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Introduction
Serotonin was the name given to an unknown
vasconstrictor substance found in serum after blood has clotted It was identified chemically as 5hydroxytryptamine (5-HT) in 1948 It was shown to originate from the platelets It was subsequently found in the gastrointestinal tract and central nervous system (CNS) and shown to function both as a neurotransmitter and as a local hormone in the peripheral vascular system
5-HT seems to be 'involved in everything, but
responsible for nothing', a Autacoids 2011: Serotonin Apr 19, 2012 kind of mediator-
Distribution of 5-HT
5-HT occurs in the highest concentrations in three
About 90% of the total amount in the body is present in enterochromaffin cells, which are cells derived from the neural crest, similar to those of the adrenal medulla, that are interspersed with mucosal cells, mainly in the stomach and small intestine Some 5-HT also occurs in nerve cells of the myenteric plexus, where it functions as an excitatory neurotransmitter 5-HT is present in high concentration in platelets, which accumulate it from the plasma by an active transport system and release it when they aggregate at sites of tissue damage 5-HT is a transmitter in the CNS and is present in high concentrations in localised regions of the midbrain
Autacoids 2011: Serotonin Apr 19, 2012
In blood:
In the CNS:
5-HT
Biosynthesis of 5-HT
issynthesizedfrom theamino acidLtryptophan pathway consisting of twoenzymes:
tryptophan
Process is metabolic
The TPH-mediated
1) oxidation
5-HIAA excreted
by the kidneys
2) oxidation
Metabolism closely parallels that of noradrenaline. 5-HT is formed from dietary tryptophan, which is
Overview
o GIT: increased gastrointestinal motility
o o
o o o
(direct excitation of smooth muscle and indirect action via enteric neurons) SMOOTH MUSCLES: contraction of other smooth muscle (bronchi, uterus) BLOOD VESSELS: mixture of vascular constriction (direct and via sympathetic innervation) and dilatation (endothelium dependent) PLATELETS: platelet aggregation NERVE ENDINGS: stimulation of peripheral nociceptive nerve endings CNS: excitation/inhibition of CNS neurons.
Autacoids 2011: Serotonin Apr 19, 2012
Overview
Postulated physiological and
aggregation and haemostasis, inflammatory mediator, sensitisation of nociceptors and microvascular control in CNS: many postulated functions, including control of appetite, sleep, mood, hallucinations, stereotyped behaviour, pain perception and vomiting.
Gastrointestinal tract
5-HT stimulates gastrointestinal motility
partly through a direct effect on the smooth muscle cells
(5-HT2-receptors) and partly as a result of an indirect excitatory effect on enteric neurons (5-HT3- and 5-HT4-receptors)
5-HT also stimulates fluid secretion and elicits nausea and vomiting by stimulating smooth muscle and sensory nerves in the stomach (5HT3- and 5-HT4-receptors)
pressure within a segment of intestine, is mediated, partly at least, by the release of 5-HT from chromaffin cells in response to the mechanical stimulus Chromaffin cells also respond to vagal stimulation Autacoids 2011: Serotonin Apr 19, 2012 by releasing 5-HT
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Blood vessels
5-HT causes vasoconstriction of both arteries and
veins, via a direct action on vascular smooth muscle cells, mediated through 5-HT2A-receptors
Activation of 5-HT1-receptors causes constriction
on endothelial cells to release nitric oxide and partly by inhibiting noradrenaline release from sympathetic nerve terminals
If 5-HT is injected intravenously, the blood pressure usually first rises, owing to the constriction of large vessels, and then falls, owing to arteriolar Autacoids 2011: Serotonin Apr 19, 2012 dilatation
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Platelets
5-HT causes platelet aggregation via 5-
HT2A-receptors, and the platelets that collect in the vessel release more 5-HT If the endothelium is intact, 5-HT release from adherent platelets causes vasodilatation, which helps to sustain blood flow if it is damaged (e.g. by atherosclerosis), 5-HT causes constriction and impairs blood flow further These effects of platelet-derived 5-HT are
Autacoids 2011: Serotonin Apr 19, 2012
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Nerve endings
5-HT stimulates nociceptive (pain-mediating)
systemically, it elicits a variety of autonomic reflexes through stimulation of afferent fibres in the heart and lungs, which further complicate the cardiovascular response
Nettle stings contain 5-HT, amongst other things
5-HT also inhibits transmitter release from adrenergic neurons in theAutacoids 2011: Serotonin Apr 19, 2012 periphery
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inhibits others It also acts presynaptically to inhibit transmitter release from nerve terminals Different receptor types and different membrane mechanisms mediate these effects
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5-HT receptors
There are seven types (5-HT1-7), with
except 5-HT3, which is a ligand-gated cation channel 5-HT1-receptors occur mainly in CNS (all subtypes) and some blood vessels (5-HT1D subtype)
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5-HT1 Receptors..
Effects are neural inhibition and
vasoconstriction
Act by inhibiting adenylate cyclase Specific agonists include sumatriptan
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5-HT2 Receptors
5-HT2-receptors occur in CNS and
many peripheral sites (especially blood vessels, platelets, autonomic neurons) Neuronal and smooth muscle effects are excitatory. Some blood vessels dilated as a result of nitric oxide release from endothelial cells 5-HT2-receptors acts through phospholipase C/inositol
Autacoids 2011: Serotonin Apr 19, 2012
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5-HT2 Receptors..
Specific ligands include LSD (lysergic
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5-HT3-Receptors
5-HT3-receptors occur in peripheral
nervous system, especially nociceptive afferent neurons and enteric neurons, and in CNS
Effects are excitatory, mediated via direct
and tropisetron
Antagonists are used mainly as antiemetic
Autacoids 2011: Serotonin Apr drugs but may also be anxiolytic 19, 2012
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5-HT4-Receptors
5-HT4-receptors occur mainly in the enteric
pharmacology of 5-HT5-7-receptors
Many new receptor-selective agonists and
Autacoids 2011: Serotonin antagonists are being developed Apr 19, 2012
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Ergot alkaloids
These active substances are produced by a fungus
that infects cereal crops; it is responsible for occasional poisoning incidents. The most important compounds are:
ergotamine, dihydroergotamine, used in migraine ergometrine, used in obstetrics to prevent postpartum
haemorrhage methysergide, used to treat carcinoid syndrome, and occasionally for migraine prophylaxis bromocriptine, used in parkinsonism and endocrine disorders.
receptors and adrenoceptors (mixed agonist, antagonist and partial agonist effects) Unwanted effects include nausea and vomiting, Autacoids 2011: vasoconstriction (ergot alkaloidsSerotonin Apr 19, 2012 are
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paracetamol) can be given with metoclopramide to speed up absorption Ergotamine (5-HT1D-receptor partial agonist) Sumatriptan (5-HT1D agonist) is effective but short acting (half-life about 2 hours) Newer compounds (e.g. zolmitriptan) are claimed to be faster acting and not to cause chest pain
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antimuscarinic effects
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and calcium antagonist actions methysergide: rarely used because of risk of retroperitoneal fibrosis and renal failure
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agonist has been used, but efficacy is doubtful. Calcium antagonists (e.g. dihydropyridines, verapamil): headache is a side-effect of these drugs but, paradoxically, may reduce frequency of migraine attacks Their mechanism of action is unknown
Autacoids 2011: Serotonin Apr 19, 2012
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