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
C
OH
COOH
Tryptophan
hydroxylase
NH2
C
N
NH2
N
Tryptophan In diet. Active
CNS transport
C
5-Hydroxytryptophan
5-OH Tryptophan
decarboxylase
COOH
OH
H
N
C
5-Hydroxy Indole
Acetic Acid
NH2
N
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
•
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.