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Lisham Ashrafioun Michele San George

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

2 Melatonin

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

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

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