1.
Serotonin
5-Hydroxytryptamine (5-HT)
By: Dr. Vahid Nikoui
Email: nikoui@razi.tums.ac.ir

2.
(Rate limiting) OH
COOH COOH
Tryptophan
C NH2 hydroxylase C NH2
N N
In diet. Active
Tryptophan CNS transport 5-Hydroxytryptophan
5-OH Tryptophan
decarboxylase
C COOH
OH H
N
C NH2
5-Hydroxy Indole N
Acetic Acid 5-OH Indole
Acetaldehyde 5-Hydroxytryptamine

3.
Distribution (PNS)
 Majority released from gut
 Responsible for smooth muscle contractions
 Release stimulated by food intake
 Inhibits release of gastric acid
 Softens stool
 Cardiovascular system –
vasoconstrictor/vasodilator of vessels
 Bronchioconstriction
 Uterine contractions

4.
Serotonin roles
 Peripheral
 Peristalsis
 Vomiting
 Platelet aggregation and haemostasis
 Inflammatory mediator
 Sensitisation of nociceptors
 Microvascular control
Hunter Area Toxicology
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5.
Serotonin roles
 Central
 Control of appetite
 Sleep
 Mood
 Hallucinations
 Stereotyped behaviour
 Pain perception
 Vomiting
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6.
5-HT Receptors
Receptor 5-HT 1 5-HT 2 5-HT 3 5-HT 4 5-HT 5 5-HT 6 5-HT 7
5-HT1A 5-HT 2A 5-HT 3A 5–HT5A
5-HT 1B 5-HT 2B 5-HT 3B 5–HT5B
Subtype 5-HT 1D
5-HT 2C
5-HT 1E
5-HT 1F
Major
ion
signaling cAMP↓ IP3 cAMP cAMP ↓ cAMP cAMP 
channel
pathway

7.
Serotonin receptors
 5–HT1
 7 trans–membrane domains
 G protein linked
 cAMP dependant
 Anxiolytic and antidepressant
 Subtypes
 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F
Hunter Area Toxicology
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8.
5-HT1A Receptor
CNSforum.com

9.
5-HT1A Partial Agonist Mechanism

10.
5-HT1A Antagonist mechanism

11.
5–HT1
 5–HT1A
 Limbic system
 Regulation of emotions
 Neocortex
 Hypothalamus
 Substantia gelatinosa
 Proprioception
 5–HT1B
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12.
5–HT1
 5–HT1D
 Autoreceptors
 Inhibitory feedback
 Heteroreceptors
 Modulate release
 Acetylcholine
 Glutamate
 Anti–migraine effect of Sumatriptan
Hunter Area Toxicology
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13.
Serotonin in Migraine
 Neurogenic vs. Vascular theories
1. Cyproheptadine, Methysergide – prophylaxis
2. Sumatriptan, Ergotamine – acute attacks
3. MAO inhibitors and TCAs – both

14.
5–HT1
 5–HT1E
 ? functional role
 5–HT1F
 ? functional role
 Distribution includes CNS, uterus, mesentery
 Inhibit cAMP
 High affinity for
 Sumatriptan, Methysergide
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15.
Serotonin receptors
 5–HT2
 7 trans–membrane domains
 G protein linked
 Phospholipase C dependant
 Subtypes
 5–HT2A, 5–HT2B, 5–HT2C
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16.
5-HT2 Receptor Mechanism

17.
5-HT2 Antagonist Mechanism

18.
5–HT2
 5–HT2A
 Periphery
 Contraction of vascular/non–vascular smooth
muscle
 Platelet aggregation
 Increased capillary permeability
 Modulation of the release of other
neurotransmitters and hormones
 ACh, Adrenaline, Dopamine, Excitatory amino acids,
Vasopressin
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19.
5–HT2
 5–HT2A
 CNS
 Motor behaviour
 Head twitch
 Sleep regulation
 Nociception
 Neuroexcitation
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20.
5–HT2
 5–HT2B
 Stomach fundus
 5–HT2C
 CSF production
 Locomotion
 Eating disorders
 Anxiety
 Migraine
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21.
Serotonin receptors
 5–HT3
 Ligand gated cation channels
 5-HT4
 Coupled to adenylyl cyclase
 5-HT5
 Coupled to adenylyl cyclase
 Subtypes
 5–HT5A, 5–HT5B
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22.
5–HT3
 Peripheral
 Located exclusively on neurons and mediate
neurotransmitter release - parasympathetic,
sympathetic, sensory and enteric
 Cardiac inhibition/activation, pain, initiation of the
vomiting reflex
 Central
 Facilitate dopamine and 5–HT release, inhibit
ACh and noradrenaline release
 Anxiety, depression, memory, tolerance and dependence
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23.
Serotonin receptors
 5-HT6
 Coupled to adenylyl cyclase
 Significance unknown
 5-HT7
 Coupled to adenylyl cyclase
 Significance unknown
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24.
Serotinergic Drugs
 5-HT1A : Buspirone, Ipsapirone, Tandospirone
Treat anxiety, depression (partial agonist)
 5-HT 1D/1B : Sumatriptan, Naratriptan, Zolmitriptan
Treat migraine (partial agonist)
 5-HT 2A/2C : Methysergide, Trazodone,
Risperidone, Ketanserin, Ritanserin, Mianserin
Treat migraine, depression, schizophrenia
(antagonist)

25.
Serotinergic Drugs
 5-HT 3 : Ondansetron, Granisetron,
Tropisetron, Memantine, Mirtazapine
Treat chemotherapy-induced emesis
(antagonist)
 5-HT 4 : Cisapride, Metoclopramide,
Mosapride, Dazopride, Tegaserod
Treat GI disorders (agonist)

26.
Serotinergic drugs
 Serotonin precursors
 S–adenyl–L–methionine
 L–tryptophan
 5–hydroxytryptophan
 Dopamine
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27.
Serotinergic drugs
 Serotonin re–uptake inhibitors
 Citalopram, Fluoxetine, Fluvoxamine,
Paroxetine, Sertraline, Venlafaxine
 Clomipramine, Imipramine
 Nefazodone, Trazodone
 Chlorpheniramine
 Cocaine, Dextromethorphan, Pentazocine,
Pethidine
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28.
Serotinergic drugs
 Serotonin agonists
 Fenfluramine, P–chloramphetamine
 Bromocriptine, Dihydroergotamine, Gepirone
 Eltoprazin, Quipazine
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29.
Serotinergic drugs
 Irreversible Monoamine oxidase inhibitors
(MAOIs)
 Clorgyline, Isocarboxazid, Nialamide,
Pargyline, Phenelzine, Tranylcypromine
 Selegiline
 Furazolidone
 Procarbazine
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30.
Serotinergic drugs
 Reversible inhibitors of MAO (RIMAs)
 Brofaramine
 Befloxatone, Toloxatone
 Moclobemide
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31.
Serotinergic drugs
 Miscellaneous/mixed
 Lithium
 Lysergic acid diethylamide (LSD)
 3,4–methylenedioxymethamphetamine
(MDMA, ecstasy),
methylenedioxyethamphetamine (eve)
 Propranolol, Pindolol
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32.
Serotonin Syndrome
 Toxic, potentially fatal effects
 Require a combination of serotonergic agents,
such as an SSRI with an MAOI.
 Other agents is including TCAs,
Dextromethorphan, Meperidine and MDMA.

33.
Sternbach criteria
Mental status changes (confusion, hypomania)
Agitation
Myoclonus
Hyperreflexia
Diaphoresis
Shivering
Tremor
Diarrhoea
Incoordination
Diarrhoea
Fever
Hunter Area Toxicology Service

34.
Treatment
 Suspected agents should be discontinued.
 OTC drugs containing ingredients known to
increase serotonin levels, such as
Dextromethorphan, Pseudoephedrine or
Phenylpropanolamine, also should be
discontinued.
 Benzodiazepines for mild to moderate cases
 Cyproheptadine, Methysergide, and Propranolol
for severe cases

35.
Drugs used to treat serotonin
syndrome
 Non–specific blocking agents
 Methysergide
 Cyproheptadine
 –blockers
 Propranolol
 Pindolol
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36.
Drugs used to treat serotonin
syndrome
 Benzodiazepines
 Lorazepam
 Diazepam
 Clonazepam
 Neuroleptics
 Chlorprothixene
 Chlorpromazine
 Haloperidol
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37.
Drugs used to treat serotonin
syndrome
 Miscellaneous
 Chlormethiazole
 Nitroglycerine
 Drugs used for neuroleptic malignant
syndrome
 Dantrolene
 Bromocriptine
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38.
Antagonist potencies
 Ki values (5–HT2)
 Chlorprothixene (0.43 nM) > Chlorpromazine
> Cyproheptadine > Haloperidol (36 nM)
 limited experience suggests haloperidol
ineffective
 Ki values (5–HT1)
 Chlorprothixene (230 nM) > Haloperidol >
Chlorpromazine > Cyproheptadine (3200 nM)
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39.
Receptor Overview

40.
5-HT2 Subtypes

41.
Thanks for Your Attention