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Serotonin
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'''Serotonin''' ('''5-hydroxytryptamine''', or '''5-HT''') is a
monoamine neurotransmitter synthesised in serotonergic
neurons in the
central nervous system and
enterochromaffin cell (biology) cells in the
gastrointestinal tract.
In the central nervous system, serotonin is believed to play an important role in the regulation of
mood,
sleep,
emesis (vomiting),
sexuality and
appetite. Serotonin has been thought to play a part in many disorders, notably as part of the
biochemistry of
Clinical depression depression,
migraine,
bipolar disorder and
anxiety.
The name "serotonin" is something of a misnomer and reflects the circumstances of the compound's discovery. It was initially identified as a vasoconstrictor substance in blood serum - hence ''serotonin'', a serum agent affecting vascular tone. This agent was later chemically identified as 5-hydroxytryptamine (5-HT), and, as the broad range of physiological roles were elucidated, 5-HT became the preferred name in the pharmacological field.
Biochemistry
Serotonin is found extensively in the human
gastrointestinal tract, or gut, as well as in the blood stream.
In the body, serotonin is synthesized from the
amino acid tryptophan by short
metabolic pathway consisting of two
enzymes - TPH(
Tryptophan hydroxylase 1 1,
Tryptophan hydroxylase 2 2) and
Aromatic-L-amino-acid decarboxylase DDC. TPH1
chemical_reaction reaction controls the flux through the pathway.
image:5htsynt_2.png frame|left|403px|The pathway for the synthesis of serotonin from Trp
Serotonin taken orally does not pass into the serotonergic pathways of the
central nervous system because it does not cross the
blood-brain barrier. However, the
amino acid tryptophan and its metabolite
5-HTP 5-hydroxytryptophan, from which serotonin is synthesized, can and does cross the blood-brain barrier. These agents are available as
dietary supplements and may be effective serotonergic agents.
One breakdown product of serotonin is '''5-hydroxyindoleacetic acid (
5 HIAA)''' which is excreted in the
urine. Serotonin and 5HIAA are sometimes produced in excess amounts by certain
cancer cancer tumors, and levels of these substances may be measured in the urine to test for these tumors.
Neurotransmission
The neurons of the
Raphe nuclei release 5-HT. These neurons are grouped into about nine pairs, distributed along the entire length of the brainstem. 5-HT is thought to be released from serotonergic varicosities into the extra neuronal space, in other words from swellings (varicosities) along the axon, rather than from synaptic terminal buttons (in the manner of classical neurotransmission). From here it is free to diffuse over a relatively large region of space (>20µm) and activate
5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.
Serotonergic action is terminated primarily via
reuptake uptake of 5-HT from the synapse. This is through the specific
monoamine transporter for 5-HT,
Serotonin transporter 5-HT reuptake transporter, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including
MDMA,
cocaine,
tricyclic antidepressants (TCAs) and
selective serotonin reuptake inhibitors (SSRIs).
Pharmacology
The
pharmacology of 5-HT is extremely complex, with its actions being mediated by a large and diverse range of
5-HT receptors.
As with all neurotransmitters, the actual effects of 5-HT on the human
mood and state of
mind, and its role in
consciousness, are very difficult to ascertain.
One way of understanding it is through the use of
MDMA, which is thought to cause a mass release of 5-HT, possibly by drawing it back through the transporter.
The effects of
MDMA are in large part due to the 5-HT which floods synapses during an MDMA "roll," an experience which typically includes feelings of well-being, comfort, tactile sensitivity, and, at high doses, feelings of emotional empathy or
entactogenesis. (MDMA also releases
norepinephrine, and to a much lesser extent,
dopamine.
MDEA, a closely related drug, appears to be purely a serotonin releasing agent, and lacks the strong stimulant effect of MDMA.)
5-HT receptors are also used by other psychoactive drugs, including
LSD,
Dimethyltryptamine DMT, and
psilocybin, the active ingredient in
psychedelic mushrooms.
Modulating levels of 5-HT
A variety of
psychiatric medications affect serotonin levels, including the
monoamine oxidase inhibitors (MAOIs),
tricyclic antidepressants (TCAs),
atypical antipsychotics, and the
selective serotonin reuptake inhibitors (SSRIs).
Antidepressants
The
MAOIs prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain.
MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive crisis triggered by foods with high
tyramine-content and certain drugs.
Some drugs inhibit this re-uptake of serotonin, again making it stay in the synapse longer. The
tricyclic antidepressants inhibit the re-uptake of both serotonin and
norepinephrine. The newer Selective Serotonin Re-uptake Inhibitors (SSRIs) have fewer (though still numerous) side effects and fewer interactions with other drugs.
Recent research conducted at
Rockefeller University shows that in both patients who suffer from depression and in mice that model that disease, levels of the
p11 protein are decreased. This protein is related to serotonin transmission within the brain{{an|Svenningsson}}.
Antiemetics
5-HT
3 Receptor antagonist antagonists such as
ondansetron,
granisetron and
tropisetron are important antiemetic agents. They are particularly important in treating the
nausea and
vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in treatment of post-operative nausea and vomiting. Applications to the treatment of depression and other mental and psychological conditions have also been investigated with some positive results.
Deficiency
Deficient (and sometimes, excessive) intake of various
dietary minerals,
drugs, and
vitamins can lead to disturbed levels of serotonin via disrupting either the production or reuptake processes.
Serotonin syndrome
Care must be taken in any attempt to increase serotonin levels, as a dangerous condition known as
serotonin syndrome may result. This is especially a concern if multiple serotonergic agents
interaction interact to increase 5-HT levels - such as can happen when
St John's wort is taken in combination with an
SSRI.
References
* Rang HP, Dale MM, Ritter JM, Moore PK (2003). ''Pharmacology'' (5 ed). Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4
#{{anb|Svenningsson}} Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, Yacoubi ME, Vaugeois JM, Nomikos GG, Greengard P. Alterations in 5-HT1B receptor function by p11 in depression-like states. ''Science'' 2006;311(5757):77–80. PMID 16400147
See also
*
5-HTP a serotonin precursor found in food and often sold as a supplement.
External links
-
Molecule of the Month: Serotonin
{{Tryptamines}}
Category:Biogenic amines
Category:Neurotransmitters
Category:Tryptamines
ar:سيروتونين
cs:Serotonin
da:Serotonin
de:Serotonin
es:Serotonina
fr:Sérotonine
he:סרוטונין
hu:Szerotonin
nl:Serotonine
ja:セロトニン
pl:Serotonina
pt:Serotonina
ru:Серотонин
fi:Serotoniini
sv:Serotonin
tr:Serotonin
sr:Серотонин
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