Lecture 7: Serotonin Flashcards
Synthesis of serotonin
From essential amino acid tryptophan
Tryptophan hydroxylase is rate limiting step
Tryptophan concentration limits synthesis in brain (requires O2 and reduced pteridine cofactor)
L-aromatic amino acid decarboxylase, similar used for catecholamine synthesis
Serotonin is converted to melatonin in pineal gland
Metabolism and termination of action
Metabolized to 5-hydroxyindole acetic acid by monoamine oxidase.
Neuronal action terminated primarily by a high affinity active uptake system (SERT) and then intraneuronal conversion to 5-hydroxyindoleacetic acid
The types of Serotonin receptors
at least 13 subtypes, most are g protein coupled (not 5-HT3).
5-HT 1(a-e): Gi, inhibite adenylate cyclase. 5-HT1a also opens K+ channels
5-HT 2(a-c): PI hydrolysis
5-HT3: ligand gated cation channel
5-HT4-7: Activation of adenylate cyclase or unknown
Auto-receptors- decrease serotonin release
Serotonin pharmacology in the GI system
Contracts GI smooth muscle including esophagus stomach and intestine-increasing tone, peristalsis and diarrhea.
Emesis- 5-HT3 receptors in GI tract and brain
Carcinoid syndrome- tumors of enterochromaffin cells.
Serotonin pharmacology in the CV
Potent vasoconstriction of large arteries and veins; cranial (5-HT1D) blood vessels
Vasodilation in coronary, skeletal muscle and cutaneous blood vessels
Bezold-Jarisch reflex- coronary chemoreceptors (Bradycardia, hypotension, and hypoventilation)
Platelet aggregation- activate uptake of serotonin from circulation.
lysergic acid diethylamide
5-HT2 receptor agonist. Hallucinogen
buspirone
5-HT1A receptor partial agonist- antianxiety
sumatriptan
Agonist for 5-HT1D receptor on cerebral blood vessels.
Promote vasoconstriction. Treatment of migraine headaches, stops existing ones.
SE: nausea, vomiting, angina, dizziness, flushing
fluoxetine
Serotonin specific reuptake inhibitors (SSRIs), block active reuptake of serotonin. Increases amount of transmitter in synapse.
Uses: Treatment of affective disorders,, OCD, panic attacks.
SE:Sexual dysfunction nausea etc.
phenelzine
Monoamine oxidase inhibitor, block metabolism of serotonin, NE, and DA. Increased synaptic serotonin.
Uses: Treatment of affective disorders and narcolepsy
SE: hypertensive crisis
cyproheptadine
5-HT2 antagonist, also histamine H1 antagonist.
Uses: Treatment of allergies, pruritis, urticaria. Carcinoid.
ondansetron
5-HT3 antagonist, CNS and GI action
Uses: Treatment of chemotherapy induced nausea and vomiting, post op and x ray therapy induced nausea and vomiting
alosetron
Selective 5-HT3 antagonist
Uses: treat diarrhea predominant IBS in women.
SE: Can produce severe GI adverse effects. A restricted prescribing program must be followed
Melatonin
Syntheized from serotonin in pineal. Own receptors M1, M2- Gi associated
Uses: Entrains circadian clock, target for insomnia treatment.
