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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
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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
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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
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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
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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