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  1. Indoleamines Lisham Ashrafioun Michele San George

  2. Melatonin

  3. 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)

  4. Serotonin 5-Hydroxytryptamine (5-HT)

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

  6. Metabolism Monoamine 5-HT 5-HIAA 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. receptor 5HT1 5HT2 5HT3 5HT4 5ht5 5ht6 5HT7 subtype 5HT1A, 5HT1B, 5HT1D, 5ht1E, 5HT1F 5HT2A, 5HT2B, 5HT2C 5HT3A, 5HT3B 5ht1A, 5ht1B major signaling pathway cAMP↓ IP3 ion channel cAMP cAMP? cAMP cAMP 5HT Receptors

  11. A few words aboutsignaltransduction 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 • GsStimulatory- Activates Ca channels, activates adenylyl cyclase • GiInhibitory- 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. Depression Anxiety Social phobia Schizophrenia Obsessive-compulsive Panic disorder Migraine Hypertension Pulmonary hypertension Eating disorders Vomiting Irritable bowel syndrome The Swiss army knife of Neurotransmitters

  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 togetherLSD • 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