Elsevier

Sleep Medicine Reviews

Volume 15, Issue 1, February 2011, Pages 65-74
Sleep Medicine Reviews

Physiological Review
Histamine in the regulation of wakefulness

https://doi.org/10.1016/j.smrv.2010.06.004Get rights and content

Summary

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.

Introduction

The state of wakefulness is an ensemble of multiple and coherent behaviors that allows the interaction with the external world. It is the manifestation of increased activity in the cortex (cortical activation or desynchronization). Increased activation of cortex is the result of concerted increase in the activity of multiple neuronal aggregates, localized in various brain regions, and utilizing multiple neurotransmitters. Each system is distinct and has a special role in the maintenance of wakefulness. For example, the glutamatergic neurons of the brainstem reticular formation and the cholinergic neurons of the ponto-mesencephalic tegmentum and basal forebrain display maximal activity during wakefulness and rapid eye movement (REM) sleep and may promote cortical activation during wakefulness and REM sleep. In contrast, the monoaminergic systems namely, the norepinephrine containing locus coeruleus neurons, the serotonin containing neurons of the raphe nuclei and the histamine containing neurons of the tuberomammillary nucleus (TMN) are unique in the sense that these groups increase their discharge during wakefulness and completely cease firing during REM sleep. It is believed that the monoaminergic systems act in concert with other arousal systems to maintain wakefulness and inhibit REM sleep. We have focused this review on histaminergic neurons of the TMN and their role in the regulation of sleep-wakefulness. An interested reader is encouraged to consult more detailed reviews about other arousal systems and their role in sleep-wakefulness.1, 2, 3, 4, 5

Section snippets

History of histamine

It was in early 20th century when the sedative side effects of antihistamines were first discovered. This propelled histamine into the central nervous system (CNS) and histamine was termed as a “waking substance”.6 While research on other monoamines (norepinephrine and serotonin) in the CNS thrived during the first half of 20th century, research on histamine lagged behind, mainly because fluorescent histochemistry that revealed the presence of norepinephrinergic and serotonergic systems in the

Anatomical localization of histamine neurons

The histamine containing neurons (Fig. 1) are mainly localized in the tuberomammillary nucleus (TMN) and adjacent areas within the posterior hypothalamus. The TMN, (the name derived from tuber cinerium meaning a pale swelling; see 16) was named by Malone and consists of several dense clusters of large, characteristic neurons, as well as scattered neurons with the same morphology and staining properties in surrounding, more heterogeneous regions. The TMN is localized rostral to the mammillary

Synthesis and metabolism of histamine

Two distinct pools of histamine exist in the brain: the neuronal and the non-neuronal pool. All brain histaminergic actions are the result of histamine released by histamine neurons. The histamine contribution from the non-neuronal pool (mainly by mast cells) is limited.10 The blood brain barrier is impermeable to histamine. Histamine in the brain is formed from the essential amino acid l-histidine (Fig. 2). Histamine synthesis occurs in two steps: 1) neuronal uptake of l-histidine by l-amino

Histamine in sleep-wakefulness

The first study examining the effects of antihistamines on sleep-wakefulness was performed in cats and reported an increase in non-rapid eye movement (NREM) sleep coupled with a reduction in REM sleep.25 Similar results were also obtained in dogs and humans.26, 27 Intraventricular (icv) application of histamine in anesthetized rat produces a dose-dependent decrease in narcosis duration, whereas in conscious animals, it produces classical signs of wakefulness including EEG desynchronization,

Pharmacological studies in animals

The bulk of evidence supporting the role of histamine in control of wakefulness was derived from pharmacological studies in animal models. For easier reading these preclinical studies are divided into subgroups and described below:

Pharmacological studies in humans

The first generation antihistamine can easily penetrate the blood brain barrier and cause drowsiness and sedation. Several of these antihistamines including the non-selective HI receptor antagonists from the phenothiazine class and “over the counter” diphenhydramine, have been examined for their effects on daytime sleepiness as well as on subjective and objective measures of nocturnal sleep in healthy human subjects and are extensively reviewed elsewhere.70, 71 We have sampled some studies and

The TMN neurons

The histamine containing TMN neurons are spontaneously active at resting potential (−50 mV) with broad shouldered spike (mid-amplitude duration ∼2 ms), mainly due to fast Na+ and Ca2+ conductions and a deep (∼15 mV) and long-lasting Ca+ independent after-hyperpolarization (∼450 ms duration) that brings the membrane potential down to −80 mV.81 The onset of an action potential is the result of slow depolarizing potential mediated by voltage dependent Ca2+ current and a slow tetrodotoxin (TTX)

Measurement of histamine release and turnover

The histaminergic system appears to be under strong circadian control. Microdialysis measurement of histamine release from the anterior hypothalamic area of freely behaving rats, maintained under 12:12 h light:dark cycle, reveals that histamine release anticipates wakefulness and increases during the second half of the light period. Histamine release peaks during the dark period when the rats are fully awake and active.101 Similar results have been obtained after push-pull cannula measurement of

Inactivation/lesion studies

Inactivation of the ventrolateral posterior hypothalamus (in and around the TMN) by local application of muscimol (0.1–1.0 μg/0.5 μL), a potent agonist of GABA, induces long-lasting NREM sleep followed by a significant increase in REM sleep. Systemic administration of p-chlorophenylalanine, a potent serotonin synthesis inhibitor produces long-lasting insomnia. Local administration of muscimol in these insomniac cats promotes NREM and REM sleep with short latency.124

Local administration of the

Histamine in diseased states

The monoaminergic neurons of the locus coeruleus and dorsal raphe reduce or cease their activity during cataplexy in narcoleptic dogs. However, the histaminergic neurons of the TMN remain active.127 Narcoleptic dogs display histamine deficit in the cortex and thalamus. In contrast, dopamine and NE levels remain elevated in the same brain structures.128 Similarly, CSF levels of histamine are reduced in non-medicated human subjects with narcolepsy or idiopathic hypersomnia. However, similar

Conclusion

Does the histaminergic system regulate wakefulness? The histaminergic system is localized within the TMN, which is a nucleus in the posterior hypothalamus. Since the early part of the 20th century, posterior hypothalamus has been implicated in the regulation of wakefulness. The histaminergic neurons send strong projections especially to the wakefulness-promoting regions including the orexin rich perifornical hypothalamus and the cholinergic rich basal forebrain. The discharge activity of

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