Histamine

Elevated histamine in the brain would manifest primarily as heightened wakefulness and alertness. Sleep would feel impossible. The mind would be buzzing with a restless, activated quality that lacks the rewarding focus of dopaminergic stimulation. There might be an increase in appetite and a vague sense of inflammation or allergic-like discomfort, itching, sneezing, or nasal congestion. The experience would resemble the wired, uncomfortable insomnia of severe allergies without the cognitive clarity that makes wakefulness useful.

Histamine acts on four receptor subtypes (H1-H4). H1 receptors (Gq-coupled) mediate allergic symptoms, smooth muscle contraction, and in the brain, wakefulness and cognition. H2 receptors (Gs-coupled) stimulate gastric acid secretion and are targeted by ranitidine and famotidine. H3 receptors (Gi-coupled) are presynaptic autoreceptors in the brain that regulate histamine release and also modulate release of other neurotransmitters including acetylcholine, norepinephrine, and serotonin. H4 receptors are expressed primarily on immune cells.

Histamine is synthesized from L-histidine by histidine decarboxylase (HDC), which requires pyridoxal phosphate (vitamin B6) as a cofactor. It is metabolized by two enzymes: histamine N-methyltransferase (HNMT) in the brain, and diamine oxidase (DAO) in the periphery. The tuberomammillary nucleus (TMN) is the sole source of neuronal histamine in the brain and is active during waking and silent during sleep.

Histamine was first synthesized in 1907 by Adolf Windaus and W. Vogt. Its biological activity was characterized by Henry Dale and Patrick Laidlaw in 1910, who described its effects on smooth muscle contraction and blood pressure. The role of histamine in allergic reactions was established in the 1920s-1930s, leading to the development of the first antihistamines in the 1940s.

Histamine's role as a neurotransmitter was established much later. Jean-Charles Schwartz and his colleagues at INSERM in Paris demonstrated in the 1970s-1980s that histamine met the criteria for a neurotransmitter in the brain. The identification of H3 receptors in 1983 by Jean-Michel Arrang provided further evidence of sophisticated histaminergic regulation in the CNS.

The clinical importance of brain histamine became apparent with the observation that classical antihistamines caused sedation by blocking H1 receptors in the brain, and that modafinil and pitolisant (an H3 receptor inverse agonist) promote wakefulness through histaminergic mechanisms.