Pharmacology of 5-HT Synthesis and Signaling

Study Notes

5-HT synthesis involves the rate-limiting enzyme tryptophan hydroxylase and is mainly degraded by the action of monoamine oxidases.
5-HT is best known as a neurotransmitter in the brain, but about 95% of it is synthesized, stored, and released by enterochromaffin cells in the intestinal mucosa.

5-HT signaling may modulate the peripheral immune system.
Different immune cells, including T cells, macrophages, mast cells, dendritic cells, and platelets, can generate, store, respond to, and/or transport serotonin.
In monocytes/macrophages, serotonin modulates cytokine secretion.
Serotonin can suppress the release of TNF-α and IL-1β by activating serotonin receptors (5-HT2A).

Serotonin can affect food intake via activation of the anorexigenic melanocortin system involving 5-HT2c receptors.
It also inhibits the orexigenic NPYergic system.
Reduction of brain serotonin by reducing availability of its precursor tryptophan has been shown to be beneficial in the treatment of anorexia during cancer.

Receptors of the CTZ that have been identified to induce emesis include opioid µ, κ, D2, NK-1, and 5-HT3.
Ondansetron and Granisetron are selective serotonin antagonists used for treating chemotherapy-induced nausea and vomiting.

The 5-HT receptors occur on other neurons in the ENS, where they can be stimulatory (5-HT3 and 5-HT4).
Prucalopride is a specific 5-HT4R agonist that facilitates cholinergic neurotransmission and is used in chronic idiopathic constipation.
Cisapride is a 5-HT4 agonist that stimulates adenylyl cyclase activity in neurons, but was withdrawn due to potential serious and occasionally fatal cardiac arrhythmias.

Migraine is a complex neurovascular disorder marked by vasodilation of intracranial and extracerebral vessels.
CGRP is released via activation of the trigeminovascular system.
There are markedly decreased levels of 5-HT in migraineurs.
Serotonin principally acts on serotonin receptors in the trigeminovascular system to lower levels of key molecules such as CGRP.

Out of the 7 receptor types, 5-HT1, 5-HT2, and 5-HT3 are identified to be responsible for migraine.
Lysergic acid diethylamide (LSD), methysergide, and other ergot derivatives bind to multiple 5-HT receptors and have antimigraine action.
Triptans (e.g., Sumatriptan, Zolmitriptan, Rizatriptan, Frovatriptan) are potent cranial vasoconstrictors with neural antimigraine activity.
Ditans (e.g., Lasmiditan) are serotonin receptor agonists that bind to 5-HT1F receptor subtype and have fewer side effects than triptans.
CGRP receptor antagonists (e.g., Rimegepant, Ubrogepant) and monoclonal antibodies targeting CGRP or its receptors (e.g., Eptinezumab, Galcanezumab, Erenumab) are used as antimigraine therapy.

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