More Related Content


Serotonin : diseases and therapeutics

  2. Source & Chemistry  3-(β-aminoethyl)-5-hydroxyindole  Widely distributed in animals and plants.  Present in sea food, meat, nuts, seeds, various grains.  It is also present in venoms; common stinging nettles and of wasps and scorpions.  In humans it is found in high concentrations in enterochromaffin cells throughout the gastrointestinal tract, in storage granules in platelets and broadly throughout the CNS.
  3. HISTORY  1930s Erspamer studied distribution of enterochromaffin cells.  1948 Page and colleagues isolated and chemically characterized vasoconstrictor substance from platelets as 5-HT.  1957 Gaddum and Piccarelli classified 5-HT receptors into M and D type.  1959 Udenfriend discovered biosynthetic and degradative pathways.  1976 Page coined term SEROTONIN.  1979 Peroutka &Snyder identified 5HT1 and 5HT2 receptors by radioligand binding studies.
  4. Synthesis and Metabolism  5-HT is synthesized by a two step pathway from the essential amino acid tryptophan.  Tryptophan is actively transported into the brain by a carrier protein.  Tryptophan hydroxylase is rate limiting enzyme .  Rate limiting enzyme not saturated by substrate.  5-OHTr decarboxylase same as DOPA decarboxylase  Breakdown mainly by MAO (MAO-A and MAO-B)  5-HIAA actively extruded from CNS and excreted in urine.
  5. N C N C NH2 COOH COOH NH2 OH N C NH2 OH H Tryptophan 5-Hydroxytryptophan 5-Hydroxytryptamine N C COOH 5-OH Indole Acetaldehyde 5-Hydroxy Indole Acetic Acid Tryptophan hydroxylase 5-OH Tryptophan decarboxylase M AO Aldehyde dehydrogenase (Rate limiting) In diet. Active CNS transport
  6. Serotonin Receptors There are 7 families (5-HT1-7) with further subtypes of 5- HT1(A,B,D,E,F) and 5-HT2(A-C) Multiple transduction mechanisms All are G-protein coupled receptors, except 5-HT3 which is a ligand gated cation channel 5-HT1 acts by decreasing cAMP, while 5-HT4-7 act by increasing cAMP. 5-HT2 acts by phospholipase C/inositol triphosphate pathway.
  7. 5-HT1 receptor Subtyp e Transduction mechanism Location Physiological roles and therapeutic applications 5HT1A GPCR Inhibit AC Decrease cAMP Autorecepto r Raphe nuclei Hippocamp us Cortex Approved In alleviation of anxiety – Buspirone, Tandospirone (partial agonist) Under trial (Gepirone, Flesinoxan, Flibanserin, Naluzotan) Atypical antipsychotics – increased DA release Aripiprazole (partial agonist) Other roles Thermoregulation – vasodilation of blood vessels in skin (central receptors) Decreased BP and HR- by inducing peripheral vasodilation (rostroventrolateral medulla) Antiemetic and analgesic – In dorsal raphe nuclei, colocalized with NK1 receptor Impairs memory and learning by inhibiting release of Ach and glutamate Lecozotan (5- HT1a antagonist) for Alzheimer's Vilazodone Vortioxetine– SERT inhibitor with 5HT1a partial agonist activity ; novel antidepressant Increased secretion of oxytocin- prosocial,
  8. 5-HT1 receptor Subtyp e Transduction mechanism Location Physiological roles and therapeutic applications 5-HT1B GPCR Inhibit AC Decrease cAMP Coronary & cerebral arteries Frontal cortex (postsynaptic receptor) Basal ganglia and striatum (autoreceptor) Vascular smooth muscle Vasoconstriction- Triptans (migraine) Ergotamine Inhibits release of dopamine (antipsychotic) Inhibits release of serotonin & decrease glutamatergic transmission Pulmonary vasoconstriction Promotes bone growth and bone formation rate. 5-HT1D GPCR Inhibit AC Decrease cAMP CNS Blood vessels (poorly in coronary circulation) Trigeminal ganglion Locomotion, anxiety Vasoconstriction (Triptans, Ergotamine) Inhibit release of proinflammatory
  9. 5-HT1 receptor Subtype Transduction mechanism Location Physiological roles and therapeutic applications 5-HT1E GPCR Inhibit AC Decrease cAMP Frontal cortex Hippocampu s Speculated in regulation of memory 5-HT1F GPCR Inhibit AC Decrease cAMP Brain, uterus, mesentary Blood vessels Physiological roles at these sites are unknown Constriction Lasmiditan (agonist)- antimigraine
  10. 5-HT2 receptors Subty pe Transductio n mechanis m Location Physiological roles and therapeutic applications 5-HT2A GPCR Increase IP3/DAG -Neocortex (pyramidal cells in prefrontal cortex) -Smooth muscles (GIT bronchi) -Platelets -CVS & gut Hallucinogenic property of agonists (LSD) Enhance dopamine release (memory, attention, learning) Contraction Aggregation Anti inflammatory effects 5-HT2a antagonism (along with D2 antagonism) useful in antipsychotics Aripiprazole, Quetiapine, Asenapine, Risperidone, Sertindole, Olanzapine, Clozapine, Ziprasidone Lurasidone (5-HT2a 5-HT7 & D2 ant) Anxiolytic, antidepressant, procognitive benefits in schizophrenia patients. Antidepressants Nefazodone (5-HT2a & SERT ant) Amoxapine
  11. 5-HT2 receptor Subtyp e Transduction mechanism Location Physiological roles and therapeutic applications 5-HT2B GPCR Increase IP3/DAG Gastric fundus Blood vessels Heart Contraction Pulmonary vasoconstriction Possible role in treatment of migraine Agonists may lead to valvulopathy Antagonists might be useful in chronic heart diseases. Lisuride (DA agonist, 5-HT2b antagonist, 5- HT1a & 5-HT2a,2c partial agonist) antiparkinsonian, antimigraine 5-HT2C GPCR Increase IP3/DAG CNS Regulation of mood, sleep CSF production Control dopamine release in brain Antagonists increase release of DA and NA in frontal cortex, possible use as antidepressant (Agomelatine) Antipsychotics 5-HT2c antagonism (Sertindole, Ziprasidone)
  12. Type Transductio n mechanism Location Physiological roles and therapeutic applications 5-HT3 Ligand gated ion channels CNS- nausea and vomiting centre PNS- enteric neurons nociceptive neurons Cause emesis Antagonists used as antiemetic Palonosetron, Ondanseton, Granisetron Metaclopramide Alosetron, cilansetron(trial) Reduce seizure potential (Granisetron being investigated) 5-HT4 GPCR Induce AC Increase cAMP GIT CNS Myentric plexus- stimulation of gastric emptying Agonists- Metaclopramide Prucalopride (under trial) Possible role in learning, memory, Reduced respiratory depression by opioids Stimulation of aldosterone secretion from adrenal cortex Reducing susceptibility to seizures
  13. Type Transductio n mechanism s Location Physiological roles and therapeutic applications 5-HT5 2 subtypes 5-HT5A in humans and rats 5-HT5B in rats only GPCR Increase cAMP CNS Modulation of exploratory behavior in rodents Potential role in circadian rhythm. Valerenic acid (partial agonist) tried for insomnia 5-HT6 GPCR Increase cAMP CNS Role in motor control, emotion, cognition, memory 5-HT6 agonist enhance GABAergic signaling 5-HT6 antagonist increase glutamatergic & cholinergic neurotransmission, increase DA & NA release in frontal cortex Idalopirdine (5-HT6 ant) improves cognition learning memory, reduce appetite, promotes weight loss. SB – 271046 (ant) cognitive dysfunction 5-HT7 GPCR GIT Smooth muscle relaxation
  14. Migraine  Various theories proposed  Vascular theory by Wolff suggests initially humorally mediated intracerebral vasoconstriction causing aura, followed by extracerebral vasodilation causing headache.  Neural hypothesis by Lauritzen “cortical spreading depression”  Inflammation hypothesis by Waeber & Moskowitz activation of trigeminal nerve terminals & release of inflammatory neuropeptides. (CGRP; telcagepant)  2 important factors that implicate 5-HT in its pathogenesis are - there is a sharp increase in the urinary excretion of the main 5-HT metabolite, 5-HIAA, during the attack. - Several drugs that modulate the serotonin system are effective in migraine.
  15. Neurovascular Theory of Migraine
  16. Depression  Monoamine theory of depression which was first proposed in 1965 by Schildkraut suggests that depression results from deficient monoaminergic (5-HT or NA) transmission in the CNS.  Noradrenaline depletion may be due to inhibition of tyrosine hydroxylase, whereas reduced synthesis of serotonin may be due to depletion of dietary tryptophan or mutations of tryptophan hydroxylase  Based on the ability of known antidepressant drugs TCAs, SSRIs and MAO inhibitors to facilitate monoaminergic transmission.  Recent approaches show that depression may be associated with neurodegeneration and reduced neurogenesis in the hippocampus.
  17.  Stress & hypothalamic-pituitary-adrenal axis -The hypothalamic-pituitary-cortisol hypothesis postulates that depression is associated with elevated cortisol levels in response to stress.  Other possible disease mechanisms - Reduced level GABA & dopamine - Melatonin dysfunction - Abnormal circadian rhythms - Neuronal loss and reduced neurogenesis
  18. SSRIs  Selectively block 5-HT reuptake by the neurons  Include Citalopram, Fluoxetine, Paroxetine, Sertraline and Fluvoxamine  Increase synaptic 5-HT availability stimulates post-synaptic neurons and contributes to mood elevating and anxiolytic properties  Other uses OCD, Panic disorder , social phobia , PTSD.
  19. Other new drugs for depression  Newer mixed 5-HT and noradrenaline reuptake inhibitors Venlafaxine Desvenlafaxine Duloxetine Milnacipran  5-HT2a receptor antagonist – Trazodone, Mianserin
  20. Other Drugs affecting 5-HT system  Precursors of serotonin- - s-adenyl-l-methionine, tryptophan  Inhibit synthesis  p-chlorophenylalanine (irreversible)  Inhibit neuronal re-uptake  SSRI (e.g. fluoxetine), TCA (e.g. imipramine)  Inhibit storage-deplete:  Reserpine  Inhibit metabolism:  MAO inhibitors  Promote release:  p-chloroamphetamine (e.g. fenfluramine to ↓ appetite)
  21. Serotonin syndrome  Serotonin syndrome is a symptom complex of varying drug interactions which may lead to excess serotonin in body.  These are toxic and potentially fatal effects.  Require a combination of serotonergic drugs such as SSRIs with MAO inhibitors.  Other drugs implicated are TCAs, meperidine, MDMA.  Symptoms- mental status changes, confusion, agitation, hypomania, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhoea, incoordination, fever.  Treatment Remove suspected agent BZDs Propranolol

Editor's Notes

  1. M - parasympathetic nerve endings, controlling the release of Ach. morphine D – located on smooth muscle. dibenzyline
  2. L amino acid decarboxylase
  3. Aripiprazole- aripiprazole acts as a D2 partial agonist, partial agonist at the 5-HT1A receptor, and like the other atypical antipsychotics displays an antagonist profile at the 5-HT2A receptor.It also antagonizes the 5-HT7 receptor and acts as a partial agonist at the 5-HT2C receptor, both with high affinity.
  4. Lasmiditan – no action at 5-HT1b/1d receptors, therefore no cardiac side effects.
  5. Al34662 devoid of hallucinatory effects due to non crossing of bbb. Aripiprazole- D2 partial agonist, partial agonist at the 5-HT1A receptor, antagonist profile at the 5-HT2A receptor.It also antagonizes the 5-HT7 receptor and acts as a partial agonist at the 5-HT2C receptor Quetiapine- D1 D2 D3 D4 antagonist, 5-HT1a partial agonist, 5-HT2a 2c 5-HT7 antagonist, α1 α2 H1 mAch antagonist Asenapine – 5-HT1a partial agonist, antagonist at 5-HT1b, 2a, 2b, 2c, H1, D1 D2 Sertindole – 5-HT2c antagonism in addition to D2 and 5-HT2a antagonism
  6. 5ht2c agonist –POMC production, satiety
  7. Migraine trigger initiates CSD(Excitation f/b depression; 3-5 mm/min). CSD is followed by a phase of hyperoxygenation, which is believed to cause aura. The claims that hypoxemia/ischemia induced by vasoconstriction causes aura are unsupported. Following CSD, release of H+,K+ will stimulate meningeal nociceptors: neuronal bodies in the trigeminal nucleus stimulated. Release of mediators-subP,CGRP,NK-1, NO, 5HT-from trigeminal nerve endings innervating blood vessels. Vasodilatation, plasma extravasation and a sterile, neurogenic inflammation at the trigemino-vascular complex in the brainstem. Pain producing cranial structures: scalp, middle meningeal artery, dural sinuses, falx cerebri, and proximal segments of the large pial arteries