Serotonin
Clinical Pharmacology

 

Serotonin
  •  Chemistry: serotonin
    • Widely distributed indoleethylamine formed from L-tryptophan:
      • hydroxylation of the indole ring
      • decarboxylation
      • hydroxylation at C-5: rate-limiting step
        • inhibited by p-chlorophenylalanine (PCPA, fenclonine)
    • Following synthesis:
      • storage or
      • rapid inactivation-- oxidation (monoamine oxidase, MAO)
      • Pineal gland: serotonin -- precursor for melatonin (melanocyte-stimulating hormone)

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    • Storage:
      • Most serotonin (> 90%):enterochromaffin cells -- GI tract
      • Blood: platelets (active carrier-mediated transport system {similar to nerve endings})
      • CNS locations:serotonin
        • raphe nuclei (brain stem)
          • localization of neuronal cell bodies that:
            1. synthesize
            2. store
            3. release
        • CNS serotonin involvement:
          • mood
          • sleep
          • appetite
          • temperature regulation
          • pain perception
          • blood-pressure regulation
          • vomiting
    • Degradation:
      • Catabolism: monoamine oxidase -- product: 5-hydroxyindoleacetaldehyde
        • 5-hydroxyindoleacetaldehyde: further oxidation catalyzed aldehyde dehydrogenase
        • amount of 5-hydroxyindoleacetic acid (5-HIAA) excreted is a measure of serotonin synthesis.
          • excessive serotonin synthesis may be helpful as a diagnostic test for certain tumors (e.g. carcinoid)

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Some Serotonin Receptor Subtypes
Receptor subtype Distribution Coupling mechanism; comments

5-HT1A

Raphe nuclei, hippocampus

cAMP, potassium channels:partially selective agonist:  8-OH-DPAT

5-HT1D(a,b)

brain

cAMP,partially selective agonist:  sumatriptan (Imitrex)

5-HT3

area postrema, sensory and enteric nerves

receptor:Na-K ion channel: partially selective antagonists  ondansetron (Zofran), ggranisetron (Kytril), tropisetron

5-HT4

CNS, ,smooth muscle

cAMP; partially selective agonists:  metoclopramide (Reglan)

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Burkhalter, A, Julius, D.J. and Katzung, B. Histamine, Serotonin and the Ergot Alkaloids (Section IV. Drugs with Important Actions on Smooth Muscle), in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 261-286.