Histamine is critical for maintaining arousal and wakefulness. The sole source of histamine in the brain is a region called the TMN (tuberomammillary nucleus) in the posterior hypothalamus. The hypothalamus is also where orexin comes from in the brain. Like orexin, neurons which make histamine (called histaminergic neurons) have far-reaching projections in the brain. Because of this, again, like orexin, these neurons are implicated in many different physiological states including sleep-wake control, learning, emotional status, and memory formation.

Most of us have experienced the histamine wakefulness-promoting effect when we have taken anti-histamines (Benadryl, etc.). The #1 side effect that most people notice is drowsiness. This is due to the fact that anti-histamines bind and antagonize histamine receptors (H1 receptors). Anti-histamines block histamine signaling in the brain.

In health, histominergic neuron activity is highest during wakefulness, and is becomes nearly undetectable during sleep (REM and NREM).

It has been shown previously that  people with narcolepsy have low CSF histamine. In addition, the lower the corresponding orexin levels, the lower the histamine levels; indicating that proper orexin signaling in the brain is crucial for proper histaminergic signaling. The same trend has been shown for those with idiopathic hypersomnia.

Mouse models have also demonstarted a link between histamine and sleep impairment. Histamine deficient (HDC KO) mice display sleep fragmentation and increased REM sleep during the light period along with profound wakefulness deficit at dark onset, a condition that sounds intriguingingly similar to narcolepsy. Moreover, sex differences in histamine deficiency have been demonstated in mice: female HDC KO mice demonstrated “hypoactivity, increased measures of anxiety, impairments in water-maze performance, but enhanced passive avoidance memory retention.”

Currently, it has been hypothesized that histaminergic neuron activity of the TMN may be reduced in individuals with narcolepsy.

It was recently demonstrated that, contrary to expectation, individuals with narcolepy may have more histaminergic neurons in the TMN.

Histamine has been implicated in neuroinflammation. Experimentally, histamine has been demonstrated to be neuromodulatory/regulatory in multiple sclerosis (“EAE” is the murine experimental version of the human disease MS).  Unlike individuals with narcolpesy, people with active multiple sclerosis have higher levels of CSF histamine, although it is probable that elevated histamine is a feature of neuroinflammation in general.  If narcolepsy is a true neurological autoimmune disease, one would expect elevated CSF histamine. It’s important to note that how CSF histamine changes over time in narcolepsy is not known.
Histamine has also been implicated in neurogenesis. I’ve already discussed this concept to some degree here (although I should point out that was discussing a different region of adult neurogenesis).  This has been demonstrated largely in the subventricular zone (SVZ), which is a known area of adult neurogenesis and has implications for repair following injury. The image below shows the respective regions (SVZ) in relation to the hypothalamus (where orexin neurons are).What does it mean for narcolepsy?  Why would narcoleptics have low histamine and a compensatory increase in the number of histmaine-containing neurons?