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Indoleamines Lisham Ashrafioun Michele San George.

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Presentation on theme: "Indoleamines Lisham Ashrafioun Michele San George."— Presentation transcript:

1 Indoleamines Lisham Ashrafioun Michele San George

2 Melatonin vivo.colostate.edu

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

4 Serotonin 5-Hydroxytryptamine (5-HT)

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

6 Metabolism 5-HT5-HIAA Monoamine Oxidase 5-HIAA: 5-Hydroxy indole amine acid

7 Inactivation- 5HT reuptake

8 Distribution(PNS) Majority released from gut Majority released from gut Responsible for smooth muscle contractions Responsible for smooth muscle contractions Release stimulated by food intake Release stimulated by food intake Inhibits release of gastric acid Inhibits release of gastric acid Softens stool Softens stool Cardiovascular system – vasoconstrictor/vasodilator of vessels Cardiovascular system – vasoconstrictor/vasodilator of vessels Bonchioconstriction Bonchioconstriction Uterine contractions Uterine contractions

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

10 receptor5HT15HT25HT35HT45ht5 5ht65HT7 subtype5HT1 A, 5HT1 B, 5HT1 D, 5ht1E, 5HT1 F 5HT2A, 5HT2B, 5HT2C 5HT3A, 5HT3B 5ht1A, 5ht1B major signaling pathway cAMP IP3 ion channel cAMP cAMP? cAMP 5HT Receptors

11 A few words about signal transduction mechanisms…

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

13 Ionotropic receptors

14 G-Protein coupled receptors

15 The Major G Proteins G s Stimulatory- Activates Ca channels, activates adenylyl cyclase G s Stimulatory- Activates Ca channels, activates adenylyl cyclase G i Inhibitory- Activates K channels, inhibits adenylyl cyclase G i Inhibitory- Activates K channels, inhibits adenylyl cyclase G q – Activates phospholipase C G q – Activates phospholipase C G o - Inhibits Ca channels G o - Inhibits Ca channels G 12/13 – Diverse ion transporter interactions G 12/13 – Diverse ion transporter interactions

16 Second Messengers- Adenylyl Cyclase

17 Second Messenger- Phospholipase C

18 5HT 1A receptor CNSforum.com

19 5HT 1A Partial Agonist mechanism

20 5HT 1A Antagonist mechanism

21 5HT 2 receptor mechanism

22 5HT 2 Antagonist mechanisms

23 The Swiss army knife of Neurotransmitters Depression Depression Anxiety Anxiety Social phobia Social phobia Schizophrenia Schizophrenia Obsessive-compulsive Obsessive-compulsive Panic disorder Panic disorder Migraine Migraine Hypertension Hypertension Pulmonary hypertension Pulmonary hypertension Eating disorders Eating disorders Vomiting Vomiting Irritable bowel syndrome Irritable bowel syndrome

24 Serotenergic Drugs 5HT 1A Buspirone, ipsapirone treat anxiety, depression (partial agonist) 5HT 1A Buspirone, ipsapirone treat anxiety, depression (partial agonist) 5HT 1D Sumatriptan, treat migraine (partial agonist) 5HT 1D Sumatriptan, treat migraine (partial agonist) 5HT 2A/2C methysergide, trazodone, risperidone, ketanserin treat migraine, depression, schizophrenia (antagonist) 5HT 2A/2C methysergide, trazodone, risperidone, ketanserin treat migraine, depression, schizophrenia (antagonist)

25 Drugs continued… 5HT 3 Ondansetron treat chemotherapy- induced emesis (antagonist) 5HT 3 Ondansetron treat chemotherapy- induced emesis (antagonist) 5HT 4 Cisapride treat GI disorders (agonist) 5HT 4 Cisapride treat GI disorders (agonist) 5HT transporter SSRIs (Fluoxetine, sertraline) treat depression, OCD, panic disorder, social phobia, post traumatic stress disorder (inhibitor) 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 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 Antidepressants attempt to increase 5-HT levels

27 Serotonin Syndrome Toxic, potentially fatal effects Toxic, potentially fatal effects require a combination of serotonergic agents, such as an SSRI with an MAOI. 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 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 suspected agents should be discontinued OTC drugs containing ingredients known to increase serotonin levels, such as dextromethorphan, pseudoephedrine or phenylpropanolamine, also 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 Benzodiazepines for mild to moderate cases Cyproheptadine, Methysergide, and Propranolol for severe 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 Non-selective 5HT agonist/partial agonist Ergot derivative Ergot derivative Mimics 5HT at 5HT 1A autoreceptors on raphe cell bodies, slows firing rate of serotonergic neurons Mimics 5HT at 5HT 1A 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 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 Animal model thought to reflect subjective effects Mediated by activation of 5HT 2A receptors Mediated by activation of 5HT 2A receptors Acts as partial or full agonist at 5HT 2A and 5HT 2C receptors Acts as partial or full agonist at 5HT 2A and 5HT 2C receptors Phenethylamine derivatives (psilocybin) are selective 5HT 2A/2C agonists Phenethylamine derivatives (psilocybin) are selective 5HT 2A/2C agonists

31 Human Studies Psilocybin and PET imaging studies- pattern resembles brain activation in schizophrenic patients Psilocybin and PET imaging studies- pattern resembles brain activation in schizophrenic patients Action of psilocybin is blocked by pretreatment with 5HT 2A/2C antagonists Action of psilocybin is blocked by pretreatment with 5HT 2A/2C antagonists

32 Yeah rub Vaseline on my eyelids – 5-HT & MDMA MDMA causes an increased release of 5- HT and blocks reuptake MDMA causes an increased release of 5- HT and blocks reuptake High affinity for SERT High affinity for SERT Effects fine axons Effects fine axons Responsible for temperature increases Responsible for temperature increases

33 Receptor Overview

34 5HT 2 subtypes


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