Scientists discovered the histamine 3 (H3) receptor in 1983, and its discovery has led to a fascinating understanding of the many roles of histamine throughout the body. Researchers continue to learn how the effects of histamine extend beyond the immune system into the nervous system and the endocrine system. As such, histamine helps to maintain arousal, modulate circadian rhythms, maintain energy and endocrine homeostasis, and influence motor behavior and cognition.
The initial studies of the H3 receptor revealed that it is located primarily in the brain. In particular, scientists found that the H3 receptor is expressed at high levels in several very important areas of the brain including the cerebral cortex, thalamus, caudate putamen, ventromedial nucleus of the hypothalamus, and the histaminergic tuberomamillary nucleus (TMN). Initially, researchers focused their attention on neurons that, not only expressed the H3 receptor, but also contain (and release) histamine. These are known as histaminergic neurons. The H3 receptor controls the production and release of histamine by these histaminergic neurons. In this way, histamine provides feedback that determines its own production. This means that it is an autoreceptor.
Histaminergic neurons primarily form distinct clusters in the TMN of the hypothalamus. Closer examination reveals that they are organized into functionally distinct circuits that influence different regions of the brain. The histaminergic system thus affects arousal, brain energy metabolism, locomotor activity, neuroendocrine, autonomic, and vestibular functions, feeding, drinking, sexual behavior, and pain sensation. Not surprisingly, then, the histaminergic neurons appear to fire at variable levels during waking and appear to be particularly activated during stress. They also tend to not fire much during drowsiness or sleep.
While H3 receptors are found on histamine-containing neurons, they are not limited to these neurons. The H3 receptor exists on many different neurons throughout the brain. When it is present on these different neurons, it does not act as an autoreceptor. Instead, in many cases, it pairs with other receptors, such as a dopamine receptor. This wide variety of expression suggests that the H3 receptor modulates many different effects throughout the brain. In particular, the H3 receptor can modify the release of neurotransmitters such as acetylcholine, dopamine, glutamate, noradrenaline, and serotonin.
Throughout the Body
The role of the H3 receptor extends, however, beyond the brain. A study of the H3 receptor in developing rat tissues revealed that it is also present throughout the body. For example, the H3 receptor can be found in the spine (spinal ganglia), salivary glands, brown fat, and gastric and intestinal mucosa.
While research into the function of the H3 receptor throughout the body is still limited, studies suggest that the H3 receptor in the intestine appears to affect gastric acid secretion in a way that is distinct from the H2 receptor and the H4 receptor. The presence of H3 receptors in brown fat has led some investigators to suggest that they may play a role in energy metabolism and/or the development of brown fat cells. In particular, studies in ground squirrels suggest that histamine and the H3 receptor are important for hibernation.
One approach that scientists use to study the role of a receptor within the body is to genetically engineer a mouse so that it does not have that receptor. Researchers have used this approach to study the H3 receptor and found that mice that have been genetically engineered to not have the H3 receptor (H3 receptor knockout mice) move less than normal mice, eat more than normal mice, have late-onset obesity, and increased levels of insulin and leptin. These results have led scientists to conclude that the H3 receptor plays an important role in movement, hunger, obesity, and response to carbohydrates. Studies with the H3 receptor knockout mice have also suggested a connection between central H3 receptor signaling and the peripheral immune response.
Taken together, the data thus suggest that, while a drug that targets the H3 receptor is likely to affect he sleep/wake state, it may also affect multiple physiological functions. Intriguingly, the many functions of the H3 receptor closely align with the many deficits associated with Prader-Willi Syndrome (PWS). It may be possible, then, that a drug such as pitolisant, which targets the H3 receptor may be able to improve many of the other symptoms of PWS. These symptoms could include: resistance to movement, hunger, obesity, intolerance to carbohydrates, and abnormal immune responses.
Physicians and patients should thus be aware that the physiological implications for pitolisant extend beyond those seen for any of the other drugs approved for the treatment of narcolepsy.