serotonin

セロトニン 5-HT 5HT 　

WordNet

1. a neurotransmitter involved in e.g. sleep and depression and memory (同)5-hydroxytryptamine

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/11/24 18:22:21」(JST)

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For other uses, see Serotonin (disambiguation).

Serotonin
IUPAC name 5-Hydroxytryptamine or 3-(2-aminoethyl)-1H-indol-5-ol
Other names 5-Hydroxytryptamine, 5-HT, Enteramine; Thrombocytin, 3-(β-Aminoethyl)-5-hydroxyindole, Thrombotonin
Identifiers
CAS number	50-67-9 Y
PubChem	5202
ChemSpider	5013 Y
UNII	333DO1RDJY Y
KEGG	C00780 Y
MeSH	Serotonin
ChEBI	CHEBI:28790 Y
ChEMBL	CHEMBL39 Y
IUPHAR ligand	5
Jmol-3D images	Image 1
SMILES c1cc2c(cc1O)c(c[nH]2)CCN
InChI InChI=1S/C10H12N2O/c11-4-3-7-6-12-10-2-1-8(13)5-9(7)10/h1-2,5-6,12-13H,3-4,11H2 Y Key: QZAYGJVTTNCVMB-UHFFFAOYSA-N Y InChI=1/C10H12N2O/c11-4-3-7-6-12-10-2-1-8(13)5-9(7)10/h1-2,5-6,12-13H,3-4,11H2 Key: QZAYGJVTTNCVMB-UHFFFAOYAX
Properties
Molecular formula	C10H12N2O
Molar mass	176.215 g/mol
Appearance	White powder
Melting point	121–122°C (ligroin)
Boiling point	416 ±30.0°C (at 760 Torr)
Solubility in water	slightly soluble
Acidity (pKa)	10.16 in water at 23.5 °C
Dipole moment	2.98 D
Hazards
MSDS	External MSDS
LD50	750 mg/kg (subcutaneous, rat), 4500 mg/kg (intraperitoneal, rat), 60 mg/kg (oral, rat)
Y (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Serotonin /ˌsɛrəˈtoʊnɨn/ or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS) of animals, including humans. It is popularly thought to be a contributor to feelings of well-being and happiness.

Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the alimentary canal (gut), where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.

Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they release serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing.

Serotonin is mainly metabolized to 5-HIAA, chiefly by the liver. Metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic acid derivative. The latter is then excreted by the kidneys. One type of tumor, called carcinoid, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing, diarrhea, and heart problems. Because of serotonin's growth-promoting effect on cardiac myocytes,^{[citation needed]} persons with serotonin-secreting carcinoid may suffer a right heart (tricuspid) valve disease syndrome, caused by proliferation of myocytes onto the valve.^{[citation needed]}

In addition to animals, serotonin is found in fungi and plants. Serotonin's presence in insect venoms and plant spines serves to cause pain, which is a side effect of serotonin injection. Serotonin is produced by pathogenic amoebae, and its effect on the gut causes diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.

Functions

Serotonin is a neurotransmitter and is found in all bilateral animals, where it mediates gut movements and the animal's perceptions of resource availability^{[citation needed]}. In less complex animals, such as invertebrates, resources simply mean food availability. In more complex animals, such as arthropods and vertebrates, resources also can mean social dominance. In response to the perceived abundance or scarcity of resources, an animal's growth, reproduction or mood may be elevated or lowered. This may somewhat depend on how much serotonin the organism has at its disposal.

Gauge of food availability (appetite)

Serotonin functions as a neurotransmitter in the nervous systems of simple, as well as complex, animals. For example, in the roundworm Caenorhabditis elegans, which feeds on bacteria, serotonin is released as a signal in response to positive events, e.g., finding a new source of food or in male animals finding a female with which to mate. When a well-fed worm feels bacteria on its cuticle, dopamine is released, which slows it down; if it is starved, serotonin also is released, which slows the animal down further. This mechanism increases the amount of time animals spend in the presence of food. The released serotonin activates the muscles used for feeding, while octopamine suppresses them. Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability. When humans smell food, dopamine is released to increase the appetite. But unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs which block 5-HT_2C receptors make the body unable to recognize when it is no longer hungry or otherwise in need of nutrients, and are associated with increased weight gain, especially in people who have a low number of receptors. The expression of 5-HT_2C receptors in the hippocampus follows a diurnal rhythm, just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest.

Effects of food content

In humans, serotonin levels are affected by diet. An increase in the ratio of tryptophan to phenylalanine and leucine will increase serotonin levels. Fruits with a high ratio include dates, papayas and bananas. Research also suggests eating a diet rich in carbohydrates and low in protein will increase serotonin by secreting insulin, which helps in amino acid competition. However, increasing insulin for a long period may trigger the onset of insulin resistance, obesity, type 2 diabetes, and lower serotonin levels. Muscles use 12 of the 13 amino acid groups (not using tryptophan), allowing more muscular individuals to produce more serotonin.

In the digestive tract (emetic)

The gut is surrounded by enterochromaffin cells, which release serotonin in response to food in the lumen. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin.

If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting. The enterochromaffin cells not only react to bad food, but they are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.

Gauge of social situation

How much food an animal gets not only depends on food availability, but also on the animal's ability to compete with others. This is especially true for social animals, where the stronger individuals might steal food from the weaker (this is not to say anti-social animals, who do not concern themselves with the needs of others, do not steal food from others). Thus, serotonin is not only involved in the perception of food availability, but also of social rank.

If a lobster is injected with serotonin, it behaves as if it were alpha, while octopamine causes subordinate behavior. A crayfish that is frightened may flip its tail to flee, and the effect of serotonin on this behavior depends largely on the animal's social status. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals. The reason for this is social experience alters the proportion between serotonin receptors (5-HT receptors) that have opposing effects on the fight-or-flight response. The effect of 5-HT₁ receptors predominates in subordinate animals, while 5-HT₂ receptors predominates in dominants. In humans, levels of 5-HT_1A receptor activation in the brain show negative correlation with aggression, and a mutation in the gene that codes for the 5-HT_2A receptor may double the risk of suicide for those with that genotype. Serotonin in the brain is not usually degraded after use, but is collected by serotonergic neurons by serotonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy.

Growth and reproduction

In the nematode C. elegans, artificial depletion of serotonin or the increase of octopamine cues behavior typical of a low-food environment: C. elegans becomes more active, and mating and egg-laying are suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal. Serotonin is necessary for normal nematode male mating behavior, and the inclination to leave food to search for a mate. The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects insulin-like signaling and the TGF beta signaling pathway, which control long-term adaption.

Aging and age-related phenotypes

Serotonin is known to regulate aging, learning and memory. The first evidence comes from the study of longevity in C. elegans. During early phase of aging, the level of serotonin increases, which alters locomotory behaviors and associative memory. The effect is restored by mutations and drugs (including mianserin and methiothepin) that inhibit serotonin receptors. The observation does not contradict with the notion that the serotonin level goes down in mammals and humans, which is typically seen in late but not early phase of aging.

Bone metabolism

In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass. Mice that lack brain serotonin have osteopenia, while mice that lack gut serotonin have high bone density. In humans, increased blood serotonin levels have been shown to be significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. ThroughHtr1b receptors, it negatively regulates bone mass, while it does so positively through Htr2b and Htr2c. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events. These studies have opened a new area of research in bone metabolism that can be potentially harnessed to treat bone mass disorders.

Organ development

Since serotonin signals resource availability it is not surprising that it affects organ development. Many human and animal studies have shown that nutrition in early life can influence, in adulthood, such things as body fatness, blood lipids, blood pressure, atherosclerosis, behavior, learning and longevity. Rodent experiments shows that early life exposure to SSRI:s makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants. By treating normal and knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.

In the fruitfly, where insulin both regulates blood sugar and acts as a growth factor, serotonergic neurons regulate the adult body size by affecting insulin secretion. Serotonin has also been identified as the trigger for swarm behavior in locusts. In humans, though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones, so serotonin suppresses insulin release from the beta cells in the pancreas, and exposure to SSRIs reduces fetal growth. Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors. Serotonin present in the blood then stimulates cellular growth to repair liver damage. 5HT2B receptors also activate osteocytes, which build up bone However, serotonin also inhibits osteoblasts, through 5-HT1B receptors.

Cardiovascular growth factor

Main article: Cardiac fibrosis

Serotonin, in addition, evokes endothelial nitric oxide synthase activation and stimulates, through a 5-HT1B receptor-mediated mechanism, the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures. In blood, serotonin is collected from plasma by platelets, which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing.

Some serotonergic 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 epidemiologically linked with these syndromes. They are the serotonergic vasoconstrictive antimigraine 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 declining in 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 is not 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).

Local effects of injection: venoms and pain

Since serotonin is an indicator of bleeding, a sudden large increase in peripheral levels causes pain. The reason wasps and deathstalker scorpions have serotonin in their venom may be to increase the pain of their stings on large animals, and also to cause lethal vasoconstriction in smaller prey.

Deficiency

Genetically altered C. elegans worms that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a dormant larval state.

Serotonin in mammals is made by two different tryptophan hydroxylases: TPH1 produces serotonin in the pineal gland^{[citation needed]} and the enterochromaffin cells, while TPH2 produces it in the raphe nuclei and in the myenteric plexus. Genetically altered mice lacking TPH1 develop progressive loss of heart strength early on. They have pale skin and breathing difficulties, are easily tired, and eventually die of heart failure. Genetically altered mice that lack TPH2 are normal when they are born. However, after three days, they appear to be smaller and weaker, and have softer skin than their siblings. In a purebred strain, 50% of the mutants died during the first four weeks, but in a mixed strain, 90% survived. Normally, the mother weans the litter after three weeks, but the mutant animals needed five weeks. After that, they caught up in growth and had normal mortality rates. Subtle changes in the autonomic nervous system are present, but the most obvious difference from normal mice is the increased aggressiveness and impairment in maternal care of young. Despite the blood–brain barrier, the loss of serotonin production in the brain is partially compensated by intestinal serotonin. The behavioural changes become greatly enhanced if one crosses TPH1- with TPH2-lacking mice and gets animals that lack TPH entirely.

In humans, defective signaling of serotonin in the brain may be the root cause of sudden infant death syndrome (SIDS). Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy genetically modified lab mice to produce low levels of the neurotransmitter serotonin. The results showed the mice suffered drops in heart rate and other symptoms of SIDS, and many of the animals died at an early age. Researchers now believe low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may have caused sudden death, they said in the July 4, 2008 issue of Science. If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).

Recent research conducted at Rockefeller University shows, in both patients who suffer from depression and mice that model the disorder, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.

Depletion of serotonin is common between disorders such as obsessive-compulsive disorder, depression, and anxiety. However, Dr. Marazziti and his researchers at the University of Pisa in Italy, found that depletion of serotonin also occurs in people who have recently fallen in love. This leads to the obsessive component associated with early stages of love.

Consumption of an average amount of alcohol (.8g/kg of body weight) shows to decrease tryptophan by about 25%, leading to a similar decrease in serotonin. The sexual and impulsive behavior resulting from an intoxicated state is at least partially an effect of the decrease in serotonin because serotonin regulates these behaviors.

In the brain

Serotonin system, contrasted with the dopamine system

Gross anatomy

The neurons of the raphe nuclei are the principal source of 5-HT release in the brain. There are 7 or 8 raphe nuclei (some scientists chose to group the nuclei raphes lineares into one nucleus), all of which are located along the midline of the brainstem, and centered around the reticular formation. Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord, while the axons of the higher nuclei spread out in the entire brain.

Microanatomy

Serotonin is released into the space between neurons, and diffuses over a relatively wide gap (>20 µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.

Receptors

Main article: 5-HT receptor

The 5-HT receptors, the receptors for serotonin, 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.

Termination

Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). Interestingly, a 2006 study conducted by the University of Washington suggested a newly discovered monoamine transporter, known as PMAT, may account for "a significant percentage of 5-HT clearance". Contrasting with the high-affinity SERT, the PMAT has been identified as a low-affinity transporter, with an apparent K_m of 114 micromoles/l for serotonin; approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport 'capacity' than SERT, "..resulting in roughly comparable uptake efficiencies to SERT in heterologous expression systems." The study also suggests some SSRIs, such as fluoxetine and sertraline, inhibit PMAT but at IC₅₀ values which surpass the therapeutic plasma concentrations by up to four orders of magnitude; therefore, SSRI monotherapy is "ineffective" in PMAT inhibition. At present, no known pharmaceuticals are known to appreciably inhibit PMAT at normal therapeutic doses. The PMAT also suggestively transports dopamine and norepinephrine, albeit at K_m values even higher than that of 5-HT (330–15,000 μmoles/L).

Serotonylation

Main article: Serotonylation

Serotonin can also signal through a nonreceptor mechanism called serotonylation, in which serotonin modifies proteins. This process underlies serotonin effects upon platelet-forming cells (thrombocytes) in which it links to the modification of signaling enzymes called GTPases that then trigger the release of vesicle contents by exocytosis. A similar process underlies the pancreatic release of insulin. The effects of serotonin upon vascular smooth muscle tone (this is the biological function from which serotonin originally got its name) depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.

Biosynthesis

The pathway for the synthesis of serotonin from tryptophan.

In animals including humans, serotonin is synthesized from the amino acid L-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 neuron-specific isoform.

Serotonin can be synthesized from tryptophan in the lab using Aspergillus niger and Psilocybe coprophila as catalysts. The first phase to 5-hydroxytryptophan would require letting tryptophan sit in ethanol and water for 7 days, then mixing in enough HCl (or other acid) to bring the pH to 3, and then adding NaOH to make a pH of 13 for 1 hour. Asperigillus niger would be the catalyst for this first phase. The second phase to synthesizing tryptophan itself from the 5-hydroxytryptophan intermediate would require adding ethanol and water, and letting sit for 30 days this time. The next two steps would be the same as the first phase: adding HCl to make the pH = 3, and then adding NaOH to make the pH very basic at 13 for 1 hour. This phase uses the Psilocybe coprophila as the catalyst for the reaction.

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, 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.

Drugs targeting the 5-HT system

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.

Psychedelic drugs

The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD are agonists, primarily at 5HT_2A/2C receptors. The empathogen-entactogen MDMA releases serotonin from synaptic vesicles of neurons.

Antidepressants

Main articles: SSRI and MAOI

Drugs which alter serotonin levels are used in treating depression, generalized anxiety disorder and social phobia. Monoamine oxidase inhibitors (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 the re-uptake of serotonin, making it stay in the synaptic cleft longer. The tricyclic antidepressants (TCAs) inhibit the reuptake of both serotonin and norepinephrine. The newer selective serotonin reuptake inhibitors (SSRIs) have fewer side effects and fewer interactions with other drugs. The side effects that have become apparent recently include a decrease in bone mass in elderly and increased risk for osteoporosis. However, it is not yet clear whether it is due to SSRI action on peripheral serotonin production and or action in the gut or in the brain. Investigation into whether SSRIs benefits to mood are somehow related to dopamine receptor sensitivity indirectly influenced by antidepressant mechanisms. In one study, patients with depression taking an SSRI were given low dose D2 receptor antagonist administration, and reported negative effect on mood. Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases. This has been connected to the observation that the benefit of SSRIs may decrease in selected patients after a long-term treatment. A switch in medication will usually resolve this issue (up to 70% of the time). The novel antidepressant tianeptine, a selective serotonin reuptake "enhancer", as well as mirtazapine and mianserin (5HT2 and 5HT3 receptors antagonists), have mood-elevating effects. This provides evidence for the theory that serotonin is most likely used to regulate the extent or intensity of moods, rather than level directly correlating with mood. In fact, the 5-HTTLPR gene codes for the number of serotonin transporters in the brain, with more serotonin transporters causing decreased duration and magnitude of serotonergic signaling. The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety. Therefore, increasing levels of extracellular serotonin may be associated with increased affect, for good or for worse.

Although phobias and depression might be attenuated by serotonin-altering drugs, this does not mean the individual's situation has been improved, but only the individual's perception of the environment. Sometimes, a lower serotonin level might be beneficial, for example in the ultimatum game, where players with normal serotonin levels are more prone to accept unfair offers than participants whose serotonin levels have been artificially lowered.

Serotonin syndrome

Main article: Serotonin syndrome

Extremely high levels of serotonin can cause a condition known as serotonin syndrome, with toxic and potentially fatal effects. In practice, such toxic levels are essentially impossible to reach through an overdose of a single antidepressant 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 nontoxic levels.

Antiemetics

Some 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 the treatment of postoperative nausea and vomiting.

In unicellular organisms

Serotonin is used by a variety of single-cell organisms for various purposes. 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 E. histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection. E. histolytica also responds to the presence of serotonin by becoming more virulent. This means serotonin secretion not only serves to increase the spread of enteamoebas by giving the host diarrhea, but also to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing. Outside a host, the density of entoamoebas is low, hence also the serotonin concentration. Low serotonin signals to the entoamoebas they are outside a host and they become less virulent to conserve energy. When they enter a new host, they multiply in the gut, and become more virulent as the serotonin concentration increases.

In plants

In drying seeds, serotonin production is a way to get rid of the buildup of poisonous ammonia. The ammonia is collected and placed in the indole part of L-tryptophan, which is then decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by a cytochrome P450 monooxygenase, yielding serotonin.

However, since serotonin is a major gastrointestinal tract modulator, it may be produced by plants in fruits as a way of speeding the passage of seeds through the digestive tract, in the same way as many well-known seed and fruit associated laxatives. Serotonin is found in mushrooms, fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genera. Serotonin concentrations of 3–30 mg/kg have been found in plantains, pineapples, 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 stinging nettles (Urtica dioica), where it causes pain on injection in the same manner as its presence in insect venoms (see above). It is also naturally found in Paramuricea clavata, or the Red Sea Fan.

Serotonin and tryptophan have been found in chocolate with varying cocoa contents. The highest serotonin content (2.93 ug g-1) was found in chocolate with 85% cocoa, and the highest tryptophan content (13.27-13.34 ug g-1) was found in 70-85% cocoa. The intermediate in the synthesis from tryptophan to serotonin, 5-hydroxytryptophan, was not found.

Unlike its precursors, 5-HTP and tryptophan, serotonin does not cross the blood–brain barrier, which means ingesting serotonin in the diet has no effect on brain serotonin levels.

Methyl-tryptamines and hallucinogens

Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH₂) and (OH) groups, are N-oxides, or miss the OH group. These compounds do reach the brain, although some portion of them are metabolized by MAO-B enzymes in the liver. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff. These compounds are widely present in the leaves of many plants, and may serve as deterrents for animal ingestion. Serotonin occurs in several mushrooms of the genus Panaeolus. Serotonin is also naturally occurring in toad venom.

History

In 1935, Italian Vittorio Erspamer showed an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later, Erspamer was able to show it was a previously unknown amine, which he named "enteramine". In 1948, Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin. In 1952, enteramine was shown to be the same substance as serotonin, and as the broad range of physiological roles was elucidated, the abbreviation 5-HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field. Synonyms of serotonin include: 5-hydroxytriptamine, thrombotin, enteramin, substance DS, and 3-(β-Aminoethyl)-5-hydroxyindole. In 1953, Betty Twarog and Page discovered serotonin in the central nervous system.

References

External links

• Serotonin bound to proteins in the PDB
• PsychoTropicalResearch Extensive reviews on serotonergic drugs and Serotonin Syndrome.
• Molecule of the Month: Serotonin at University of Bristol
• 60-Second Psych: No Fair! My Serotonin Level Is Low, Scientific American
• Serotonin Test Interpretation on ClinLab Navigator.
• Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation at the National Center for Biotechnology Information.

UpToDate Contents

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• 1. セロトニン症候群 serotonin syndrome
• 2. セロトニンモジュレータ：薬理学、投与、および副作用 serotonin modulators pharmacology administration and side effects
• 3. 選択的セロトニン再取り込み阻害剤：薬理学、投与方法、および副作用 selective serotonin reuptake inhibitors pharmacology administration and side effects
• 4. 選択的セロトニン再取り込み阻害剤中毒 selective serotonin reuptake inhibitor poisoning
• 5. セロトニン - ノルエピネフリン再取り込み阻害剤（SNRIs）：薬理学、投与、および副作用 serotonin norepinephrine reuptake inhibitors snris pharmacology administration and side effects

English Journal

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• International journal of bipolar disorders.Int J Bipolar Disord.2016 Dec;4(1):6. doi: 10.1186/s40345-016-0047-3. Epub 2016 Feb 16.
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• Underlying molecular and cellular mechanisms in childhood irritable bowel syndrome.

• Chumpitazi BP1,2, Shulman RJ3,4,5.
• Molecular and cellular pediatrics.Mol Cell Pediatr.2016 Dec;3(1):11. doi: 10.1186/s40348-016-0036-8. Epub 2016 Feb 16.
• Irritable bowel syndrome (IBS) affects a large number of children throughout the world. The symptom expression of IBS is heterogeneous, and several factors which may be interrelated within the IBS biopsychosocial model play a role. These factors include visceral hyperalgesia, intestinal permeability
• PMID 26883355

• Quality assurance of histamine analysis in fresh and canned fish.

• Evangelista WP1, Silva TM1, Guidi LR1, Tette PA1, Byrro RM1, Santiago-Silva P1, Fernandes C2, Gloria MB3.
• Food chemistry.Food Chem.2016 Nov 15;211:100-6. doi: 10.1016/j.foodchem.2016.05.035. Epub 2016 May 6.
• Histamine determination is relevant for fish safety, quality and trade. Recently a study by the European Union (EU) compared the Codex and the EU mandated methods for the analysis of histamine and observed that they underestimated and overestimated the results, respectively. To solve this problem, a
• PMID 27283612

Japanese Journal

• Effect of Psilocin on Extracellular Dopamine and Serotonin Levels in the Mesoaccumbens and Mesocortical Pathway in Awake Rats

• Sakashita Yuichi,Abe Kenji,Katagiri Nobuyuki [他]
• Biological & pharmaceutical bulletin 38(1), 134-138, 2015-01
• NAID 40020311999

• Serotonin 2C Receptor as a Superhero : Diversities and Talents in the RNA Universe for Editing, Variant, Small RNA and Other Expected Functional RNAs

• Tohda Michihisa
• Journal of pharmacological sciences 126(4), 321-328, 2014-12
• NAID 40020313580

• Brief Note : Correlation between blood biomarkers and depression and anxiety scales in apparently healthy individuals

• Isobe Kazumasa,Ishizu Tomoko,Oikawa Hitoshi [他]
• International journal of analytical bio-science 2(4), 163-166, 2014-12
• NAID 40020305122

Related Links

• セロトニンDojo 公式サイト

セロトニンDojoは、ストレスとセロトニン研究の第一人者、有田秀穂が代表を務める日本初のメンタル・ヘルスケアのためのエクササイズDojoです。 セロトニンDojo,セロトニン,オキシトシン、ストレス,有田秀穂,メンタルヘルス ...

• セロトニンとは - 快適.Life | QOL（quality of life）を向上させる ...

よく読まれているページ セロトニンとは セロトニンは人間の精神面に大きな影響与える神経伝達物質で、 セロトニンが不足すると、うつ病や不眠症などの精神疾患に陥りやすいと言われています。 メラトニンとは メラトニンは眠り ...

Related Pictures

---

★リンクテーブル★

リンク元	「セロトニン」「hydroxytryptamine」「5HT」「5-HT」「5-hydroxytryptamine」
拡張検索	「serotonin reuptake inhibitor」「N,N-dimethylserotonin」「serotonin transporter gene」「serotonin-dopamine antagonist」

「セロトニン」

　　[★]

英

serotonin, 5-HT, 5-hydroxytryptamine

関

神経伝達物質、セロトニン受容体、セロトニン作動性ニューロン、5-ヒドロキシインドール酢酸 5-HIAA

• トリプトファンから生合成される。
• 生合成：(1)トリプトファンの5位にヒドロキシ基付加　→　(2)脱炭酸
• 酵素は、芳香族アミノ酸デカルボキシラーゼ(補酵素はピリドキサル5'-リン酸(PLP))
• 脳や神経で起こる。

生合成
　トリプトファン　　 　　　　　　 →　　　　　　5-ヒドロキシトリプトファン
　　　　　　　　　トリプトファン5-モノオキシゲナーゼ

　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　   　　　OH
　　　　　　　　           ／＼　　　   　　　　　　　       　 ／＼／
　-OOC-CH(NH3+)-CH2----|○｜　→　-OOC-CH(NH3+)-CH2----| ○|
　　　　　　　      ||    |  |　　     　　　　　　   ||    |　 ｜
　　 　　　　 　      ＼ ／ ＼／　　　   　　　　　　     ＼ ／ ＼／
　　　 　　 　          NH　　　　　　          　　　　　　NH
　　　　　　　　　　+                              +
　　　　テトラヒドロビオプテリン　　　　　ジヒドロビオプテリン
　　　　　　　　　　+
　　　　　　　　　　O2

　5-ヒドロキシトリプトファン　　 →　　　　　　セロトニン
　　　　　　　　　芳香族アミノ酸デカルボキシラーゼ

　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　OH
　　　　　　　　           ／＼　　　   　　　　      　 ／＼／
　-OOC-CH(NH3+)-CH2----|○ |　→　H2N-CH2-CH2----| ○|
　　　　　　　      ||    |  ｜ 　    　　　   ||    |   |
　　 　　　　 　      ＼ ／ ＼／　　　   　　　     ＼ ／＼／
　　　 　　 　          NH　　　　　　        　　　　NH

薬理学

セロトニン再取り込み阻害薬

• フルボキサミン fluvoxamine

セロトニン・ノルアドレナリン再取り込み阻害薬

• ミルナシプラン milnacipran

「hydroxytryptamine」

　　[★]

ヒドロキシトリプタミン

関

5-HT、5-hydroxytryptamine、serotonin

「5HT」

　　[★]

• セロトニン serotonin 5-HT 5-hydroxytryptamine

「5-HT」

　　[★] セロトニン 5-hydroxytryptamine serotonin

「5-hydroxytryptamine」

　　[★] セロトニン serotonin 5-HT

「serotonin reuptake inhibitor」

　　[★]

• セロトニン再取り込み阻害薬、セロトニン再取り込み抑制薬、セロトニン再取り込み阻害剤、セロトニン再取り込み抑制剤

関

5-HT uptake inhibitor、serotonin uptake inhibitor

「N,N-dimethylserotonin」

　　[★] ブホテニン。N,N-ジメチルセロトニン

「serotonin transporter gene」

　　[★] セロトニントランスポーター遺伝子

「serotonin-dopamine antagonist」

　　[★] セロトニン・ドパミン拮抗薬