C O NTENTS

• Biosynthesis, storage and metabolism of

Serotonin
• Serotonergic Receptors and their distribution
• Actions of Serotonin and Physiological Roles
• 5-HT receptor antagonists
What is 5- HT ?
•Serotonin and Enteramine

•Both are 5-Hydroxytryptamine (5-HT) – a monoamine

neurotransmitter - derived from tryptophan.

•Feelings of well-being
•Present in GI cells (90%)
– 90% in E C cells and 10% in neurones of different plexuses .
• 10% in platelets and brain
 PHYSIOLOGIC DISTRIBUTION OF
SEROTONIN (5-HYDROXYTRYPTAMINE
10% CNS (5-HT)

90% GI tract
90% ECs
10% 5-Hydroxytryptamine
Neurons
SYNTHESIS, METABOLISM AND DESTRUCTION

• Dietary tryptophan
– converted to 5–hydroxy– tryptophan by tryptophan
hydroxylase
– then to 5-HT by a non–specific decarboxylase
– 5 –HT is β-aminoethyl -5-Hydroxyindole
• Degradation
– mainly monoamine oxidase (MAO–A > MAO–B)
– 5–hydroxyls Indole acetic acid (5-HIAA) in urine
 (Rate limiting)
COOH OH COOH
Tryptophan
hydroxylase
C NH2 C NH2

N
Dietary N
Tryptophan In diet. Active 5-Hydroxytryptophan
CNS
transport
5-OH Tryptophan
decarboxylase
C
COOH
Ald OH H
de ehyd
N hy
dr e
og
ena
se C NH2
AO
M
5-Hydroxy Indole
N
Acetic Acid 5-OH Indole
Acetaldehyde 5-Hydroxytryptamine
SEROTONIN UPTAKE
•Non-specific Decarboxylase produces 5-HT (also CA)

•Like NA, serotonin actively takes up by Serotonin transporter – specific

mono amino transporter (SERT) present on pre synaptic neurons.

• Na+ dependent carrier – on membrane of platelets.

(No 5-HT free form in plasma)

• Inhibited by SSRIs (fluoxetine), cocaine and TCAs.

• Platelets do not synthesize 5-HT (absence of tryptophan
hydroxylase) – takes up from intestinal blood vessels.
• Stored in storage vesicles by active uptake – Vesicular
monoamine transporter (VMAT2) – inhibited by Reserpine
5-HT RECEPTORS
•Musculotropic (D type) and Neurotropic (M type) – blockade
by Dibenzyline (phenoxybenzamine) and Morphine

•Currently – molecular characterization and cloning

•4 Families and 14 subtypes

•Only some are functionally correlated.

•Selective agonists and antagonists – clinically relevant

5-HT RECEPTORS - CHARACTERS
•All are GPCRs except 5-HT3
– Decrease cAMP production – 5-HT1
– Increase cAMP production – 5-HT4,5-HT6, 5-HT7
– Generating IP3/DAG – 5-HT2
•5-HT3 – Ligand gated Na+ K+channel – faster depolarization
5-HT1 – RECEPTORS

5HT1A ,B,D,E,F - all are autoreceptors and inhibit firing of neurones

or release of 5-HT – inhibit cAMP (Gi/Go)
– 5-HT1A– also activates K+channel and inhibits Ca++ channel.
• Somadendritic synapse in Raphe nucleus – Brainstem
and hippocampus (antianxiety – Buspirone)
– 5-HT1D– Basal ganglia and substantia nigra (dopeminergic).
– 5-HT1D/1B – Cranial Blood Vessels (for constriction – sumatriptan - agonist)
Also inhibits 5-HT release in forebrain and NA release
in sympathetic nerve endings.
5-HT2
• 5-HT2:Gq type GPCRfamily – Phospholipase C– IP3/DAG

• Mainly 3 subtypes (5-HT2A,BC, )

– 5-HT 2A- - also inhibits K+channels

– Located in all smooth muscles - vascular, visceral, platelets and cerebral
neurones (prefrontal cortex)
– Mediates direct effects of 5-HT (D-type)
• Vasoconstriction, intestinal, uterine and bronchial constrictions, platelet aggregation and
activation of cerebral neurones
• Ketanserin, Cyproheptadine, Methysergide are antagonists
• 5-HT2B– contraction of Rat gastric fundus
• 5-HT2C– Vascular endothelium – EDRF release (Vasodilatation) and CSF
5-HT3
•Neuronal receptors – depolarizes rapidly by acting on Na+K+channel and
also Ca++ channel
•Mediates indirect and reflex actions
– Somatic and autonomic nerve endings – pain, itch, and coronary
chemoreflex (bradycardia, fall in BP, respiratory stimulation/apnoea
depending on stimulation of receptors in coronary bed)
– Myenteric plexus – increased peristalsis and emetic reflex
– Area postrema and NTS – vomiting and nausea
•Ondansetron in specific antagonist – CNS as well as peripheral action
5-HT4-7
• Gs type of receptor – activates adenylyl cyclase
• Mucosa, plexuses and smooth muscles of Gut
– Augmentation of Intestinal secretion and peristalsis
• In Brain: hippocampaus area
– Specific role is unknown till now
– Cizapride – specific agonist of these receptors and
also Metoclopramide.
ACTIONS OF 5-HT

Potent depolarizer of Nerve endings

Exerts DIRECT + INDIRECT + REFLEX ACTIONS
 Tachyphylaxis – variable effects
ACTIONS OF 5-HT – CVS

• Triphasic response on BP:

– Early sharp fall: Coronary chemoreflex
– Brief rise in BP: vasoconstriction and increased cardiac output -
also due to vasoconstriction
– Prolonged fall in BP: arteriolar dilatation and extravasation of
fluid – skeletal muscle
•(Not involved in Physiological Regulation of BP)
• – Preeclmpsia
•Ketanserin – 5-HT antagonist (5-HT2)
PATHOPHYSIOLOGICAL ROLES – 5-HT
1. Neurotransmitter: Confirmed now – raphe nuclei, brainstem, substantia
nigra and few other sides – send axons to LS, cortex and spinal cord.
– Role: sleep, temperature regulation, thought, cognitive function,
behaviuor and mood, appetite, vomiting and pain perceptions – SSRIs,
TCAs etc.
2. Precursor of Melatonin: Pineal body – circadian rhythm and biological
clock
3. Neuroendocrine function: Hypothalamo-Pituitary neurones
4. Nausea and vomiting: 5-HT3 mediated chemotherapy and radiotherapy
induced vomiting
5. Migraine: Vasoconstrictor phage of migraine – and neurogenic
inflammation – Methysergide, Sumatriptans
6. Haemostasis: Released by platelets – accelerates platelet aggregation and
clot formation – amplifying response
7. Raynaud`s Phenomenon: Acute vasospasm due to
release of 5-HT by platelets – Ketanserin
8. Variant angina: Coronary vasospasm induced by 5 –HT
also TXA2 – preeclamsia
9. Intestinal Motility: Regulate peristalsis and local gut
reflexes
10. Hypertension: Increased responsiveness to 5-HT and
low uptake and clearance of 5_HT by platelets in
hypertensives – Ketanserin
11.Carcinoid syndrome: Carcinoid tumours produce
massive 5- HT – bowel hypermotility and
broncoconstriction – Pellagra (tryptophan diversion)