Indoleamines

Lisham Ashrafioun

Michele San George

 Melatonin

vivo.colostate.edu
 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)
 Serotonin

5-Hydroxytryptamine (5-HT)
 Synthesis
Tryptophan
Tryptophan Hydroxylase 5-Hydroxytrophan (5-HTP)

Amino Acid
5-Hydroxytryptamine (5-HT) Decarboxylase
 Metabolism

Monoamine
5-HT Oxidase
5-HIAA

5-HIAA: 5-Hydroxy indole amine acid

Inactivation- 5HT reuptake
 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
 Bonchioconstriction
 Uterine contractions
 Distribution: rodent

(Cooper, Bloom, Roth, 2003)

 5HT Receptors
receptor 5HT1 5HT2 5HT3 5HT4 5ht5 5ht6 5HT7

     
subtype 5HT1 5HT2A, 5HT3A, 5ht1A,
A, 5HT2B, 5HT3B 5ht1B
5HT1 5HT2C
B,  
 

5HT1
D,
  5ht1E,

major cAMP IP3 ion cAMP cAMP? cAMP cAMP 

signaling ↓ channel
pathway
5HT1
F
 A few words about
signal transduction
mechanisms…
 4 Families of Receptors
 Channel linked (Ionotropic)
 G-protein coupled

(Metabotropic)
 Kinase- linked (enzymatic)
 Intracellular (gene transcription)
Ionotropic receptors
 G-Protein coupled receptors

 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
 Second Messengers-
Adenylyl Cyclase


 
              
                                                                           

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

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
 Depression  Migraine
 Anxiety  Hypertension
 Social phobia  Pulmonary
 Schizophrenia hypertension
 Obsessive-compulsive  Eating disorders
 Panic disorder  Vomiting
 Irritable bowel
syndrome
 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)
 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)
 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
 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
 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
 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
 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
 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
 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
Receptor Overview
5HT2 subtypes