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  • Review Article
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The role of histamine and the tuberomamillary nucleus in the nervous system

Key Points

  • Since the discovery that antihistamines have a sedative action, it has become clear that histamine has important actions in the central nervous system (CNS). Early on, it was suggested that it acts as a 'waking' substance. The tuberomamillary (TM) nucleus was found to be the sole source of histaminergic neurons and their projections, and it is now thought that the histaminergic TM nucleus system commands general states of metabolism and consciousness.

  • Histamine is synthesized in the brains of almost all animal species, although the histamine content varies greatly between species. The main terminal areas of the histaminergic projections cover essentially all areas of the CNS.

  • The histaminergic neurons in the TM nucleus are pacemakers that fire at a slow regular rate, although this rate can vary depending on the behavioural state — their activity is high during waking and attention, and low or absent during sleep. The rate of histamine turnover is high during hibernation, implying that histamine might be involved in the maintenance of the hibernating state and/or arousal from hibernation.

  • Four histamine receptors — H1, H2, H3 and H4 — have been identified in vertebrates. H1, H2 and H3 are prominently expressed in the brain in specific cellular compartments, whereas H4 is detected predominantly in the periphery. The H1 and H2 receptors mostly excite neurons or potentiate excitatory inputs. By contrast, H3 receptor activation causes autoinhibition of TM neurons and inhibition of the release of excitatory and inhibitory neurotransmitters.

  • Malfunctioning of the histaminergic system has been associated with several neurological diseases, including Alzheimer's and Parkinson's. Histamine has also been shown to protect against convulsions.

Abstract

The histaminergic system in the brain is a phylogenetically old group of neurons that project to most of the central nervous system. It holds a key position in the regulation of basic body functions, including the sleep–waking cycle, energy and endocrine homeostasis, synaptic plasticity and learning. Four histamine receptors have now been cloned, and three of them are widely distributed in the mammalian brain. Here, we will discuss the localization, biochemistry and physiological functions of the components of the histaminergic system.

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Figure 1: The histaminergic system in the human brain: origin and projections.
Figure 2: Distribution of histamine and its receptors in the brain.
Figure 3: Properties of histaminergic neurons.
Figure 4: Tuberomamillary neurons and their targets.
Figure 5: Signalling pathways activated by histamine receptors.
Figure 6: Neurophysiological action of histamine.
Figure 7: Histamine and synaptic plasticity.

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Acknowledgements

We thank K. Eriksson, J. Kaslin, M. Lintunen, K. Michelsen, T.-K. Kukko-Lukjanov, O. Selbach and O. Sergeeva for valuable comments on the manuscript. The Academy of Finland, the Alcohol Research Foundation and the Sigrid Juselius Foundation support the research of P.P., and the Deutsche Forschungsgemeinschaft supports the work of H.L.H.

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DATABASES

LocusLink

Gi

Gs

Gq/11

H1

H2

H3

H4

OMIM

Alzheimer disease

Down syndrome

Parkinson disease

schizophrenia

FURTHER INFORMATION

Encyclopedia of Life Sciences

Alzheimer disease

epilepsy

histamine biosynthesis and function

learning and memory

Parkinson disease

schizophrenia

sleep disorders

Glossary

POLYAMINES

Organic compounds that contain two or more amino groups. Putrescine, spermine and spermidine are prime examples.

GALANIN

A neuropeptide the functions of which include the regulation of appetite and hormone secretion.

MAST CELL

A type of leukocyte, of the granulocyte subclass, with large secretory granules containing histamine and various protein mediators.

SLOW-WAVE SLEEP

The deepest phase of sleep associated with slow delta waves in the electroencephalogram.

FOS

An immediate early gene that is rapidly turned on when neurons increase their activity. It can therefore be used as a sign of neuronal activity.

AFTERHYPERPOLARIZATION

The membrane hyperpolarization that follows the occurrence of an action potential.

A-TYPE CURRENT

A K+-current whose steady-state inactivation at resting potential is removed with hyperpolarization. It activates transiently in the subthreshold range of the membrane potential and thus prolongs the afterhyperpolarization.

RECTIFICATION

The property whereby current through a channel does not flow with the same ease from the inside as from the outside. In inward rectification, for instance, current into the cell flows more easily than out of the cell through the same population of channels.

PREPOTENTIALS

Fluctuations of membrane voltage that bring neurons closer to threshold but are not immediately followed by an action potential.

TETRODOTOXIN

(TTX). A potent neurotoxin from the Tetraodon puffer fish that blocks voltage-gated sodium channels.

PATCH-CLAMP ANALYSIS

Technique whereby a very small electrode tip is sealed onto a patch of cell membrane, thereby making it possible to record the flow of current through individual ion channels or the whole cell.

OREXINS

A hypothalamic peptide with a key role in sleep regulation that is also associated with feeding behaviour.

LEAK POTASSIUM CONDUCTANCE

A fixed background current that is present at rest, and depends on the presence of the KCNK family of K+ channels.

ACCOMMODATION

Cessation of neuronal firing despite persistent depolarization above threshold.

LONG-TERM POTENTIATION

(LTP). An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways.

PORTACAVAL-SHUNTED RATS

Animals in which the portal vein has been surgically connected to the inferior vena cava, thereby reducing the flow of blood to the liver.

NEGATIVE SYMPTOMS

Schizophrenia is characterized by two kinds of symptoms: negative symptoms (the absence of behaviours that are found in people that do not have the disease, such as communicative speech and emotional reactivity) and positive symptoms (the presence of behaviours that are not found in normal people, such as delusions and hallucinations).

POLYMORPHISM

The simultaneous existence in the same population of two or more genotypes in frequencies that cannot be explained by recurrent mutations.

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Haas, H., Panula, P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 4, 121–130 (2003). https://doi.org/10.1038/nrn1034

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