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Definição e significado de Serotonin

Definição

serotonin (n.)

1.a neurotransmitter involved in e.g. sleep and depression and memory

Serotonin (n.)

1.(MeSH)A biochemical messenger and regulator, synthesized from the essential amino acid L-TRYPTOPHAN. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (RECEPTORS, SEROTONIN) explain the broad physiological actions and distribution of this biochemical mediator.

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⇨ Antagonists, Serotonin • Inhibitors, Serotonin Reuptake • Inhibitors, Serotonin Uptake • Platelet Serotonin Transporter • Receptor Agonists, Serotonin • Receptor, Serotonin 1D • Receptor, Serotonin 1Dalpha • Receptor, Serotonin 2A • Receptor, Serotonin 2B • Receptor, Serotonin 3 • Receptor, Serotonin 4 • Receptor, Serotonin Type 1Dbeta • Receptor, Serotonin, 5-HT1A • Receptor, Serotonin, 5-HT1B • Receptor, Serotonin, 5-HT1D • Receptor, Serotonin, 5-HT2A • Receptor, Serotonin, 5-HT2B • Receptor, Serotonin, 5-HT2C • Receptor, Serotonin, 5-HT3A • Receptor, Serotonin, 5-HT3B • Receptors, Serotonin • Receptors, Serotonin S2 • Receptors, Serotonin, 5-HT1 • Receptors, Serotonin, 5-HT2 • Receptors, Serotonin, 5-HT3 • Receptors, Serotonin, 5-HT4 • Receptors, Serotonin, 5-HT4L • Receptors, Serotonin, 5-HT4S • Receptors, Serotonin-2 • Reuptake Inhibitors, Serotonin • Serotonin 1A Receptor • Serotonin 1B Receptor • Serotonin 1D Alpha Receptor • Serotonin 1D Beta Receptor • Serotonin 1D Receptor • Serotonin 1D Receptors • Serotonin 1Dalpha Receptor • Serotonin 1Dalpha Receptors • Serotonin 1Dbeta Receptor • Serotonin 1Dbeta Receptors • Serotonin 2A Receptor • Serotonin 2A Receptors • Serotonin 2B Receptor • Serotonin 2B Receptors • Serotonin 2C Receptor • Serotonin 3 Receptor • Serotonin 3 Receptors • Serotonin 4 Receptor • Serotonin 4 Receptors • Serotonin 5-HT1 Receptor • Serotonin 5-HT2 Receptors • Serotonin Acetylase • Serotonin Acetyltransferase • Serotonin Agents • Serotonin Agonist • Serotonin Agonists • Serotonin Antagonists • Serotonin Blockaders • Serotonin Drugs • Serotonin N-Acetyltransferase • Serotonin Plasma Membrane Transport Proteins • Serotonin Plasma Membrane Transporter Proteins • Serotonin Receptor Agonist • Serotonin Receptor Agonists • Serotonin Receptor, 5-HT1A • Serotonin Receptors • Serotonin Receptors, 5-HT1 • Serotonin Receptors, 5-HT2 • Serotonin Reuptake Inhibitors • Serotonin S2 Receptors • Serotonin Syndrome • Serotonin Transporter • Serotonin Transporter, Platelets • Serotonin Uptake Inhibitors • Serotonin, 5-HT1 Receptors • Serotonin, 5-HT1a Receptor • Serotonin-2 Receptors • Serotonin-Containing Enterochromaffin Cells • Sodium-Dependent Serotonin Transporter • Uptake Inhibitors, Serotonin • selective-serotonin reuptake inhibitor • serotonin receptor

Dicionario analógico

Wikipedia

Serotonin

                   
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 YesY
PubChem 5202
ChemSpider 5013 YesY
UNII 333DO1RDJY YesY
KEGG C00780 YesY
MeSH Serotonin
ChEBI CHEBI:28790 YesY
ChEMBL CHEMBL39 YesY
IUPHAR ligand 5
Jmol-3D images Image 1
Properties
Molecular formula C10H12N2O
Molar mass 176.215 g/mol
Appearance White powder
Melting point

121–122° C (ligroin) [1]
Boiling point

416 ±30.0° C (at 760 Torr) [2]
Solubility in water slightly soluble
Dipole moment 2.98 D
Hazards
MSDS External MSDS
LD50 750 mg/kg (subcutaneous, rat),[3] 4500 mg/kg (intraperitoneal, rat),[4] 60 mg/kg (oral, rat)
 YesY (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Serotonin (play /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.[5]

Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the gut (Alimentary canal), where it is used to regulate intestinal movements.[6][7] 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 disgorge 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, persons with serotonin-secreting carcinoid may suffer a right heart (tricuspid) valve disease syndrome, caused by proliferation of myocytes onto the valve.

In addition to animals, serotonin is also found in fungi and plants.[8] 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 amoebas, 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.

Contents

  Functions

Serotonin is a neurotransmitter, and is found in all bilateral animals, where it mediates gut movements and the animals' perceptions of resource availability. In the simplest animals, resources are equivalent with food, but in advanced animals, such as arthropods and vertebrates, resources also can mean social dominance.[citation needed] In response to the perceived abundance or scarcity of resources, an animal's growth, reproduction or mood may be elevated or lowered. Recent studies involving the serotonin transporter gene 5-HTT have shown the short allele of this gene increases synaptic serotonin levels[citation needed].

  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.[9] The released serotonin activates the muscles used for feeding, while octopamine suppresses them.[10] Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability. This system has been partially conserved during the 700 million years of evolution which separate C. elegans from humans. 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-HT2C receptors make the body unable to shut off appetite, and are associated with increased weight gain,[11] especially in people who have a low number of receptors.[12] The expression of 5-HT2C receptors in the hippocampus follows a diurnal rhythm,[13] just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest.[14]

  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 good ratio include dates, papayas and bananas. Foods with a lower ratio inhibit the production of serotonin. These include whole wheat and rye bread.[15] 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.[16] However, increasing insulin for a long period may trigger the onset of insulin resistance, obesity, type 2 diabetes, and lower serotonin levels.[17][18] Muscles use many of the amino acids except tryptophan, allowing more muscular individuals to produce more serotonin.[19] Myoinositol, a carbocyclic polyol present in many foods, is known to play a role in serotonin modulation.[20]

  In the digestive tract (antiemetic)

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.[21] 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.[22]

  Gauge of social situation

How much food an animal gets not only depends on the abundance of food, 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. 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 like a dominant animal, while octopamine causes subordinate behavior.[23] A frightened crayfish flips its tail to flee, and the effect of serotonin on this behavior depends 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.[clarification needed] The effect of 5-HT1 receptors predominates in subordinate animals, while 5-HT2 receptors predominates in dominants.[24] In humans, levels of 5-HT1A receptor activation in the brain show negative correlation with aggression,[25] and a mutation in the gene that codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype.[26] Most of the brain serotonin is not 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.[27]

  Growth and reproduction

In C. elegans, artificial depletion of serotonin or 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.[28] Serotonin is necessary for normal nematode male mating behavior,[29] and the inclination to leave food to search for a mate.[30] 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[31], which control long-term adaption.

  Aging and age-related phenotypes

Serotonin is known to regulate aging and learning and memory. The first evidence comes from the study of longevity in C. elegans [32]. During early phase of aging, the level of serotonin increases, which alters locomotory behaviors and associative memory [33]. 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 go down in mammals and humans, which are 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.[34][35][36][37] 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. Through Htr1b receptors, it negatively regulates bone mass, while it does so positively through Htr2b and Htr2c. These studies have opened a new area of research in bone metabolism that can be potentially harnessed to treat bone mass disorders.[38]

  Behavior

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.[39][40] Serotonin has also been identified as the trigger for swarm behavior in locusts.[41] 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,[42] and exposure to SSRIs reduces fetal growth.[43] Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors.[44] Serotonin present in the blood then stimulates cellular growth to repair liver damage.[45] 5HT2B receptors also activate osteocytes, which build up bone[46] However, serotonin also inhibits osteoblasts, through 5-HT1B receptors.[47]

  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.[48] 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.[49]

Some serotonergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as cardiac valve fibrosis.[50] 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),[50] the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-Parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride.[51] 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.[52] Two independent studies published in the New England Journal of Medicine in January 2007, implicated pergolide, along with cabergoline, in causing valvular heart disease.[53][54] As a result of this, the FDA removed pergolide from the U.S. market in March, 2007.[55] (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).[56]

  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 for wasps and deathstalker scorpions to have serotonin in their venom [57][58] 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.[59][60]

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.[61] 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.[62] 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.[63]

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[64] 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.[44] If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).[65]

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.[66]

  In the brain

In this drawing of the brain, the serotonergic system is red and the mesolimbic dopamine pathway is blue. There is one collection of serotonergic neurons in the upper brainstem that sends axons upwards to the whole cerebrum, and one collection next to the cerebellum that sends axons downwards the spinal cord. Slightly forward the upper serotonergic neurons is the ventral tegmental area (VTA), the dopaminergic neurons there sends axons to the nucleus accumbens, hippocampus and the frontal cortex. Over the VTA is another collection of dopamine cells, the substansia nigra, which send axons to the striatum.
  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.[67] The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation.[68] 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.[69]

  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".[48] Contrasting with the high-affinity SERT, the PMAT has been identified as a low-affinity transporter, with an apparent Km 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 Km 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.[42] 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.[70] A similar process underlies the pancreatic release of insulin.[42] 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.[71]

  Biosynthesis

On top a L-tryptophan molecule with an arrow down to a 5-HTP molecule. Tryptophan hydroxylase catalyses this reaction with help of O2 and tetrahydrobiopterin which becomes water and dihydrobiopterin. From the 5-HTP molecule goes an arrow down to a serotonin molecule. Aromatic L-amino acid decarboxylase or 5-Hydroxytryptophan decarboxylase catalyses this reaction with help of pyridoxal phosphate. From the serotonin molecule goes an arrow to a 5-HIAA molecule at the bottom ot the image. Monoamine oxidase catalyses this reaction, in the process O2 and water is consumed, and ammonia and hydrogen peroxide is produced.
  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 brain-specific isoform.[72]

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 5HT2A/2C receptors.[73][74] The empathogen-entactogen MDMA releases serotonin from synaptic vesicles of neurons.[75]

  Antidepressants

Main articles: SSRI and MAOI

The most prescribed drugs in many parts of the world are drugs which alter serotonin levels. They are used in 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 reuptake 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.[47] 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).[76] The novel antidepressant tianeptine, a selective serotonin reuptake "enhancer", has 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.[77] The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety.[78][79] 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.[80]

  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.[81] The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at nontoxic levels.[82]

  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.[83] The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.[84][85] Patients infected with E. histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.[86] E. histolytica also responds to the presence of serotonin by becoming more virulent.[87] 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.[88]

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.[89]

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).

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.

  History

[icon] This section requires expansion.

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".[90] 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.[91] 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.[92]

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  92. ^ Feldberg W, Toh CC (1953). "Distribution of 5-hydroxytryptamine (serotonin, enteramine) in the wall of the digestive tract". J. Physiol. (Lond.) 119 (2–3): 352–62. PMC 1392800. PMID 13035756. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1392800. 

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Amino acids
Endocannabinoids
Gasotransmitters
Monoamines
Purines

Adenosine · ADP · AMP · ATP
Trace amines
Others
         
TAAR1
Selective: O-Phenyl-3-iodotyramine • RO5166017; Non-selective: 3-Iodothyronamine • 3-Methoxytyramine • 5-MeO-DMT • Amphetamine • Apomorphine • Bromocriptine • Bufotenin • DMT • DOI • Dopamine • LSD • m-Octopamine • m-Tyramine • MDMA • Methamphetamine • N-Methylphenethylamine • N-Methyltryptamine • N-Methyltyramine • Nomifensine • Norepinephrine • p-Octopamine • p-Tyramine • Phenethylamine • Serotonin • Synephrine • Tryptamine; Unknown: RG7351
* Note that many other phenethylamines, tryptamines, ergolines, and thyronamines are either known to or are likely to act as non-selective TAAR1 agonists as well.
Selective: EPPTB (RO5212773)
         

2-Methyl-5-HT • 4-Acetoxy-DET • 4-Acetoxy-DiPT • 4-Acetoxy-DMT • 4-Acetoxy-MiPT • 4-AcO-MET • 4-HO-αMT • 4-HO-DiPT • 4-HO-MET • 4-MeO-DMT • 4-Methyl-αET • 4-Methyl-αMT • 4,5-DHP-DMT • 4,5-MDO-DMT • 4,5-MDO-DIPT • 5-Benzyloxytryptamine • 5-Bromo-DMT • 5-Carboxamidotryptamine • 5-Ethoxy-αMT • 5-Fluoro-αMT • 5-HO-αMT • 5-HTP • 5-Ethoxy-DMT • 5-Ethyl-DMT • 5-Fluoro-DMT • 5-Methyl-DMT • 5-Methoxytryptamine • 5-MeO-7,N,N-TMT • 5-Methyl-αET • 5-MeO-αET  • 5-MeO-αMT • 5-MeO-DALT • 5-MeO-DET • 5-MeO-DiPT • 5-MeO-DMT • 5-MeO-DPT • 5-MeO-MALT • 5-MeO-MiPT • 5-MeO-NBpBrT • 5,7-Dihydroxytryptamine • 5-(Nonyloxy)tryptamine • 6-Fluoro-αMT • 7-Methyl-αET • 7-Methyl-DMT • αET • αMT • Aeruginascin • AL-37350A • BW-723C86 • Baeocystin • Bufotenidine • Bufotenin • DALT • Desformylflustrabromine • DET • DiPT • DMT • DPT • Ethocybin • EiPT • EMDT • EPT • Ethocin • FGIN-127 • FGIN-143 • Ibogaine • Indorenate • Iprocin • MET • MiPT • MPT • Miprocin • Melatonin • MS-245 • NAS • NMT • Norbaeocystin • Normelatonin • Oxypertine • PiPT • Psilocin • Psilocybin • Rizatriptan • Serotonin • Sumatriptan • Tryptamine • Tryptophan • Yohimbine • Yuremamine • Zolmitriptan

   
   
Retrieved from "http://en.wikipedia.org/w/index.php?title=Serotonin&oldid=497330019"
           

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