor and regulates the synthesis and release of histamine. Activation of H₃ receptor reduces histamine release and promotes sleep. Conversely, blockade of H₃ receptor promotes wakefulness. Histamine release in the hypothalamus and other target regions is highest during wakefulness. The histaminergic neurons display maximal activity during the state of high vigilance, and cease their activity during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. The cerebrospinal levels of histamine are reduced in diseased states where hypersomnolence is a major symptom. The histamine deficient L-histidine decarboxylase knockout (HDC KO) mice display sleep fragmentation and increased REM sleep during the light period along with profound wakefulness deficit at dark onset, and in novel environment. Similar results have been obtained when histamine neurons are lesioned. These studies strongly implicate the histaminergic neurons of the TMN to play a critical role in the maintenance of high vigilance state during wakefulness.

Figure 1

Schematic representation of the location and distribution of the histaminergic system in the brain. The histamine containing neurons are localized in the tuberomammillary nucleus (TMN) within the posterior hypothalamus and send projections throughout the brain. Abbreviations: BF = basal forebrain; HPO= hippocampus; HY = hypothalamus; OB = Olfactory bulb; ST= Striatum; TMN = tuberomammillary nucleus; Adapted from (118).

Figure 2

Histamine synthesis and metabolism in neurons. The L-histidine is transported into neurons by L-amino acid transporter. Once inside the neuron, L-histidine is converted into histamine by a specific enzyme histidine decarboxylase. Subsequently histamine is taken up into vesicles by the vesicular monoamine-transporter and stored until released. In absence of high affinity uptake mechanism in the brain, released histamine is quickly degraded by histamine methyltransferase which is located post-synaptically and in glia to tele-methyl-histamine, a metabolite that does not show any histamine-like activity.

Figure 3

Histamine release measured from the preoptic/anterior hypothalamus of freely behaving cats across sleep-wakefulness. Histamine release was higher during wakefulness as compared non-REM and REM sleep values in each experiment (represent by each line) producing a highly significant group effect [N=5; for details see (105); Adapted from (105).