1. Lisham Ashrafioun Michele San George
Indoleamines
Lisham Ashrafioun
Michele San George

2. Melatonin
vivo.colostate.edu

3. Melatonin Receptors (ML1A) CNS locations PNS 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) -

4. 5-Hydroxytryptamine (5-HT)
Serotonin
5-Hydroxytryptamine (5-HT)

5. Synthesis Tryptophan 5-Hydroxytrophan (5-HTP)
Hydroxylase
Amino Acid
5-Hydroxytryptamine (5-HT)
Decarboxylase

6. Metabolism 5-HT 5-HIAA 5-HIAA: 5-Hydroxy indole amine acid Monoamine
Oxidase
5-HIAA: 5-Hydroxy indole amine acid

7. Inactivation- 5HT reuptake

8. 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

9. Distribution: rodent
(Cooper, Bloom, Roth, 2003)

10. 5HT Receptors receptor 5HT1 5HT2 5HT3 5HT4 5ht5 5HT7 subtype
5HT1A, 5HT1B, HT1D, 5ht1E, HT1F
5HT2A, 5HT2B, 5HT2C
5HT3A, 5HT3B
5ht1A, 5ht1B
major signaling pathway
cAMP↓
IP3
ion channel
cAMP
cAMP?
cAMP 

11. A few words about signal transduction mechanisms…

12. 4 Families of Receptors Channel linked (Ionotropic)
G-protein coupled (Metabotropic)
Kinase- linked (enzymatic)
Intracellular (gene transcription)

13. Ionotropic receptors

14. G-Protein coupled receptors

15. 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

16. Second Messengers- Adenylyl Cyclase
                                                                                          

17. Second Messenger- Phospholipase C

18. 5HT1A receptor
CNSforum.com

19. 5HT1A Partial Agonist mechanism

20. 5HT1A Antagonist mechanism

21. 5HT2 receptor mechanism

22. 5HT2 Antagonist mechanisms

23. 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

24. 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)

25. 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)

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. Receptor Overview

34. 5HT2 subtypes