Histamine (HA), is a monoamine neurotransmitter promoting wakefulness in the central nervous system. Histaminergic neurons are found in the bilateral tuberomammillary nuclei in the hypothalamus and is part of the sleep/wake switch. In the periphery, histamine is an important paracrine signal molecule produced and released by leukocytes like mast cells and basophils to mediate local immune responses. 1st generation antihistamine drugs readily cross the blood-brain barrier and affected the brains receptors too, while 2nd generation drugs mainly affect receptors outside the CNS. Enterochromaffin-like cells in the stomach release histamine to stimulate gastric acid secretion from nearby parietal cells. Histamine is produced from the essential amino acid histidine. After its release, the signalling action of histamine is terminated by enzymatic breakdown. Antihistamines, acid reducers and certain kinds of antipsychotic and antidepressant medications affect histamine receptors.
Histamine production and release
Histamine (HA) is produced from the essential amino acid histidine (HIS), found in high-protein foods. Meat, poultry, eggs, fish, dairy, green vegetables and some grain products, including rice, wheat and rye, are examples of HA rich foods. After being absorbed in the gastrointestinal tract, histidine is transported by the bloodstream to the brain, where it crosses the blood-brain barrier (BBB) and enters the extracellular space by the use of the large neutral amino acid transporter (LAT). A specialized histidine transporter (TT) on histaminergic neurons moves histidine across the cell membrane (CM) into the cell. Inside, histidine is converted to HA by the enzyme histidine decarboxylase (HDC). Histamine is then packed into synaptic vesicles by the vesicular monoamine transporter (VMAT2). The neurotransmitter is then stored until a neuronal impulse signals its release into the synaptic cleft, where it can bind to various histamine receptors (HA-R)
Histamine termination of action and metabolism
The signalling action of histamine can be terminated by one of two enzymes. In the central nervous system, this enzyme is histamine N-methyltransferase (HNMT), which converts HA to N-methylhistamine with with S-adenosylmethionine (SAMe) as the methyl donor. HNMT is present in the cytosol of histaminergic neurons and nearby astroglial cells, but no specific histamine transporter is apparently present on the presynaptic terminal. Histamine is therefore more likely to diffuse away from the synapse, just like dopamine in the prefrontal cortex. Histamine in the synaptic cleft can be transported into nearby astroglia by two low-affinity transporters; plasma membrane monoamine transporter (PMAT) and organic cation transporter 3 (OCT3). PMAT and OCT3 on nearby astroglia seem to be the main mechanisms for clearing HA from the synaptic cleft, but this mechanism is still not fully understood. After HA has been methylated by HNMT, N-methylhistamine (NMH) can be converted by the enzyme monoamineoxidase B (MAO-B) to N-methylimidazole acetaldehyde (N-MIA), which is then quickly converted by aldehyde dehydrogenase (ALDH) to N-methylimidazole acetic acid (N-MIAA). N-MIAA is the major metabolite of histamine excreted in the urine, but NMH may also be excreted in urine directly. Histamine can also be inactivated by the enzyme diamine oxidase (DAO) outside the CNS. DAO converts histamine to imidazole acetaldehyde (IA), which is then quickly converted to imidazole acetic acid (IAA) by ALDH, and then subsequently ribosylated to imidazole acetic acid riboside (IAAR). The highest content of DAO is found in the digestive tract and the placenta.
Histamine act on four different histaminergic receptors in the human body. All are G protein-coupled receptors. Histamine can also act as an allosteric modulator when binding to the polyamine binding site on the NMDA receptor, which alters the effect of glutamate binding to it.
The H1-receptor is a Gq protein-coupled receptor that activates the enzyme phospholipase C (PLC) to produce the second messengers diacyl glycerol (DAG) and inositol trisphosphate (IP3). Activation of this receptor in the CNS promotes wakefulness, normal alertness and pro-cognitive actions. When H1-receptors are blocked by an antihistamine (H1-antagonist) capable of crossing the blood-brain barrier, the result is sedation, drowsiness and sleep. H1-antagonism may also contribute to weight gain, at least when combined with 5-HT2C antagonism. Outside the CNS, histamine is not a neurotransmitter, but a local messenger. H1-receptors are expressed on endothelium, smooth muscle and sensory nerves. Release of HA from local mast cells or basophils due to injury or immune system activation can result in increased endothelial permeability, vasodilation, bronchoconstriction, pruritus and hypernociception. H1-receptor stimulation also promotes NF-κB, a transcription factor that regulates inflammatory processes.
The H2-receptor is a Gs protein-coupled receptor that activates the enzyme adenylate cyclase to produce the second messenger cAMP. Stimulation of H2-receptors present on parietal cells results in gastric acid secretion, making it the target of anti-ulcer drugs with H2-blocking properties. Stimulation of H2-receptors on vascular smooth muscle lead to vasodilation. Not much is known about the function of the H2-receptors that are present in the CNS, but they are not connected to the hypothalamic wake/sleep switch as the H1-receptors are.
The H3-receptor is a Gi protein-coupled receptor that inhibits the enzyme adenylate cyclase, reducing the formation of the second messenger cAMP. It is found as a presynaptic autoreceptor on histaminergic neurons as part of a negative feedback loop, inhibiting the release of histamine when activated. It is also found as a postsynaptic heteroreceptor on other neurons, where it inhibits release of other monooamines, ACh and GABA. H3-receptors are also present outside the CNS, but to a lesser extent. Drugs targeting the H3-receptor are currently under investigation for the potential treatment of several different conditions.
The H4-receptor, as the H3-receptor, is a Gi protein-coupled receptor. It is expressed primarily in the cells and tissues of the immune system, especially in leukocytes and in the bone marrow. The receptor regulates the release of neutrophils from the bone marrow and play a role in mast cell chemotaxis, pruritus and cytokine production. H4-receptor antagonists may potentially have a role in the treatment of asthma and allergy.
All histamine neurons are located in the brain are located in the bilateral tuberomammillary nucleus (TMN) in the hypothalamus, from where they project to most brain regions and the spinal cord. The TMN is part of the sleep/wake-switch of the hypothalamus, with TMN being the “wake promoter”. The histaminergic neurons are active during the wake cycle, slows down during relaxation and tiredness, and are inactive during sleep. However, the majority of the histamine in the body is produced outside the CNS by leukocytes. Particularly mast cells and basophils, which are filled with granules of histamine, and is released as a paracrine signal molecule in response to immune activation or injury. Both mast cells and basophils can be sensitized by IgE antibodies and promptly degranulate to release histamine when exposed to antigens. Mast cells are numerous at sites of potential injury. Enterochromaffin-like cell of the stomach also stores histamine, which when released stimulates nearby parietal cells to secrete gastric acid into the lumen of the stomach.
Several different classes of medical drugs affect our histamine receptors:
“Antihistamines” is a somewhat inaccurate term referring to drugs with H1-receptor antagonist properties that have been used to treat allergy. 1st generation antihistamines blocked H1-receptors both in the periphery and in the brain, and usually also blocked other receptors, particularly the muscarinic acetylcholine M1-receptor. As a result, these drugs were quite sedating and are now primarily used as hyponotics or anxiolytics due to this side effect. 2nd generation antihistamines are much less able to cross the blood-brain barrier, and do not block H1-receptors in the brain to the extent that this results in sedation as a common side effect.
H2-receptor antagonists are used to treat gastric ulcer and gastroesophageal reflux disease, but have now somewhat fallen out of use, as drugs of the proton-pump inhibitor class are more effective for these conditions.
Many antipsychotics have H1-receptor antagonistic properties, especially low-potency traditional antipsychotics and atypical psychotics of the “pine” group, e.g. clozapine, olanzapine and quetiapine. Antipsychotics with high affinity for the H1-receptor are more sedating, which may be beneficial during acute phase treatment, but can be detrimental for long-term treatment.
Antidepressants of the tricyclic antidepressant (TCAs) and noradrenergic and specific serotonergic antidepressant (NaSSA) class have potent H1-receptor blocking properties, making them more sedating than most other antidepressants.
Other useful and interesting facts about histamine:
Fermented foods and beverages naturally contain small quantities of histamine (HA) due to a conversion of histidine to histamine performed by fermenting bacteria or yeasts. Ingested HA is usually inactivated by the enzyme diamine oxidase (DAO) which is present in the gut. In the case of scombroid food poisoning, a common type of seafood poisoning, the ingestion of spoiled fish leads to the intake of large quantities of HA produced in the decaying fish. This intake of histamine is larger than the DAO in the gut has capacity to clear, leading to symptoms similar to food allergy. For people with deficient DAO activity, symptoms similar to food allergy can also occur when fermented food and beverages are ingested. This is an uncommon condition sometimes referred to as histamine intolerance, which is treated with a histamine-restricted diet.
Histidine supplements are sold over the counter to treat a range of conditions, including allergy, ulcers, rheumatoid arthritis and anemia. There is no good evidence that this has any effect for these conditions, but at least it is unlikely to do any harm.
Author: Sverre Gunnarsson Larne. Last updated: June 8th 2016.