serotonin

Serotonin5-Hydroxytryptamine (5-HT)

By: Dr. Vahid Nikoui

Email: [email protected]

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

MAO

Aldehyde

dehydrogenase

(Rate limiting)

In diet. ActiveCNS transport

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

Hunter Area Toxicology Service

Serotonin roles

Peripheral Peristalsis Vomiting Platelet aggregation and haemostasis Inflammatory mediator Sensitisation of nociceptors Microvascular control


Serotonin roles Central

Control of appetite Sleep Mood Hallucinations Stereotyped behaviour Pain perception Vomiting

Receptor 5-HT 1 5-HT 2 5-HT 3 5-HT 4 5-HT 5 5-HT 6

5-HT 7

Subtype

5-HT1A

5-HT 1B 5-HT 1D

5-HT 1E

5-HT 1F

5-HT 2A

5-HT 2B

5-HT 2C

5-HT 3A

5-HT 3B

Major signaling pathway

cAMP↓ IP3ion

channel cAMP cAMP ↓ cAMP cAMP

5-HT Receptors

5–HT5A

5–HT5B


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

5-HT1A Receptor

CNSforum.com

5-HT1A Partial Agonist Mechanism

5-HT1A Antagonist mechanism


5–HT1

5–HT1A

Limbic system Regulation of emotions

Neocortex Hypothalamus Substantia gelatinosa

Proprioception

5–HT1B


5–HT1

5–HT1D Autoreceptors

Inhibitory feedback Heteroreceptors

Modulate release Acetylcholine Glutamate

Anti–migraine effect of Sumatriptan

Serotonin in Migraine

Neurogenic vs. Vascular theories

1. Cyproheptadine, Methysergide – prophylaxis

2. Sumatriptan, Ergotamine – acute attacks

3. MAO inhibitors and TCAs – both


5–HT1 5–HT1E

? functional role

5–HT1F

? functional role Distribution includes CNS, uterus,

mesentery Inhibit cAMP High affinity for

Sumatriptan, Methysergide


Serotonin receptors

5–HT2

7 trans–membrane domains G protein linked Phospholipase C dependant Subtypes

5–HT2A, 5–HT2B, 5–HT2C

5-HT2 Receptor Mechanism

5-HT2 Antagonist Mechanism


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


5–HT2

5–HT2A

CNS Motor behaviour Head twitch Sleep regulation Nociception Neuroexcitation


5–HT2

5–HT2B

Stomach fundus

5–HT2C

CSF production Locomotion Eating disorders Anxiety Migraine


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


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


Serotonin receptors

5-HT6

Coupled to adenylyl cyclase Significance unknown

5-HT7

Coupled to adenylyl cyclase Significance unknown

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)

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)

Serotinergic Drugs


Serotinergic drugs

Serotonin precursors S–adenyl–L–methionine L–tryptophan 5–hydroxytryptophan Dopamine


Serotinergic drugs

Serotonin re–uptake inhibitors Citalopram, Fluoxetine, Fluvoxamine,

Paroxetine, Sertraline, Venlafaxine Clomipramine, Imipramine Nefazodone, Trazodone Chlorpheniramine Cocaine, Dextromethorphan,

Pentazocine, Pethidine


Serotinergic drugs

Serotonin agonists Fenfluramine, P–chloramphetamine Bromocriptine, Dihydroergotamine,

Gepirone Eltoprazin, Quipazine


Serotinergic drugs

Irreversible Monoamine oxidase inhibitors (MAOIs) Clorgyline, Isocarboxazid, Nialamide,

Pargyline, Phenelzine, Tranylcypromine Selegiline Furazolidone Procarbazine


Serotinergic drugs

Reversible inhibitors of MAO (RIMAs) Brofaramine Befloxatone, Toloxatone Moclobemide


Serotinergic drugs

Miscellaneous/mixed Lithium Lysergic acid diethylamide (LSD) 3,4–methylenedioxymethamphetamine

(MDMA, ecstasy), methylenedioxyethamphetamine (eve)

Propranolol, Pindolol

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.


Sternbach criteria

Mental status changes (confusion, hypomania) Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhoea Incoordination Fever

Diarrhoea

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


Drugs used to treat serotonin syndrome

Non–specific blocking agents Methysergide Cyproheptadine

–blockers Propranolol Pindolol



Benzodiazepines Lorazepam Diazepam Clonazepam

Neuroleptics Chlorprothixene Chlorpromazine Haloperidol



Miscellaneous Chlormethiazole Nitroglycerine

Drugs used for neuroleptic malignant syndrome Dantrolene Bromocriptine


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)

Receptor Overview

5-HT2 Subtypes

Thanks for Your Attention

serotonin

Health & Medicine