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