Neurotransmitters: Histamine

Histamine’s role as a neurotransmitter has only come to light relatively recently. In fact, Kwiatkowski’s initial discovery of histamine in nervous tissue only predates the invention of the microwave oven by 4 years. Despite an initial poor reputation tainted by fears of cancer and radiation poisoning, people have caught on to microwaves rather quickly, and they’re now present in most households and celebrated for their convenience—the public opinion of histamine, however, is hardly 4 years ahead. To most, histamine is still known solely as he driving force behind swelling, itching, seasonal allergies, hives, welts, anaphylaxis, and other painful autoimmune events.

Beyond its unsavory reputation for the roles it plays in the immune system, however, histamine is responsible for a number of crucial brain functions. Its responsibilities involve many homeostatic functions, mainly in the regulation of sleep and wakefulness. It also plays important roles in learning and memory, as well as in regulation of broader neurotransmitter release.

Receptor Mediation of Neural Histamine Function

Histamine’s effects as a neurotransmitter are receptor-mediated, meaning that the function it serves is influenced by the type of receptor that picks it up. There are four known histamine receptors, aptly labeled H1, H2, H3, and H4, but only the first three are significantly expressed in the CNS.

H1 and H2 are both excitatory, and are generally found on postsynaptic terminals. H3, found on presynaptic terminals, functions as an inhibitory neuromodulator. H4 is expressed exclusively in immune cells, and such is not associated with neurocrine signaling.

All known histamine receptors, in- and outside of the CNS, are metabotropic receptors, meaning that they are coupled to intracellular G-proteins with different functional subunits. The mechanical complexity of histamine receptors and other GPCRs is what allows them to exhibit such a wide functional range. As we will find, each of the three histamine receptors expressed in the CNS have highly specialized functions and modes of action.

H1 receptor

H1 receptors have been identified on postsynaptic terminals across all areas of the human brain. Distribution of H1 receptors is particularly dense in areas that regulate arousal and wakefulness, illustrating their importance in the process of waking. Still, they are ubiquitous throughout the CNS in both expression and functional importance, and are considered the brain’s predominant histamine receptor in terms of function.

Wherever they may be, H1 receptors are always excitatory. Gq

• Gq & αq-GTP
• IP₃,  DAG   →   PKC,  ↑ Ca²⁺

On a broader scale, H1R is associated with cortical desynchronization, facilitating attention, integrating sensory and motor information, and regulating energy expenditure. It is also involved in modulating vestibular inputs and nausea.

H2 receptor

Like the H1 receptor, H2 receptors are excitatory and abundant throughout the brain.

[cAMP pathway to LTP]

, despite similarities in quantity, density, and modes of action, their role in higher cognitive functions is more subtle than that of H1. While H2R’s function in the CNS remains rather elusive, there exists a promising body of evidence surrounding its role in facilitating long-term potentiation (LTP). There is much to be learned as to how exactly this occurs,

Many studies is that introduction of H2R antagonists significantly inhibits LTP. Confusingly, however, this effect is not seen in many H2R antagonists.

H3 receptor

The H3 receptor is unique among other histamine receptors in that it is expressed nearly exclusively within the brain, is found mainly presynaptically, and serves an inhibitory function. These receptors often work as autoreceptors, monitoring histamine levels and limiting HDC in response. They also often work as heteroreceptors, context-dependently suppressing the release of acetylcholine, dopamine, glutamate, and GABA in various cortical areas.

Additionally, H3 is unique in that it shows several different isoforms within the human brain, some of which can look radically different. The isoforms of H3 are generally sorted into “long” and “short” subcategories, but in many cases, the similarities end at the shape. While some drugs work similarly on some or all of members of a subcategory, some isoforms are so selective that they are, functionally, in a league of their own.

Summary

[ideally would like to have alternating shades of blue between rows]

Clinical Applications

First-generation antihistamines, such as diphenhydramine (Benadryl), work by binding to and blocking action at H1. These medications are able to cross the blood-brain barrier (BBB) with ease, meaning that this also applies to H1 receptors present within the cortex. Considering H1R’s role in wakefulness, it should come as no surprise that first-generation antihistamines are associated with drowsiness.

In fact, some first-generation antihistamines, such as doxylamine (Unisom, ZzzQuil), are marketed as sleep aids. Over half of all over-the-counter sleep aids contain first-generation H1 receptor antagonists. Additionally, their role in regulating vestibular input and nausea has made some first-generation H1 antagonists, such as dimenhydrinate (Dramamine), a common treatment for motion sickness.

Second-generation antihistamines, such as loratadine (Claritin), also target H1 receptors. However, unlike their predecessors, they don’t produce drowsiness, confusion, or other cognitive side effects. This is due to their highly limited capacity for BBB penetration. These “non-drowsy” allergy medicines, as they are often marketed, have become a more popular choice by both allergy sufferers and allergists due to their convenience and relative lack of side effects. So-called third-generation antihistamines are currently in development, but this name is misleading, as there are no practical differences between third- and second-generation antihistamines.

While the H1 receptors are considered to be of chief functional significance in the brain, they’re also of chief functional significance in just about everywhere that histamine receptors could go. The hugely uncomfortable whole-body autoimmune response that direct H1R (and H2R) agonists would trigger has rightfully crushed any chance they had at clinical application.

H3 receptors, however, do not have this problem. Due to their lack of somatic presence, H3 receptors are rather attractive subjects in the development of drugs concerning the brain’s histaminergic pathways. This allows both antagonists and antagonists of H3R to be safely administered without risking a massive allergic response. Through modulating H3R’s regulatory mechanisms of HDC, we can indirectly alter activity at H1 synapses.

Due to the broader role of H3 receptors as autoreceptors, we can indirectly influence the activity of neural H1 pathways through H3 agonism or antagonism. Furthermore, the high selectivity observed in many isoforms may allow for the development of highly specialized drugs that only work in certain areas. This is a luxury we do not generally have. SSRIs, for example, are agonists of the entire brain’s 5HT-2A receptors. This often leads to a laundry list of unintended side effects, which can range anywhere from sexual dysfunction to vomiting blood.

While BBB-penetrating H2 antagonist drugs are widespread in treating certain gastrointestinal conditions, therapeutic effects in the CNS are minimal and sparsely investigated. However, some have noted their ability to amplify the effects of opiates, as well as their utility in treating negative symptoms of schizophrenia. Furthermore, it has been noted that H2 receptor activity in glial cells may regulate remyelination and restoration of cognitive abilities after hypoxia/ischemia. Even still, the role of H2 receptors in the CNS remains rather elusive, and as of now, H2R modulators are seldom considered CNS drugs.

Biosynthesis and Metabolism

Histamine is a monoamine neurotransmitter derived from the amino acid L-histidine. The key enzyme involved in histamine production is histidine decarboxylase (HDC), which catalyzes the decarboxylation of L-histidine, converting it into histamine. In order to function, HDC requires pyridoxal phosphate (PLP), the active form of Vitamin B6, as a cofactor. This process occurs exclusively in the tuberomammillary nucleus (TM), an area within the hypothalamus that houses all 64,000 of the human brain’s histaminergic neurons.

Once the brain has squeezed a histamine molecule for all it can (which doesn’t take long; half-life <1h), it comes time for the histamine to retire. In the CNS, histamine is deactivated by histamine N-methyltransferase (HNMT), an enzyme that catalyzes the methylation of histamine. The addition of a methyl group turns histamine into biologically inactive tele-methylhistamine (t-MH). This process typically occurs in glial cells. From there, it is further broken down by monoamine oxidase-B (MOA-B), an enzyme that break down the inactive metabolites of histamine, dopamine, and other select monoamines.

Peripheral nerve cells opt to outsource the production and metabolism of histamine. In the PNS, most histamine is imported from nearby mast cells, a type of white blood cell, rather than being produced endogenously. If the mooching wasn’t bad enough, peripheral nerve cells litter, too—when they’re finished with their histamine, they send it out into the extracellular matrix where it is enzymatically degraded by diamine oxidase (DAO). The CNS also utilizes DAO, but under basal conditions, the extent to which it does so is negligible.

Storage and Transmission

• The synapse activity of TMN histamine neurons is at its highest during the process of waking, is stifled during non-REM sleep, and is entirely silent during REM sleep. Histamine can be considered an indirect repressor of REM sleep
• VMAT2 (brain & body)
• Volumetric & synaptic transmission
• https://www.ncbi.nlm.nih.gov/books/NBK27916/