Histamine in the Brain

When most people think of histamine, they think of allergies. Indeed, histamine was first identified as a primitive molecule of the immune system that was associated with sneezing and itchy eyes. These observations led to the discovery of drugs that targeted the histamine receptor. One of the first such drugs was the antihistamine Benadryl (diphenhydramine).

Further study of histamine revealed that it was also an important molecule in the gut. Specifically, it stimulates gastric acid secretion by binding to histamine 2 (H2) receptors in the gut. This discover y prompted the development of drugs that bind to the H2 receptor. Zantac (ranitidine) and Pepcid (famotidine) are two such drugs that bind to the H2 receptor and provide some relief from symptoms of excess stomach acid.

In 1983, researchers detected a third histamine receptor (H3 receptor) in the brain. They discovered that the H3 receptor had a profound influence on the balance of different brain chemicals (neurotransmitters) throughout the brain. The first approved drug to target the H3 receptor is Wakix (pitolisant).

The H3 receptor does not really look like the H1 or the H2 receptor. The human H3 receptor does, however, look like the H3 receptors found in the nervous system of many different species including rats, mice, and monkeys. The H3 receptor is also a bit unusual, in that it occurs naturally in the body in multiple, distinct forms. Some of these forms are expressed on the cell surface, as would be expected for a receptor, and some remain within the cell. Scientists still do not understand how or why the body creates all of these different forms of H3 receptor. That said, they hypothesize that these slight differences in the H3 receptor underlie different H3 receptor activities and functions in different parts of the brain. It is thought that pitolisant binds these different forms of the H3 receptor in slightly different ways and with slightly different strengths, although this is not well understood.

The H3 receptor is unusual in that not only can it be triggered to respond to histamine, but it is also always “on.” This makes it a constitutive receptor. When it is “on,” which is its rest state, it inhibits, or slows down the release of many other neurotransmitters in the brain.

The H3 receptors can also come together to form pairs. They can pair with another H3 receptor, or they can pair with different receptors on the nerve cells. For example, they can pair with dopamine receptors. This is of particular interest to scientists because of the many different things that dopamine does within the brain. These include motor control, reward-motivated behavior, and addiction. Scientists have studied the pairs of histamine and dopamine receptors and their early data suggest that histamine plays an important role in the control of dopamine.

When scientists look in the human brain, they find that the H3 receptor is expressed at high levels throughout the brain, including in the prefrontal cortex, ventromedial nucleus of the hypothalamus, and the tuberomamillary nucleus. The prefrontal cortex is thought to be involved in planning complex cognitive behavior, decision making, and moderating social behavior. The ventromedial nucleus in the hypothalamus is involved in feeding, thermoregulation, and satiety. The tubermamillary nucleus is involved in the control of sleep, arousal, and energy balance.

Thus, histamine appears to play a role in many different brain functions. It is a primitive molecule and it is implicated in the control of fundamental aspects of life: eating, sleeping, and moving. Its role in all of this, however, is complex and, while a drug now exists to target the H3 receptors, many physicians remain unfamiliar with its seeming dual roles as both a neuromodulator and classical transmitter.

For more details, see: http://pharmrev.aspetjournals.org/content/pharmrev/67/3/601.full.pdf


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