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The histaminergic network in the brain: basic organization and role in disease

Key Points

  • The histaminergic system is implicated in various brain disorders. A mutation in the gene encoding histidine decarboxylase, the histamine synthesizing enzyme, has been identified to be a cause of dominantly inherited Guilles de la Tourette syndrome.

  • In clinical trials, histamine H2 receptor antagonists have shown therapeutic efficacy for schizophrenia. and histamine H3 receptor antagonists have shown promise for combating daytime sleepiness in patients with narcolepsy.

  • In experimental allergic encephalomyelitis, a mouse model of multiple sclerosis, animals lacking histidine decarboxylase (and hence histamine synthesis) or histamine receptors show abnormal development of disease symptoms.

  • Histamine regulates feeding, obesity and the actions of leptin via histamine H1 receptor signalling in the hypothalamus; antipsychotic drugs bind to H1 receptors and cause obesity through this mechanism.

  • Histamine H3 receptor antagonists regulate alcohol self-administration and conditioned place preference in rodents, probably through a modulatory action on dopaminergic signalling. These drugs have already been tested for other disease conditions, so clinical trials on alcoholism could be carried out without extensive early phase studies.

Abstract

Histamine acts as a modulatory neurotransmitter in the mammalian brain. It has an important role in the maintenance of wakefulness, and dysfunction in the histaminergic system has been linked to narcolepsy. Recent evidence suggests that aberrant histamine signalling in the brain may also be a key factor in Gilles de la Tourette syndrome, Parkinson's disease and addictive behaviours. Furthermore, multiple sclerosis (MS) and experimental autoimmune encephalitis, which is an often-used model for MS, are associated with changes in the histaminergic system. This Review explores the possible roles of brain histamine in the mechanisms underlying these diseases.

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Figure 1: Human brain cortical, thalamocortical and thalamic histaminergic systems.
Figure 2: Localization of histamine receptors in different types of cells in the brain that are potentially involved in blood–brain barrier permeability and multiple sclerosis.
Figure 3: Key brain areas involved in the regulation of feeding and their innervation by histaminergic fibres.
Figure 4: Cortical, striatal and nigral neuronal systems regulated by H3 receptors.

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Acknowledgements

The authors thank H. Haas, R. Leurs, P. Blandina and B. Passani for comments on the manuscript. The authors' research on histamine is supported by COST Action BM 0806 and grants from the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Fund for Alcohol Research, Finska Läkaresällskapet and Magnus Ehrnrooth's Foundation.

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P.P. has received research supplies from Johnson & Johnson and an honorarium for speaking from Abbott Laboratories, and has stock ownership in Delichon Ltd, a biotechnology company, and Orion Pharma, a drug company. S.N. declares no competing financial interests.

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Glossary

Inverse agonists

Receptor ligands that have activity at a receptor that is independent of and opposite to the endogenous ligand; most classical receptor antagonists are in fact inverse agonists and true neutral antagonists that have no activity when bound to the receptor are rare.

Morpholino-oligonucleotide

An oligonucleotide that binds to mRNA and inhibits ribosome attachment. It is used to inhibit mRNA translation in zebrafish.

Cognition

This term refers to the mental processes involved in gaining knowledge and comprehension, including attention, learning, short-term memory, working memory and long-term memory.

Gilles de la Tourette syndrome

(GTS). This is a childhood-onset neuropsychiatric disorder with a prevalence close to 1% that is characterized by motor and vocal tics that usually diminish during later life. GTS is often associated one or several comorbidities, including attention-deficit hyperactivity disorder and obsessive-compulsive disorder.

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Panula, P., Nuutinen, S. The histaminergic network in the brain: basic organization and role in disease. Nat Rev Neurosci 14, 472–487 (2013). https://doi.org/10.1038/nrn3526

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