Serotonin Receptor

atau
5-HT Receptor
 5-hydroxytryptamine receptors or 5-HT
receptors, or serotonin receptors

 A group of G protein-coupled receptor and ligand-

gated ion channels.
 found in the central and peripheral nervous systems.
 mediate both excitatory and inhibitory
neurotransmission.
 are activated by the neurotransmitter serotonin
(natural/native ligand).
 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
• Inhibit metabolism: MAO inhibitors
• Promote release: p-chloroamphetamine Non-selective
- then
depletes (e.g. fenfluramine to ↓ appe te)
 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 mo lity 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.
 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.
 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 contrac ons 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
circula on (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
 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.