serotonin

5-HT Synthesis and Regulation

• 5-HT synthesis involves the rate-limiting enzyme tryptophan hydroxylase and is mainly degraded by monoamine oxidases.
• 95% of 5-HT is synthesized, stored, and released by enterochromaffin cells in the intestinal mucosa.

5-HT and the Immune System

• 5-HT signaling modulates 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.
• Serotonin modulates cytokine secretion in monocytes/macrophages and can suppress the release of TNF-α and IL-1β by activating serotonin receptors (5-HT2A).
• Neutrophil recruitment and T-cell activation can be mediated by serotonin.

5-HT and Food Intake

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

5-HT Receptors and Functions

• 5-HT receptors occur on other neurons in the ENS, where they can be stimulatory (5-HT3 and 5-HT4).
• The availability of serotonergic prokinetic drugs has been restricted due to serious adverse cardiac events.
• Prucalopride is a specific 5-HT4R agonist that facilitates cholinergic neurotransmission.

Migraine and 5-HT Receptors

• Recurrent unilateral headache which may be accompanied by GI and visual disorders, more prevalent in females than males (3:1).
• 5-HT receptors, particularly 5-HT1, 5-HT2, and 5-HT3, are responsible for migraine.
• Serotonin principally acts on serotonin receptors in the trigeminovascular system to lower levels of key molecules such as CGRP.

Migraine Management

• Molecules that act as agonist/antagonist of 5-HT receptors in the trigeminovascular system are used in migraine management.
• CGRP receptor antagonists, such as olcegepant and telcagepant, are under consideration as antimigraine therapy.

Ergot Derivatives and Triptans

• Lysergic acid diethylamide (LSD), methysergide, and triptans (e.g., sumatriptan, zolmitriptan, rizatriptan, frovatriptan) are used in migraine treatment.
• Triptans are potent cranial vasoconstrictors with neural antimigraine activity, selectively agonist on 5-HT1B/1D receptors.
• Olcegepant and telcagepant selectively block CGRP receptors without the vasoconstrictive effect of triptans.