(Rate limiting)

COOH
C

OH

COOH

Tryptophan
hydroxylase

NH2

diet. Active
Tryptophan In
CNS transport

C
N

NH2

5-Hydroxytryptophan
5-OH Tryptophan
decarboxylase

COOH
Al
de dehy
hy
dr de
og
en
a

5-Hydroxy Indole
Acetic Acid

OH
se

H
C

AO

5-OH Indole
Acetaldehyde

NH2

N
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 AAs)
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)

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

1.
2.
3.
4.

Cardiovascular system: Multiple direct and indirect

effects:
Direct vasoconstriction (large arteries) and indirect
vasodilation (NO and PGI2 mediated)
Heart: direct inotropic and chronotropic effects
Reflex mechanisms due to change in BP
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

1.
2.
3.
4.
5.

Neurogenic vs. Vascular theories

Several drugs that modulate the serotonin
system are effective in migraine:
Cyproheptadine/methysergide prophylaxis
Sumatriptan, ergotamine - acute
MAO inhibitors and TCA both
Caffeine ( cAMP?)
Reserpine worsens migraine

PAIN

Unknown Trigger

antidromic

Activation

Cortex
Orthodromic
conduction
Thalamus

Blood
Vessel

Trigeminal
neuron

autonomic
nausea

Mast cell
Inhibitory receptor
(5-HT1D)

Trigem.
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.