SEROTONIN : DISEASES AND
THERAPEUTICS
By: Dr. Gaurav Yadav

Source & Chemistry
 3-(β-aminoethyl)-5-hydroxyindole
 Widely distributed in animals and plants.
 Present in sea food, meat, nuts, seeds, various grains.
 It is also present in venoms; common stinging nettles
and of wasps and scorpions.
 In humans it is found in high concentrations in
enterochromaffin cells throughout the gastrointestinal
tract, in storage granules in platelets and broadly
throughout the CNS.

HISTORY
 1930s Erspamer studied distribution of enterochromaffin cells.
 1948 Page and colleagues isolated and chemically characterized
vasoconstrictor substance from platelets as 5-HT.
 1957 Gaddum and Piccarelli classified 5-HT receptors into M
and D type.
 1959 Udenfriend discovered biosynthetic and degradative
pathways.
 1976 Page coined term SEROTONIN.
 1979 Peroutka &Snyder identified 5HT1 and 5HT2 receptors
by radioligand binding studies.

Synthesis and Metabolism
 5-HT is synthesized by a two step pathway from the
essential amino acid tryptophan.
 Tryptophan is actively transported into the brain by a
carrier protein.
 Tryptophan hydroxylase is rate limiting enzyme .
 Rate limiting enzyme not saturated by substrate.
 5-OHTr decarboxylase same as DOPA decarboxylase
 Breakdown mainly by MAO (MAO-A and MAO-B)
 5-HIAA actively extruded from CNS and excreted in
urine.

N
C
N
C NH2
COOH COOH
NH2
OH
N
C NH2
OH H
Tryptophan 5-Hydroxytryptophan
5-Hydroxytryptamine
N
C COOH
5-OH Indole
Acetaldehyde
5-Hydroxy Indole
Acetic Acid
Tryptophan
hydroxylase
5-OH Tryptophan
decarboxylase
M
AO
Aldehyde
dehydrogenase
(Rate limiting)
In diet. Active
CNS transport

Serotonin Receptors
There are 7 families (5-HT1-7) with further subtypes of 5-
HT1(A,B,D,E,F) and 5-HT2(A-C)
Multiple transduction mechanisms
All are G-protein coupled receptors, except 5-HT3 which
is a ligand gated cation channel
5-HT1 acts by decreasing cAMP, while 5-HT4-7 act by
increasing cAMP.
5-HT2 acts by phospholipase C/inositol triphosphate
pathway.

5-HT1 receptor
Subtyp
e
Transduction
mechanism
Location Physiological roles and therapeutic
applications
5HT1A GPCR
Inhibit AC
Decrease
cAMP
Autorecepto
r
Raphe
nuclei
Hippocamp
us
Cortex
Approved
In alleviation of anxiety – Buspirone,
Tandospirone (partial agonist)
Under trial (Gepirone, Flesinoxan, Flibanserin,
Naluzotan)
Atypical antipsychotics – increased DA release
Aripiprazole (partial agonist)
Other roles
Thermoregulation – vasodilation of blood vessels
in skin (central receptors)
Decreased BP and HR- by inducing peripheral
vasodilation (rostroventrolateral medulla)
Antiemetic and analgesic – In dorsal raphe
nuclei, colocalized with NK1 receptor
Impairs memory and learning by inhibiting
release of Ach and glutamate Lecozotan (5-
HT1a antagonist) for Alzheimer's
Vilazodone Vortioxetine– SERT inhibitor with
5HT1a partial agonist activity ; novel
antidepressant
Increased secretion of oxytocin- prosocial,

5-HT1 receptor
Subtyp
e
Transduction
mechanism
Location Physiological roles and
therapeutic applications
5-HT1B GPCR
Inhibit AC
Decrease
cAMP
Coronary & cerebral
arteries
Frontal cortex
(postsynaptic receptor)
Basal ganglia and
striatum (autoreceptor)
Vascular smooth
muscle
Vasoconstriction- Triptans
(migraine)
Ergotamine
Inhibits release of dopamine
(antipsychotic)
Inhibits release of serotonin &
decrease glutamatergic
transmission
Pulmonary vasoconstriction
Promotes bone growth and bone
formation rate.
5-HT1D GPCR
Inhibit AC
Decrease
cAMP
CNS
Blood vessels (poorly in
coronary circulation)
Trigeminal ganglion
Locomotion, anxiety
Vasoconstriction (Triptans,
Ergotamine)
Inhibit release of proinflammatory

5-HT1 receptor
Subtype Transduction
mechanism
Location Physiological roles and
therapeutic applications
5-HT1E GPCR
Inhibit AC
Decrease cAMP
Frontal
cortex
Hippocampu
s
Speculated in regulation of
memory
5-HT1F GPCR
Inhibit AC
Decrease cAMP
Brain, uterus,
mesentary
Blood vessels
Physiological roles at these
sites are unknown
Constriction
Lasmiditan (agonist)-
antimigraine

5-HT2 receptors
Subty
pe
Transductio
n
mechanis
m
Location Physiological roles and therapeutic
applications
5-HT2A GPCR
Increase
IP3/DAG
-Neocortex
(pyramidal cells in
prefrontal cortex)
-Smooth muscles (GIT
bronchi)
-Platelets
-CVS & gut
Hallucinogenic property of agonists
(LSD)
Enhance dopamine release (memory,
attention, learning)
Contraction
Aggregation
Anti inflammatory effects
5-HT2a antagonism (along with D2
antagonism) useful in antipsychotics
Aripiprazole, Quetiapine, Asenapine,
Risperidone, Sertindole, Olanzapine,
Clozapine, Ziprasidone
Lurasidone (5-HT2a 5-HT7 & D2 ant)
Anxiolytic, antidepressant, procognitive
benefits in schizophrenia patients.
Antidepressants
Nefazodone (5-HT2a & SERT ant)
Amoxapine

5-HT2 receptor
Subtyp
e
Transduction
mechanism
Location Physiological roles and therapeutic
applications
5-HT2B GPCR
Increase
IP3/DAG
Gastric
fundus
Blood
vessels
Heart
Contraction
Pulmonary vasoconstriction
Possible role in treatment of migraine
Agonists may lead to valvulopathy
Antagonists might be useful in chronic
heart diseases.
Lisuride (DA agonist, 5-HT2b antagonist, 5-
HT1a & 5-HT2a,2c partial agonist)
antiparkinsonian, antimigraine
5-HT2C GPCR
Increase
IP3/DAG
CNS Regulation of mood, sleep
CSF production
Control dopamine release in brain
Antagonists increase release of DA and NA in
frontal cortex, possible use as antidepressant
(Agomelatine)
Antipsychotics 5-HT2c antagonism (Sertindole,
Ziprasidone)

Type Transductio
n
mechanism
Location Physiological roles and
therapeutic applications
5-HT3 Ligand
gated ion
channels
CNS- nausea and
vomiting centre
PNS- enteric neurons
nociceptive
neurons
Cause emesis
Antagonists used as antiemetic
Palonosetron, Ondanseton,
Granisetron
Metaclopramide
Alosetron, cilansetron(trial)
Reduce seizure potential
(Granisetron being investigated)
5-HT4 GPCR
Induce AC
Increase
cAMP
GIT
CNS
Myentric plexus- stimulation of
gastric emptying
Agonists- Metaclopramide
Prucalopride (under trial)
Possible role in learning, memory,
Reduced respiratory depression by
opioids
Stimulation of aldosterone secretion
from adrenal cortex
Reducing susceptibility to seizures

Type Transductio
n
mechanism
s
Location Physiological roles and
therapeutic applications
5-HT5
2 subtypes
5-HT5A in humans
and rats
5-HT5B in rats only
GPCR
Increase
cAMP
CNS Modulation of exploratory
behavior in rodents
Potential role in circadian
rhythm.
Valerenic acid (partial agonist)
tried for insomnia
5-HT6 GPCR
Increase
cAMP
CNS Role in motor control, emotion,
cognition, memory
5-HT6 agonist enhance GABAergic
signaling
5-HT6 antagonist increase
glutamatergic & cholinergic
neurotransmission, increase DA & NA
release in frontal cortex
Idalopirdine (5-HT6 ant) improves
cognition learning memory, reduce
appetite, promotes weight loss.
SB – 271046 (ant) cognitive
dysfunction
5-HT7 GPCR GIT Smooth muscle relaxation

Migraine
 Various theories proposed
 Vascular theory by Wolff suggests initially humorally mediated
intracerebral vasoconstriction causing aura, followed by
extracerebral vasodilation causing headache.
 Neural hypothesis by Lauritzen “cortical spreading depression”
 Inflammation hypothesis by Waeber & Moskowitz activation of
trigeminal nerve terminals & release of inflammatory
neuropeptides. (CGRP; telcagepant)
 2 important factors that implicate 5-HT in its pathogenesis are
- there is a sharp increase in the urinary excretion of the main
5-HT metabolite, 5-HIAA, during the attack.
- Several drugs that modulate the serotonin system are
effective in migraine.

Neurovascular Theory of
Migraine

Depression
 Monoamine theory of depression which was first proposed in
1965 by Schildkraut suggests that depression results from
deficient monoaminergic (5-HT or NA) transmission in the
CNS.
 Noradrenaline depletion may be due to inhibition of tyrosine
hydroxylase, whereas reduced synthesis of serotonin may be
due to depletion of dietary tryptophan or mutations of
tryptophan hydroxylase
 Based on the ability of known antidepressant drugs TCAs,
SSRIs and MAO inhibitors to facilitate monoaminergic
transmission.
 Recent approaches show that depression may be associated with
neurodegeneration and reduced neurogenesis in the
hippocampus.

 Stress & hypothalamic-pituitary-adrenal axis
-The hypothalamic-pituitary-cortisol hypothesis
postulates that
depression is associated with elevated cortisol levels
in
response to stress.
 Other possible disease mechanisms
- Reduced level GABA & dopamine
- Melatonin dysfunction - Abnormal circadian rhythms
- Neuronal loss and reduced neurogenesis

SSRIs
 Selectively block 5-HT reuptake by the neurons
 Include Citalopram, Fluoxetine, Paroxetine, Sertraline and
Fluvoxamine
 Increase synaptic 5-HT availability stimulates post-synaptic
neurons and contributes to mood elevating and anxiolytic
properties
 Other uses OCD, Panic disorder , social phobia , PTSD.

Other new drugs for depression
 Newer mixed 5-HT and noradrenaline reuptake inhibitors
Venlafaxine
Desvenlafaxine
Duloxetine
Milnacipran
 5-HT2a receptor antagonist – Trazodone, Mianserin

Other Drugs affecting 5-HT system
 Precursors of serotonin-
- s-adenyl-l-methionine, tryptophan
 Inhibit synthesis
 p-chlorophenylalanine (irreversible)
 Inhibit neuronal re-uptake
 SSRI (e.g. fluoxetine), TCA (e.g. imipramine)
 Inhibit storage-deplete:
 Reserpine
 Inhibit metabolism:
 MAO inhibitors
 Promote release:
 p-chloroamphetamine (e.g. fenfluramine to ↓ appetite)

Serotonin syndrome
 Serotonin syndrome is a symptom complex of varying drug
interactions which may lead to excess serotonin in body.
 These are toxic and potentially fatal effects.
 Require a combination of serotonergic drugs such as SSRIs
with MAO inhibitors.
 Other drugs implicated are TCAs, meperidine, MDMA.
 Symptoms- mental status changes, confusion, agitation,
hypomania, myoclonus, hyperreflexia, diaphoresis, shivering,
tremor, diarrhoea, incoordination, fever.
 Treatment
Remove suspected agent
BZDs Propranolol

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