Serotonergic Pharmacology
The serotonin system's role in mood, sleep, and appetite, and how SSRIs, triptans, and psychedelics interact with 5-HT receptors.
Serotonin Synthesis and Metabolism
Serotonin (5-HT) is synthesized from tryptophan. Tryptophan hydroxylase (TPH) is rate-limiting, producing 5-hydroxytryptophan, which AADC converts to 5-HT. MAO-A degrades serotonin to 5-HIAA. The serotonin transporter (SERT) mediates reuptake and is the primary target of SSRIs.
Approximately 95% of body serotonin resides in the gut (enterochromaffin cells). Central serotonergic neurons originate in the raphe nuclei and project widely throughout the brain.
Receptor Subtypes
There are 14 serotonin receptor subtypes in 7 families (5-HT1 through 5-HT7). All are GPCRs except 5-HT3, which is a ligand-gated ion channel.
- 5-HT1A -- autoreceptor on raphe neurons; agonists (buspirone) are anxiolytic
- 5-HT1B/1D -- vasoconstriction in cranial vessels; triptans activate these receptors to abort migraine
- 5-HT2A -- excitatory postsynaptic receptor; target of atypical antipsychotics (antagonism) and psychedelics (agonism)
- 5-HT2C -- appetite regulation; antagonism contributes to weight gain with some antipsychotics
- 5-HT3 -- ion channel in CTZ and vagal afferents; ondansetron blocks it to prevent chemotherapy-induced nausea
- 5-HT4 -- prokinetic in the GI tract; prucalopride is an agonist for constipation
Key Drug Classes
- SSRIs -- fluoxetine, sertraline, escitalopram block SERT; first-line for depression and anxiety
- SNRIs -- venlafaxine, duloxetine block SERT and NET
- Triptans -- sumatriptan activates 5-HT1B/1D for acute migraine
- 5-HT3 antagonists -- ondansetron for nausea/vomiting
- Psychedelics -- psilocybin, LSD are 5-HT2A agonists under investigation for treatment-resistant depression
Serotonin Syndrome
Excess serotonergic activity (e.g., SSRI + MAO inhibitor) causes a triad of neuromuscular excitation (clonus, hyperreflexia), autonomic instability (hyperthermia, tachycardia), and altered mental status. Treatment is supportive with cyproheptadine (5-HT2A antagonist) in severe cases.
Key Takeaways
- SERT blockade by SSRIs is the most common mechanism for treating depression
- 5-HT receptor diversity explains serotonin's role in mood, migraine, nausea, and GI motility
- Serotonin syndrome is a life-threatening emergency from serotonergic drug combinations