Histamine · Grey Matter

Histamine is the neuromodulator that keeps the brain awake: it is made by a small cluster of neurons in the posterior hypothalamus that fire during waking and fall silent in sleep, and blocking its receptors is why older antihistamines make people drowsy.

Histamine. Histamine is the neuromodulator that keeps the brain awake: it is made by a small cluster of neurons in the posterior hypothalamus that fire during waking and fall silent in sleep, and blocking its receptors is why older antihistamines make people drowsy.

In the brain all neuronal histamine comes from the tuberomammillary nucleus, whose axons reach the cortex, thalamus, basal forebrain and brainstem. Its firing is among the most tightly tied to waking of any cell type: about 2 Hz awake, slower in slow-wave sleep and silent in REM sleep. It acts through metabotropic receptors: H1 and H2 receptors excite their targets (H1 mainly by closing potassium conductances), and H3 receptors on histamine terminals act as autoreceptors that limit release.

The same molecule has a separate life in the body. Mast cells release histamine in allergy and inflammation, which is what antihistamines are taken for; the brain's histamine is a distinct, neuronal pool.

Crossing the barrier makes the difference. First-generation H1 blockers (diphenhydramine, doxylamine) are lipophilic, reach the brain and sedate; second-generation ones (loratadine, fexofenadine) enter it poorly and sedate little.

Raising it wakes. Pitolisant, which blocks the H3 autoreceptor and so increases histamine release, is used to treat the sleepiness of narcolepsy.

Histamine is a switch held on by waking.

A small nucleus that fires only when awake broadcasts that fact to the whole forebrain.

Questions: Why do older antihistamines make people drowsy while newer ones do not? In the brain, histamine from the tuberomammillary nucleus of the hypothalamus helps sustain wakefulness, largely by exciting its targets through H1 receptors. First-generation H1 blockers such as diphenhydramine and doxylamine are fat-soluble and cross the blood-brain barrier, so besides calming an allergy they block that waking signal, which is why they are sold as sleep aids too. Second-generation drugs such as loratadine and fexofenadine are less fat-soluble and are pumped back out by the barrier's efflux transporters, so they block H1 receptors in the body and leave the brain's mostly untouched. The difference between the two generations is a difference in crossing the barrier.