Serotonin or

5-hydroxytryptamine
• Widely distributed amine (animals + plants)
• In humans, present in GI enterochromaffin cells
(90%), platelets and brain.
• Synthesized from tryptophan (in diet) in two steps.
• Platelets do not synthesize but take up from blood
(active uptake process in platelets and nerve
terminals).
• Cell storage in granules similar to catecholamines.
 (Rate limiting)
COOH OH COOH
Tryptophan
hydroxylase
C NH2 C NH2

N N
Tryptophan In diet. Active
CNS transport
5-Hydroxytryptophan

5-OH Tryptophan
decarboxylase
C COOH
Al OH H
N de dehy
hy de
dr
og
en
a se AO
C NH2
M
5-Hydroxy Indole
N
Acetic Acid 5-OH Indole
Acetaldehyde 5-Hydroxytryptamine
 Synthesis and Metabolism
• Competition at the level of brain and neuronal
uptake
• Rate limiting enzyme not saturated usually
• No end-product negative feedback
• 5-OHTr decarboxylase same as DOPA
decarboxylase
• 5-OHIAA actively extruded from CNS
(probenecid-sensitive) and excreted in urine.
 Interference with the system
• Inhibit uptake into CNS (other AA’s)
• Inhibit synthesis: p-chlorophenylalanine
(irreversible)
• Inhibit neuronal re-uptake: cocaine, SSRA (e.g.
fluoxetine), TCA (e.g. imipramine)
• Inhibit storage-deplete: reserpine
Non-selective
• Inhibit metabolism: MAO inhibitors
• Promote release: p-chloroamphetamine - then
depletes (e.g. fenfluramine to ↓ appetite)
 Serotonin Receptors
• At least 15 types and subtypes
• Multiple transduction mechanisms
• 5HT-1A: role in anxiety/depression
• 5HT-1D: role in migraine
• 5HT-2: role in CNS various behaviors, and
in cardiovascular system
• 5-HT3: role in nausea and vomiting esp.
due to Chemotherapy.
 Endogenous Function
• Central neurotransmitter
• Precursor of melatonin
• GI tract: uncertain; motility?
• In carcinoid tumors: large amounts released
leading to diarrhea, bronchoconstriction and
edema
• Platelets: 5-HT2 receptors → aggregation
and vasoconstriction
 Serotonin
Pharmacological Effects
• Respiratory system: bronchoconstriction if
asthmatic; stimulation of aortic and carotid
chemoreceptors → ↑ RR and minute vol.
• GI tract: small intestine very sensitive to
serotonin → intense rhythmic contractions due to
direct and indirect (ganglia in wall) effects.
Also stimulates vomiting (5-HT3 receptors on
vagal afferents and centrally).
 Serotonin
Pharmacological Effects -2
• Cardiovascular system: Multiple direct and indirect
effects:
1. Direct vasoconstriction (large arteries) and indirect
vasodilation (NO and PGI2 – mediated)
2. Heart: direct inotropic and chronotropic effects
3. Reflex mechanisms due to change in BP
4. Stimulation of sensory nerve endings in
baroreceptors and in vagal afferents in coronary
circulation (Bezold Jarrisch reflex) → bradycardia
and hypotension
 Serotonin in the
Central Nervous System
• Pain perception
• Sleep/Wakefulness
• Various behaviors normal/abnormal:
depression, schizophrenia, obsessive
compulsive behavior, etc.
• Neuroendocrine regulation – controls
hypothalamic cells involved in release of
several anterior pituitary hormones.
 Migraine
• Clinical Presentations:
– Often accompanied by brief aura (visual scotomas, hemianopia)
– Severe, throbbing, usually unilateral headache (few hours to a
few days in duration)
• Migraine Pathophysiology:
–  Vasomotor mechanism -- inferred from:
• increased temporal artery pulsation magnitude
• pain relief (by ergotamine) occurs with decreased artery
pulsations
– Migraine attack associated with (based on histological studies):
• sterile neurogenic perivascular edema
• inflammation (clinically effective antimigraine medication
reduce perivascular inflammation)
 Migraine: Drug Treatment
– Ergotamine: best results when drug administered prior to the
attack (prodromal phase) -- less effective as attack progresses
• combined with caffeine: better absorption
• potentially severe long-lasting Vasoconstriction.
– Dihydroergotamine (IV administration mainly): may be
appropriate for intractable migraine
– Nonsteroidal antiinflammatory drugs (NSAIDs)
– Sumatriptan: alternative to ergotamine for acute migraine
treatment; not recommended for patients with coronary vascular
disease risk.
• formulations: subcutaneous injection, oral, nasal spray
• selective serotonin-receptor agonist (short duration of action)
• probably more effective than ergotamine for management of acute
migraine attacks (relief: 10 to 15 minutes following nasal spray)
 Migraine: Prophylaxis
–  Methysergide
• effective in about 60% of patients
• NOT effective in treating an active migraine attack or even
preventing an impending attack.
• Methysergide toxicity: retroperitoneal fibroplasia, subendocardial
fibrosis. Recommend 3-4 week drug holiday every six months
–  Propranolol - Most common for continuous prophylaxis
• best established drug for migraine attack prevention.
–  Amitriptyline (TCA)
• most frequently used among the tricyclic antidepressants
–  Valproic acid (Antiepileptic)
• effective in decreasing migraine frequency.
–  Nonsteroidal antiinflammatory drugs (NSAIDs)
• used for attack prevention and aborting acute attack
 Serotonin in Migraine
• Neurogenic vs. Vascular theories
• Several drugs that modulate the serotonin
system are effective in migraine:
1. Cyproheptadine/methysergide -
prophylaxis
2. Sumatriptan, ergotamine - acute
3. MAO inhibitors and TCA – both
4. Caffeine (↑ cAMP?)
5. Reserpine worsens migraine
 Unknown Trigger PAIN

antidromic Activation Cortex

Orthodromic
conduction
Thalamus

Blood Trigeminal
Vessel neuron autonomic

nausea

Mast cell

Inhibitory receptor Trigem.

(5-HT1D) Nucleus
caudalis
 Serotonin Agonists
• Sumatriptan: 5-HT1D agonist; contraindicated in
patients with angina
• Fluoxetine: Selective serotonin uptake inhibitors
for depression and other indications
• Buspirone: 5-HT1A agonist for anxiety
• Cisapride: 5-HT4 agonist to ↑ GI motility and
decrease G-E reflux (Removed from US market
due to fatal arrhythmias)
• LSD: 5HT1A – hallucinogen
• Ergot alkaloids: 5-HT1 and 2 and other receptors
 Serotonin Antagonists
• Methysergide and Cyproheptadine.
5HT2 antagonists. In carcinoid, migraine.
• Ketanserin: 5HT2 and Alpha antagonist –
used as antihypertensive.
• Ondansetron: 5-HT3 antagonist for
chemotherapy induced nausea and vomiting
• Clozapine: 5HT2A/2C antagonist: for
schizophrenia.