Indoleamines

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Indoleamines

• Lisham Ashrafioun
• Michele San George

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Melatonin
vivo.colostate.edu
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Melatonin

• Receptors (ML1A)
• CNS locations
• SCN (biological clock)
• Anterior pituitary (seasonal breeding)
• PNS locations
• Retina - circadian and reproductive responses
• Cardiovascular system - caudal artery that
  potentiates NE-induced contraction
• Reproductive system ovaries
• Immune system T cells
• Kidneys Na retention
• GI Tract relaxes smooth muscles (melatonin-5-HT
  feedback)

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Serotonin

• 5-Hydroxytryptamine (5-HT)

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Synthesis
Tryptophan
Tryptophan
5-Hydroxytrophan (5-HTP)
Hydroxylase
Amino Acid
5-Hydroxytryptamine (5-HT)
Decarboxylase
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Metabolism
Monoamine
5-HT
5-HIAA
Oxidase
5-HIAA 5-Hydroxy indole amine acid
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Inactivation- 5HT reuptake
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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/vasodilato
  r of vessels
• Bonchioconstriction
• Uterine contractions

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Distribution rodent
(Cooper, Bloom, Roth, 2003)
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5HT Receptors
 
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A few words about signal transduction mechanisms
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4 Families of Receptors

• Channel linked (Ionotropic)
• G-protein coupled (Metabotropic)
• Kinase- linked (enzymatic)
• Intracellular (gene transcription)

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Ionotropic receptors
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G-Protein coupled receptors

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The Major G Proteins

• Gs Stimulatory- Activates Ca channels, activates
  adenylyl cyclase
• Gi Inhibitory- Activates K channels, inhibits
  adenylyl cyclase
• Gq Activates phospholipase C
• Go - Inhibits Ca channels
• G12/13 Diverse ion transporter interactions

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Second Messengers- Adenylyl Cyclase

http//www.endocrinesurgeon.co.uk
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Second Messenger- Phospholipase C

http//www.endocrinesurgeon.co.uk
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5HT1A receptor
CNSforum.com
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5HT1A Partial Agonist mechanism
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5HT1A Antagonist mechanism
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5HT2 receptor mechanism
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5HT2 Antagonist mechanisms
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The Swiss army knife of Neurotransmitters

• Depression
• Anxiety
• Social phobia
• Schizophrenia
• Obsessive-compulsive
• Panic disorder

• Migraine
• Hypertension
• Pulmonary hypertension
• Eating disorders
• Vomiting
• Irritable bowel syndrome

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Serotenergic Drugs

• 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)

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Drugs continued

• 5HT3 Ondansetron treat chemotherapy- induced
  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)

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Antidepressants

• 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

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Serotonin Syndrome

• 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

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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

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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

• 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

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Hallucinogens and drug discrimination trials

• 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

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Human Studies

• Psilocybin and PET imaging studies- pattern
  resembles brain activation in schizophrenic
  patients
• Action of psilocybin is blocked by pretreatment
  with 5HT2A/2C antagonists

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Yeah rub Vaseline on my eyelids 5-HT MDMA

• MDMA causes an increased release of 5-HT and
  blocks reuptake
• High affinity for SERT
• Effects fine axons
• Responsible for temperature increases

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Receptor Overview
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5HT2 subtypes