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How does histamine e ect our brain

and nervous system?

How does histamine e ect our brain

and nervous system?
Histamine is a natural substance produced by the human body and is a substance with many
important functions. Histamine was rst isolated in 1907 by Windaus and Vogt, but research is
ongoing in both health and disease since its initial description more than a hundred years ago.1

Histamine was considered an amine that was only part of the local immune response in the
in ammation process (immunomodulation). However, it can cause local vasodilation, stimulation
of gastric secretion, smooth muscle contraction (as bronchial muscle), and nerve stimulation.

In fact, Kwiatkowski at 1941 and White at 1959 demonstrated its presence and formation in the
brain. Histamine recently has been considered an endogenous chemical that acts as messenger
between cells belonging to the nervous system also known as a neurotransmitter.2

How Histamine exerts its e ect on the human body

According to Per Brodal’s book named “The Central Nervous System” and Benarroch Eduardo’s
publication named “Histamine in the SNC, Multiple functions and potential neurologic
implications”, histamine exerts its e ects by binding to G protein-coupled histamine receptors.

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7/20/2020 How does histamine effect our brain and nervous system? - MTHFRSupport Australia

There exist four varieties of histamine receptors named H1, H2, H3, and H4. The H1, H2, and H3
receptors are widely distributed around all the central nervous system. However, H4 receptors are
mainly found in peripheral tissues, such as the bone marrow and white blood cells, and to a lesser
amount, in the colon, liver, lung, small intestine, spleen, testes, thymus, tonsils, and trachea.3, 4

The H1 receptors can regulate neuronal excitation in most brain regions (brain stem,
hypothalamus, thalamus, amygdala, septum, hippocampus, olfactory bulb, and cortex). This kind
of receptor activates the K+ channels through an increase of calcium ion (Ca2+) concentration
which decreases the neuronal cells excitability and inhibit the cells ring in hippocampal
pyramidal neurons. Classic antihistamines, and some antidepressants or antipsychotics perform
their function through H1R, with the well-known side-e ect of sedation.2

On the other hand, H2 receptors are mainly found in the basal ganglia, amygdala, hippocampus,
and cortex. H1R are also found in some of these locations, which leads to synergistic interactions
between these receptors types. H2R performs its function through adensyl cyclase and the
increase of intracellular cAMP, which later activates the protein kinase A (PKA) and the
transcription factor CREB. All of them are substances capable of regulating the neuronal
physiology and plasticity. In mice, a de ciency in H2R function produces selective cognitive
de cits, impairment in hippocampal LTP, and abnormalities in nociception.2, 4

Likewise, H3 receptor acts as a presynaptic heteroreceptor and releases a variety of other

transmitters like biogenic amines, acetylcholine, glutamate, GABA, and peptidergic systems. The
loss of its function in mice is associated with behavioral state abnormalities (such as hyperphagia,
late-onset obesity, increased insulin and leptin levels).2

What are the e ects of Histamine in the central nervous system?

According to the location of its receptors in the central nervous system, histamine can trigger
di erent responses in the human body including:

– Thalamus and cerebral cortex: Arousal and wakefulness.

These e ects of histamine were suggested by experts when they noted that most


antihistamines had sedation as side e ect.

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7/20/2020 How does histamine effect our brain and nervous system? - MTHFRSupport Australia

– Hypothalamus, glial cells, and blood vessels: Homeostatic processes (such as food and water
intake, hormones secretion, temperature regulation, among others).

The histaminergic system in the human brain is really extensive (approximately 64,000 neurons)
and it is located between the mammillary bodies and the chiasma opticum, in other words,
around the tuberomammillary nucleus in the posterior hypothalamus.

Histaminergic neurons mostly possess large somata and between 2 and 3 large dendrites, similar
to other species’ histaminergic neurons.2, 5, 6

How histaminergic signals are transmitted in the central nervous system?

In the human body, histamine signals are sent from the posterior hypothalamus to the forebrain,
brainstem, and spinal cord by direct action and through activation of other neurotransmitters.The
histamine release is non-synaptic, which means that a signi cant number of neuromodulators
must be activated to produce the release and help with the e ect of histamine.This is considered
the “slow” transmission mechanisms because second messengers are needed for the entire
process.7,8

Histamine is also able to carry out a fast neurotransmission in the nervous system. When the
tuberomammillary cells are excited they can evoke a fast and excitatory response in the
supraoptic neurons mediated by histamine, and these e ects can be blocked with the use of
histamine antagonists.8

What is the relationship between histamine and the pineal gland?

A lot of current studies are looking at the amount of histamine content in the pineal gland (an
endocrine gland located in the brain of vertebrates). To date, the histamine function in the pineal
gland is a mystery. A current hypothesis is histamine could convey information from the brain to
the pineal gland, but other researchers claim histamine simply acts as a local modulator in the
pineal gland.5,10

What other studies have concluded about histamine

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7/20/2020 How does histamine effect our brain and nervous system? - MTHFRSupport Australia

According to other researches, histamine could be involved in the transmission and processing of
visual signals in the brain, especially in mammals, in whom the information about light and dark
cycle is obtained through the eyes and it is processed in the retinohypothalamic tract to later be
sent to the SCN.11

What Nervous system diseases are related to alterations of histamine?

Parkinson’s disease (PD) and schizophrenia (SCZ) are frequent central nervous disorders with no
clear etiology, but currently they have been related to elevated levels of histamine and the
Thr105Ile substitution in the histamine N-methyltransferase gene (HNMT-Thr105Ile) involved in
histamine degradation.12

The result of the study named “Association of Histamine N-Methyltransferase Thr105Ile

Polymorphism with Parkinson’s Disease and Schizophrenia in Han Chinese: A Case-Control Study”
suggest that the HNMT-Thr105Ile locus is associated with the risk of both PD and SCZ in Han
Chinese while the minor Ile105 allele conferring a protective e ect against both disorders.

Other Conditions associated with Histamine

Sleep disorders13


Eating disorders and metabolic syndrome14,15



Neuroin ammation16


Migraine17


Dementia, Epilepsy and Vestibular disorders16



In conclusion, histamine is a natural substance needed for many processes in the human body. It
is considered an important substance for both physiological and pathological processes within
and outside the nervous system. It is related to alertness and is considered an important
neurotransmitter.

Histamine is being studied more and more each day. Research in the last several years has
increased the knowledge about histamine and its role in several neurodegenerative diseases,
such as multiple sclerosis, Alzheimer’s disease, and Wernicke’s encephalopathy.

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7/20/2020 How does histamine effect our brain and nervous system? - MTHFRSupport Australia

Many a ectors a ect brain histamine levels and we are learning more and more each day.

Bibliography

1Josef Donnerer, Fred Lembeck, The Chemical Languages of the Nervous System: History of
Scientists and Substances, Switzerland, 2006.

2Helmut L. Haas, Olga A. Sergeeva, Oliver Selbach, Histamine in the Nervous System, Physiological
Reviews, Published 1 July 2008 Vol. 88 no. 3, 1183-1241 DOI: 10.1152/physrev.00043.2007.

3Per Brodal, The Central Nervous System, fth edition, OXFORD university press, 2016.

4Benarroch, Eduardo E., Histamine in the CNS, multiple functions and potential neurologic
implications, Clinical Implications of Neuroscience Research, Neurology October 19, 2010 vol. 75
no. 16 1472-1479.

5Jerzy Z. Nowak, Histamine in the central nervous system: its role in circadian rhythmicity,
Department of Biogenic Amines, Polish Academy of Sciences, 3 Tylna St., 90-950 E6di,
ActaNeurobiologiaeExperimentalis 1994,54 (Suppl.): 56, 85, Poland.

6Philip Lieberman, Histamine, antihistamines, and the central nervous system, Allergy and
Asthma Proceedings, Volume 30, Number 5, September/October 2009, pp. 482-486(5).

7Scott Brady, George Siegel, R. Wayne, Basic Neurochemistry: Molecular, Cellular and Medical
Aspects, seventh edition, ELSEVIER, Canada, 2006.

8Hough Lindsay B., Histamine Actions in the Central Nervous System, Department of
Pharmacology and Neuroscience, Albany Medical College, A-136, Albany, New York 12208.

9Besharse J.C., Iuvone P.M., Pierce M.E. (1988) Regulation of rhythmic photoreceptor metabolism:
a role for post-receptoral neurons. In: Progress in retinal research (Eds N.N. Osborne and G.J.
Chader). Vol. 7. Pergamon, Oxford, p. 21-61.

10.Karl BjørnarAlstadhaug, Histamine in Migraine and Brain, The Journal of Head and Face Pain
54, January 2014 with 147 Reads DOI: 10.1111/head.12293 · Source: PubMed
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11Rogawski Michael A., Barker Je ery, Neurotransmitter Actions in the Vertebrate Nervous
System, National Institute of Neurological and Communicative Disorder and Stroke, Bethesda,
Maryland 1985.

12Xinglong Yang et al., Association of Histamine N-Methyltransferase Thr105Ile Polymorphism

with Parkinson’s Disease and Schizophrenia in Han Chinese: A Case-Control Study, Published:
March 13, 2015http://dx.doi.org/10.1371/journal.pone.0119692.

13John J, Wu MF, Boehmer LN, Siegel JM. Cataplexy-active neurons in the hypothalamus:
implications for the role of histamine in sleep and waking behavior. Neuron. 2004 May
27;42(4):619-34.

14Jørgensen EA, Vogelsang TW, Knigge U, Watanabe T, Warberg J, Kjaer A. Increased susceptibility
to diet-induced obesity in histamine-de cient mice. Neuroendocrinology. 2006 Nov 13;83(5-
6):289-94

15 Masaki T, Yoshimatsu H. The hypothalamic H 1 receptor: a novel therapeutic target for

disrupting diurnal feeding rhythm and obesity. Trends in pharmacological sciences. 2006 May
31;27(5):279-84.

16Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiological reviews. 2008
Jul 1;88(3):1183-1241.

17Alstadhaug KB. Histamine in migraine and brain. Headache: The Journal of Head and Face Pain.
2014 Feb 1;54(2):246-59

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