5-HT family receptors (all GPCR except 5-HT3 which is a ligand-gated cation channel) drive mood, sleep, appetite, vasoconstriction, GI motility, and emesis. SERT (serotonin transporter) clears synaptic 5-HT and is the primary target of SSRIs / SNRIs / TCAs. 5-HT1A — somatodendritic autoreceptor + postsynaptic anxiolysis target (buspirone partial agonist; aripiprazole partial agonist). 5-HT1B/1D — vascular vasoconstriction (triptan target for migraine). 5-HT2A — cortical pyramidal-cell depolarization (psychedelic target; atypical-antipsychotic inverse-agonist target). 5-HT2C — appetite + mood. 5-HT3 — area-postrema emesis (setron target for chemo emesis). 5-HT4 — gut motility + cognition. 5-HT7 — circadian + mood. Vortioxetine is a multimodal SERT inhibitor + 5-HT1A agonist + 5-HT3/7 antagonist (single-molecule receptor cocktail). MDMA is a SERT releaser. Psychedelics (psilocybin / LSD / DMT) are 5-HT2A agonists.
Organ Systems
nervous
digestive
cardiovascular
Pathway Steps
tryptophan → 5-hydroxytryptophan — via tryptophan hydroxylase (TPH1 peripheral, TPH2 CNS) — rate-limiting step. Serotonin synthesis starts with the essential amino acid tryptophan, hydroxylated by tryptophan hydroxylase (TPH) to 5-hydroxytryptophan (5-HTP). This is the rate-limiting step, and TPH exists as two isoforms — TPH1 (gut/periphery) and TPH2 (brain) — so central and peripheral serotonin are made separately.
5-hydroxytryptophan → serotonin — via aromatic amino-acid decarboxylase (AADC, P5P cofactor). 5-HTP is decarboxylated by aromatic L-amino-acid decarboxylase (AADC) to serotonin (5-HT). Because most body serotonin is made in the gut (enterochromaffin cells) and serotonin does not cross the blood-brain barrier, the brain must synthesize its own — a key fact for understanding serotonergic drugs.
serotonin → 5ht-receptor-activation — via extracellular binding to GPCR (1A/1B/1D/2A/2C/4/6/7) or ligand-gated channel (3). Serotonin acts on a large family of receptors (5-HT1 through 5-HT7), almost all GPCRs except the ionotropic 5-HT3. This diversity — subtypes coupling to different G proteins in different tissues — is why serotonergic drugs have such varied effects (e.g. 5-HT3 antagonists for nausea, 5-HT1B/1D agonists for migraine).
5ht-receptor-activation → downstream GPCR / ion-channel signaling — via SERT reuptake (Na+/Cl- symporter) terminates synaptic signal — SSRI/SNRI/TCA target. The 5-HT receptor families transduce differently: most are GPCRs (5-HT1 Gi→↓cAMP, 5-HT2 Gq→IP3/Ca²⁺, 5-HT4/6/7 Gs→↑cAMP), while 5-HT3 is a ligand-gated cation channel. This signaling diversity is why serotonergic drugs are so varied — and why subtype selectivity (triptans at 5-HT1B/1D, setrons at 5-HT3) matters.
serotonin → melatonin — via AANAT → HIOMT; pineal-specific (cross-link: serotonin_melatonin_axis pathway). In the pineal gland at night, serotonin is converted to melatonin by AANAT (the rate-limiting enzyme) and ASMT. This links the serotonin system to circadian output — serotonin is the daytime precursor rhythmically transformed into the “darkness hormone” melatonin.
Known Modulators
fluoxetine (inhibitor) — SERT. long-acting SSRI; active metabolite norfluoxetine adds days to effect duration; CYP2D6 inhibitor
sertraline (inhibitor) — SERT. SSRI with mild DAT activity (clinically negligible); food increases absorption
paroxetine (inhibitor) — SERT. potent SSRI; strong CYP2D6 mechanism-based inhibitor (DDI hot spot for AP/opioid/β-blocker co-administration)
citalopram (inhibitor) — SERT. racemic SSRI; QT prolongation at >40 mg led to FDA dose cap (2011)
escitalopram (inhibitor) — SERT. S-enantiomer of citalopram; same QT profile minus the inactive R-enantiomer
risperidone (inhibitor) — 5-HT2A antagonist (also D2). high 5HT2A:D2 ratio at low doses; at high doses behaves like typical AP
clozapine (inhibitor) — 5-HT2A antagonist + multi-receptor. reference atypical AP for treatment-resistant schizophrenia; agranulocytosis monitoring + CYP1A2 substrate
psilocybin (activator) — 5-HT2A (psilocin is the active metabolite). prodrug — dephosphorylated to psilocin; 5-HT2A agonism produces the classic psychedelic state
lsd (activator) — 5-HT2A (partial agonist) + 5-HT1A/2C. sub-mg potent; long duration vs psilocybin reflects β-arrestin recruitment kinetics