Serotonin (5-HT) - Addiction Science Network

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Transcript Serotonin (5-HT) - Addiction Science Network

Indoleamines
Lisham Ashrafioun
Michele San George
Melatonin
vivo.colostate.edu
Melatonin
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Receptors (ML1A)
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CNS locations
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SCN (biological clock)
Anterior pituitary (seasonal breeding)
PNS locations
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Retina - circadian and reproductive responses
Cardiovascular system - caudal artery that potentiates NEinduced contraction
Reproductive system – ovaries
Immune system – T cells
Kidneys – Na retention
GI Tract – relaxes smooth muscles (melatonin-5-HT
feedback)
Serotonin
5-Hydroxytryptamine (5-HT)
Synthesis
Tryptophan
Tryptophan
Hydroxylase
5-Hydroxytrophan (5-HTP)
5-Hydroxytryptamine (5-HT)
Amino Acid
Decarboxylase
Metabolism
5-HT
Monoamine
Oxidase
5-HIAA
5-HIAA: 5-Hydroxy indole amine acid
Inactivation- 5HT reuptake
Distribution(PNS)
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Majority released from gut
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Cardiovascular system –
vasoconstrictor/vasodilator of vessels
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Responsible for smooth muscle contractions
Release stimulated by food intake
Inhibits release of gastric acid
Softens stool
Bonchioconstriction
Uterine contractions
Distribution: rodent
(Cooper, Bloom, Roth, 2003)
5HT Receptors
receptor
5HT1
subtype
5HT1 5HT2A,
A,
5HT2B,
5HT1 5HT2C
B,
5HT1
D,
5ht1E,
5HT1
F
major
cAMP
signaling ↓
pathway
5HT2
IP3
5HT3
5HT4
5HT3A,
5HT3B
ion
channel
5ht5
5ht6
5HT7
5ht1A,
5ht1B
cAMP
cAMP? cAMP
cAMP 
A few words about
signal transduction
mechanisms…
4 Families of Receptors
Channel linked (Ionotropic)
 G-protein coupled
(Metabotropic)
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Kinase- linked (enzymatic)
Intracellular (gene transcription)
Ionotropic receptors
G-Protein coupled receptors
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The Major G Proteins
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Gs Stimulatory- Activates Ca channels,
activates adenylyl cyclase
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Gi Inhibitory- Activates K channels,
inhibits adenylyl cyclase
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Gq – Activates phospholipase C
Go - Inhibits Ca channels
G12/13 – Diverse ion transporter interactions
Second MessengersAdenylyl Cyclase
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http://www.endocrinesurgeon.co.uk
Second MessengerPhospholipase C
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http://www.endocrinesurgeon.co.uk
5HT1A receptor
CNSforum.com
5HT1A Partial Agonist mechanism
5HT1A Antagonist mechanism
5HT2 receptor mechanism
5HT2 Antagonist mechanisms
The Swiss army knife of
Neurotransmitters
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Depression
Anxiety
Social phobia
Schizophrenia
Obsessive-compulsive
Panic disorder
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Migraine
Hypertension
Pulmonary
hypertension
Eating disorders
Vomiting
Irritable bowel
syndrome
Serotenergic Drugs
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5HT1A Buspirone, ipsapirone treat anxiety,
depression (partial agonist)
5HT1D Sumatriptan, treat migraine (partial
agonist)
5HT2A/2C methysergide, trazodone,
risperidone, ketanserin treat migraine,
depression, schizophrenia (antagonist)
Drugs continued…
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5HT3 Ondansetron treat chemotherapyinduced emesis (antagonist)
5HT4 Cisapride treat GI disorders
(agonist)
5HT transporter SSRIs (Fluoxetine,
sertraline) treat depression, OCD, panic
disorder, social phobia, post traumatic
stress disorder (inhibitor)
Antidepressants
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Decreased amounts and impaired function
of 5-HT associated with aggression,
depression and other forms of antisocial
behavior
Antidepressants attempt to increase 5-HT
levels
Serotonin Syndrome
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Toxic, potentially fatal effects
require a combination of serotonergic agents,
such as an SSRI with an MAOI.
Symptoms: euphoria, drowsiness, sustained
rapid eye movement, overreaction of reflexes,
rapid muscle contraction,abnormal movements
of the foot, drunk, dizzy feeling,high body
temperature, shivering , diarrhea ,loss of
consciousness, death
Treatment
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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
Oh man I just saw God and he was playing a
mandolin and he told me to watch Fear and
Loathing in Las Vegas while listening to The Doors
self-titled album and dude they totally go together
LSD
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Non-selective 5HT agonist/partial agonist
Ergot derivative
Mimics 5HT at 5HT1A autoreceptors on raphe cell
bodies, slows firing rate of serotonergic neurons
Current theories focus on glutamate release in
thalamocortical terminals, causing dissociation
between sensory relay and cortical output
Hallucinogens and drug
discrimination trials
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Animal model thought to reflect subjective
effects
Mediated by activation of 5HT2A receptors
Acts as partial or full agonist at 5HT2A and
5HT2C receptors
Phenethylamine derivatives (psilocybin)
are selective 5HT2A/2C agonists
Human Studies
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Psilocybin and PET imaging studiespattern resembles brain activation in
schizophrenic patients
Action of psilocybin is blocked by
pretreatment with 5HT2A/2C antagonists
Yeah rub Vaseline on my eyelids –
5-HT & MDMA
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MDMA causes an increased release of 5HT and blocks reuptake
High affinity for SERT
Effects fine axons
Responsible for temperature increases
Receptor Overview
5HT2 subtypes