Everything about Serotonin totally explained
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Serotonin (
5-hydroxytryptamine, or
5-HT) is a
monoamine neurotransmitter synthesized in serotonergic
neurons in the
central nervous system (CNS) and
enterochromaffin cells in the
gastrointestinal tract of
animals including
humans. Serotonin is also found in many
mushrooms and
plants, including
fruits and
vegetables.
Function
In the
central nervous system, serotonin is believed to play an important role as a
neurotransmitter, in the modulation of
anger,
aggression,
body temperature,
mood,
sleep,
sexuality, and
appetite as well as stimulating
vomiting.
In addition, serotonin is also a
peripheral signal mediator. For instance, serotonin is found extensively in the human
gastrointestinal tract (about 80-90% of the body's total serotonin is found in the enterochromaffin cells in the gut),. In the blood, the major storage site is
platelets, which collect serotonin for use in mediating post-injury vasoconstriction.
Neurotransmission
As with all neurotransmitters, the effects of 5-HT on the human mood and state of mind and its role in consciousness are very difficult to ascertain.
Gross anatomy
The neurons of the
raphe nuclei are the principal source of 5-HT release in the brain.
The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the
brainstem, centered around the
reticular formation.
Axons from the neurons of the raphe nuclei form a
neurotransmitter system, reaching large areas of the brain. Axons of neurons in the
caudal dorsal raphe nucleus terminate in for example:
On the other hand, axons of neurons in the
rostral dorsal raphe nucleus terminate in for example:
Thus, activation of this serotonin system has effects on large areas of the brain, which explains the various resultant effects of therapeutic serotonin modulation.
Microanatomy
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
boutons (in the manner of classical neurotransmission). From here it's 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.
Receptors
5-HT receptors are the
receptors for serotonin. They are located on the cell membrane of
nerve cells and other cell types in animals and mediate the effects of serotonin as the
endogenous ligand and of a broad range of pharmaceutical and
hallucinogenic drugs. With the exception of the
5-HT3 receptor, a ligand gated
ion channel, all other 5-HT receptors are
G protein coupled seven transmembrane (or
heptahelical) receptors that activate an
intracellular second messenger cascade.
Genetic factors
Genetic variations in alleles which code for serotonin receptors are now known to have a significant impact on the likelihood of the appearance of certain psychological disorders and problems. For instance, a mutation in the allele which codes for the
5-HT2A receptor appears to double the risk of suicide for those with that genotype.
Termination
Serotonergic action is terminated primarily via
uptake of 5-HT from the synapse. This is through the specific
monoamine transporter for 5-HT,
5-HT reuptake transporter, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including
MDMA (ecstasy),
amphetamine,
cocaine,
dextromethorphan (an
antitussive),
tricyclic antidepressants (TCAs) and
selective serotonin reuptake inhibitors (SSRIs).
Endothelial cell function and Serotonin
5-hydroxytryptamine evokes endothelial nitric oxide synthase activation and stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures. .
Other functions
Recent research suggests that serotonin plays an important role in
liver regeneration and acts as a
mitogen (induces cell division) throughout the body.
Pathology
If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there's a risk of
sudden infant death syndrome (SIDS). Low levels of serotonin may also be associated with
intense religious experiences.
Recent research conducted at
Rockefeller University shows that in both patients who suffer from depression and in mice that model the disorder, levels of the
p11 protein are decreased. This protein is related to serotonin transmission within the brain.
Synthesis
In the body, serotonin is synthesized from the
amino acid tryptophan by a short
metabolic pathway consisting of two
enzymes:
tryptophan hydroxylase (TPH) and
amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several
tissues, and TPH2, which is a brain-specific
isoform. There is evidence that
genetic polymorphisms in both these subtypes influence susceptibility to anxiety and depression. There is also evidence that
ovarian hormones can affect the expression of TPH in various species, suggesting a possible mechanism for
postpartum depression and
premenstrual stress syndrome.
Serotonin taken orally doesn't pass into the serotonergic pathways of the central nervous system because it doesn't cross the
blood-brain barrier. However,
tryptophan and its
metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as
dietary supplements and may be effective serotonergic agents.
One product of serotonin breakdown is
5-Hydroxyindoleacetic acid (5 HIAA), which is excreted in the
urine. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain
tumors or
cancers, and levels of these substances may be measured in the urine to test for these tumors.
Serotonergic drugs
Several classes of
drugs target the 5-HT system including some
antidepressants,
antipsychotics,
anxiolytics,
antiemetics, and
antimigraine drugs as well as the
psychedelic drugs and
empathogens.
Psychoactive drugs
The
psychedelic drugs
psilocin/
psilocybin,
DMT,
mescaline, and
LSD mimick the action of serotonin at
5-HT2A receptors. The
empathogen MDMA (ecstasy) releases serotonin from
synaptic vesicles of
neurons.
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 emergency 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 (TCAs) 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.
Antiemetics
5-HT3 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.
Serotonin syndrome
Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a condition known as
serotonin syndrome. In practice, such toxic levels are essentially impossible to reach through an
overdose of a single anti-depressant drug, but require a combination of serotonergic agents, such as an
SSRI with an
MAOI. The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels. For example, recreational doses of
MDMA (ecstasy) will generally cause such symptoms but only rarely lead to true
toxicity.
Chronic diseases resulting from serotonin 5-HT2B overstimulation
In blood, serotonin stored in platelets is active wherever platelets bind, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic, to aid healing. Because of these effects, overdoses of serotonin, or serotonin agonist drugs, may cause acute or chronic pulmonary hypertension from pulmonary vasoconstriction, or else syndromes of
retroperitoneal fibrosis or cardiac valve fibrosis (
endocardial fibrosis) from overstimulation of serotonic growth receptors on fibrocytes .
Serotonin itself may cause a syndrome of cardiac fibrosis when it's eaten in large quantities in the diet (the Matoki banana of East Africa) or when it's over-secreted by certain mid-gut
carcinoid tumors . The valvular fibrosis in such cases is typically on the right side of the heart, since excess serotonin in the serum outside platelets is metabolized in the lungs, and doesn't reach the left circulation .
Serotonergic
agonist drugs in overdose in experimental animals not only cause acute (and sometimes fatal)
pulmonary hypertension, but there's epidemiologic evidence that chronic use of certain of these drugs produce a chronic pulmonary hypertensive syndrome in humans, also . Some serotinergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of
retroperitoneal fibrosis, as well as
cardiac valve fibrosis .
In the past, three groups of serotonergic drugs have been epidemiolgically linked with these syndromes. They are the serotonergic vasoconstrictive anti-migraine drugs (
ergotamine and
methysergide), the serotonergic appetite suppressant drugs (
fenfluramine,
chlorphentermine, and
aminorex), and certain anti-parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT
2B receptors. These include
pergolide and
cabergoline, but not the more dopamine-specific
lisuride . As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is
pergolide. The drug was in decreasing use since reported in 2003 to be associated with cardiac fibrosis. Two independent studies published in the
New England Journal of Medicine in January 2007, implicated pergolide along with
cabergoline in causing
valvular heart disease. As a result of this, the
FDA removed pergolide from the U.S. market in March, 2007. (Since cabergoline isn't approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).
Because neither the amino acid
L-tryptophan nor the
SSRI-class antidepressants raise blood serotonin levels, they're not under suspicion to cause the syndromes described. However, since 5-hydroxytryptophan (
5-HTP) does raise blood serotonin levels, it's under some of the same scrutiny as actively serotonergic drugs .
Illness Caused by lack of serotonin
Obsessive-compulsive disorder (OCD) can be a debilitating disorder with the following two anxiety-related essential features: obsessions (undesirable, recurrent, disturbing thoughts) and compulsions (repetitive or ritualized behaviors).Some research shows that it may have to do with serotonin, which helps to keep people from repeating the same behaviors over and over again. A person who has OCD may not have enough serotonin. Therefore, many people who have OCD can function better when they take medicines that increase the amount of serotonin in their brain.
In unicellular organisms
Serotonin is used by a variety of single-cell organisms for various purposes. Selective serotonin re-uptake inhibitors (SSRIs) have been found to be toxic to algae. The gastrointestinal parasite
Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients. Patients infected with
Entamoeba histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.
Entamoeba histolytica also responds to the presence of serotonin by becoming more virulent.
In plants
Serotonin is found in
mushrooms and
plants, including
fruits and
vegetables. The highest values of 25–400 mg/kg have been found in nuts of the
walnut (
Juglans) and
hickory (
Carya) genuses. Serotonin concentrations of 3–30 mg/kg have been found in
plantain,
pineapple,
banana,
kiwifruit,
plums, and
tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables. Serotonin is one compound of the poison contained in the
stinging hairs of the
stinging nettle (
Urtica dioica). It should be noted that serotonin, unlike its precursors 5-HTP and tryptophan, doesn't cross the
blood–brain barrier.
Several plants contain serotonin together with a family of related
tryptamines that are
methylated at the
amino (NH
2) and
hydroxy (OH) groups, are
N-oxides, or miss the OH group. Examples are plants from the
Anadenanthera genus that are used in the
hallucinogenic
yopo snuff.
In animals
Serotonin as a
neurotransmitter is found in all animals, including insects. Several
toad venoms, as well as that of the Brazilian Wandering Spider and
stingray, contain serotonin and related tryptamines.
History
Isolated and named in 1948 by Maurice M. Rapport, Arda Green, and
Irvine Page of the
Cleveland Clinic,
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) by Rapport, and, as the broad range of physiological roles were elucidated, 5-HT became the preferred name in the pharmacological field.
Further Information
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