34. Serotonin, serotonin receptor agonists and antagonists

Page created on June 15, 2019. Last updated on January 7, 2022 at 22:05


Serotonin or 5-hydroxytryptamine (5-HT) is an important central and peripheral neurotransmitter as well as a local hormone. 90% of serotonin in the body is found in the neuroendocrine enterochromaffin cells in the GI tract, where they function as a local hormone. It’s also found in platelets and in serotonergic neurons.

Synthesis and metabolism:

Serotonin is synthesised in two steps. Tryptophan is converted into 5-hydroxytryptophane, which is then converted into 5-hydroxytryptamine by aromatic acid decarboxylase.

Serotonin is metabolised also in two steps; first by monoamine oxidase A (MAO-A) and then by aldehyde dehydrogenase (ALDH).

Serotonin receptors:

The following serotonin receptors are most important:

Type Subtypes Signal Potential Tissue


A, B, C, D, E, F Gi-coupled. cAMP ↓ Inhibitory CNS, blood vessels


A, B, C

Gq-coupled, IP3


CNS, PNS, blood vessels, GI, platelets


Ligand-gated Na+, K+ channel



5-HT4 Gs-coupled, cAMP ↑ Excitatory


Drugs related to serotonin

Many drugs are serotonin receptor agonists or antagonists, or in other ways interact with serotonergic transmission.

Serotonin agonists:

Drug class Drug names Indications Agonized serotonin receptor


Buspirone Anxiety 5-HT1A


Sumatriptan, almotriptan Migraine episodes 5-HT1B, 5-HT1D

Recreational drugs

LSD, psilocybin “Wanna do drugs?”

5-HT1A, 5-HT2A, 5-HT2C

(Lorcaserin) Obesity


Prokinetic drugs Metoclopramide, prucalopride GERD, gastroparesis


Serotonin antagonists:

Drug class Drug names Indications Antagonized serotonin receptor

Cyproheptadine Serotonin syndrome 5-HT1A, 5-HT2A

Atypical antipsychotics

Clozapine, olanzapine Schizophrenia, bipolar disorder 5-HT2A, 5-HT2C
Pizotifen Migraine prophylaxis


Antiemetics Ondansetron, granisetron Chemotherapy, radiotherapy


Drugs acting on serotonergic neurons:

Drug class Drug names Indications Mechanism of action


Fluoxetine, paroxetine Depression Inhibit serotonin reuptake


Venlafaxine, duloxetine Depression

Inhibit serotonin and norepinephrine reuptake

MAO-A inhibitors Moclobemide Depression

Inhibit serotonin breakdown

Serotonin syndrome

Serotonin syndrome is a life-threatening condition caused by serotonergic overactivity. It can be caused by any drug that increases serotonin levels.


  • MAO inhibitors
  • SSRIs
  • SNRIs
  • Tricyclic antidepressants
  • MDMA

The risk is especially increased if two or more serotoninergic drugs are combined.

Clinical features:

Neuromuscular excitability, autonomic dysfunction, altered mental status. Hyperthermia.


Withdrawal of the causative drug. Administration of cyproheptadine, a serotoninergic antagonist. External cooling.


Migraine is characterised by recurring episodes of typically unilateral, localized headaches. They are frequently accompanied by nausea, vomiting and sensitivity to light and sound. They are sometimes preceded by an aura, which are transient neurologic symptoms like seeing flashing lights or paresis.

The pathomechanism is not well understood.

Treatment of migraine involves two components:

  • Abortive therapy – drugs taken to improve symptoms of an episode
    • NSAIDs
    • Triptans
    • (Ergotamine)
  • Prophylactic therapy – drugs taken to prevent episodes from occurring
    • Beta blockers
    • Pizotifen
    • Botulinum toxin

Antiemetics like metoclopramide and ondansetron can be useful to treat nausea.

Abortive therapy of migraine


  • NSAIDs
    • Paracetamol
    • Aspirin
    • Ibuprofen
    • Diclofenac
  • Triptans
    • Sumatriptan
    • Almotriptan
  • Ergotamine

Ergotamine can also be used but its usefulness is severely limited by its severe side effects.


Terminating or reducing pain of a migraine. NSAIDs are preferred for moderate attacks, and triptans + NSAIDs are preferred for severe attacks.

Mechanism of action:

The triptans, including sumatriptan and almotriptan, are selective 5-HT1B and 5-HT1D agonists. They vasoconstrict meningeal vessels and modulate pain sensation in the trigeminal ganglion.

Ergotamine is also a 5-HT1B and 5-HT1D agonist, with the same mechanism of action as the triptans.


Rapidly absorbed preparations like a suppository or effervescent tablets that are dissolved in water are preferred.


Triptans and ergotamine should never be given simultaneously.

Side effects:


  • Damage to the foetus
  • Nausea, vomiting
  • Severe peripheral vasoconstriction (including the coronaries) with possibility of gangrene


  • Paraesthesia
  • Temporary blood pressure increase
Prophylactic therapy of migraine


  • Beta blockers
    • Metoprolol
    • Propranolol
  • Tricyclic antidepressants
    • Amitryptiline
  • Anti-epileptics
    • Topiramate
    • Valproate
  • Calcium channel blockers
    • Verapamil
  • CGRP antagonists
    • Erenumab
  • Serotonin antagonists
    • Pizotifen

All of the mentioned can be used as first-line, depending on the comorbidities of the patients. If there are none, beta blockers are preferred.

Injecting botulinum toxin into the trigeminal nerves is also used to prevent migraines.


Reducing the frequency and severity of migraine episodes.

Mechanism of action:

Beta blockers prevents migraine episodes by unknown mechanisms. They probably cause vasoconstriction of cerebral vessels.

Pizotifen is a 5-HT2 receptor antagonist which also causes vasoconstriction of cerebral vessels.

CGRP has a role in mediating migraine pain.

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