Dictionary:

serotonin

  (sĕr'ə-tō'nĭn, sîr'-)

An organic compound, C₁₀H₁₂N₂O, formed from tryptophan and found in animal and human tissue, especially the brain, blood serum, and gastric mucous membranes, and active as a neurotransmitter and in vasoconstriction, stimulation of the smooth muscles, and regulation of cyclic body processes.

[SERO– + TON(E) + –IN.]

A compound, also known as 5-hydroxytryptamine (5-HT), derived from tryptophan, an indole-containing amino acid. It is widely distributed in the animal and vegetable kingdoms. In mammals it is found in gastrointestinal enterochromaffin cells, in blood platelets, and in brain and nerve tissue. Serotonin is a local vasoconstrictor, plays a role in brain and nerve function and in regulation of gastric secretion and intestinal peristalsis, and has pharmacologic properties. It is inactivated by monoamine oxidases (MAO-A and -B), enzymes that also inactivate other neurotransmitters such as norepinephrine and dopamine.

Serotonin is concentrated in certain areas of the brain; the hypothalamus and midbrain contain large amounts, while the cortex and cerebellum contain low concentrations. Like most neurotransmitters, it is stored in granules inside nerve endings, and is thus not exposed to inactivation by monoamine oxidases until it is released into the synaptic space between nerves. When a serotonin-containing nerve fires, serotonin is released and can bind to any one of a series of at least 14 distinct downstream serotonin receptors (5-HT receptors). Release of serotonin or other stored neurotransmitters can also be induced by alkaloids such as reserpine, which have been used as tranquilizing agents in the treatment of nervous and mental disorders. Although pharmacologic doses of serotonin produce a type of sedation and other depressant conditions of the nervous system, several types of clinically useful antidepressants, such as monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs), act by increasing the amount of active serotonin in nerve synapses in particular brain regions. Conversely, various conditions that lower serotonin levels are associated with depression, suggesting that normal to slightly elevated serotonin levels tend to elevate mood and prevent depression. See also Affective disorders; Brain; Nervous system (vertebrate); Neurosecretion; Psychopharmacology.

After blood is allowed to clot a substance can be extracted from the fluid serum which, when injected, causes an increase in blood vessel ‘tone’ (the vessels' state of contraction). This serum-derived substance was therefore called serotonin or vasotonin. Similarly, extraction of animal intestines yielded a material with similar actions termed enteramine — the name being derived from the term enteron (gut). Serotonin, vasotonin, and enteramine were found to be identical. Chemically the vasoactive agent was 5-hydroxytryptamine (5HT). This is an endogenous autacoid (a substance made by body cells, which has some action on other cells) and is derived from the amino acid tryptophan, obtained from protein in the diet.

It is now known that 5HT is widely distributed throughout the body, with a multitude of actions. Ninety per cent of the total body content of 5HT is found in the enterochromaffin cells in the wall of the intestine. Most of the rest is found in blood platelets, and released from these when blood clots. A small amount is also found in the brain, especially the mid-brain, where it acts as a neurotransmitter.

5HT can act on a cell only if the cell membrane has specific 5HT receptors, and there are sub-types of these receptors on different cells, associated with different actions of 5HT upon them. 5HT causes many smooth muscles (involuntary muscles) to contract, such that gut motility and peristalsis are increased and contraction of the smooth muscle of blood vessels causes the blood pressure to rise. The smallest arterioles, however, are dilated, resulting in increased capillary pressure and capillary permeability, causing an increase in the rate of formation of tissue fluid. But 5HT also reduces the release of noradrenaline from sympathetic nerves, by acting on 5HT₁ receptors on the nerve terminals, which tends to reduce blood pressure. The vasoconstrictor response on the larger blood vessels is mediated by 5HT₂ receptors. Consequently, in the presence of a 5HT₂ antagonist, when 5HT can act only on the 5HT₁ receptors, it causes a fall rather than a rise in blood pressure.

5HT exerts many of its actions indirectly by either stimulating or inhibiting the release of other neurotransmitters. An example of inhibition of neurotransmitter release is given above, whereas in the gut it is stimulation of acetylcholine release from neurons of the myenteric plexus in the gut wall that increases contractions and secretions. 5HT can also stimulate sensory nerve endings directly, causing a pain sensation — well known to those who have suffered nettle stings, which contain 5HT.

Although only 1% of the body's total 5HT occurs in the brain it is here that the actions of this substance are the most profound. The neurons containing 5HT are concentrated in the raphe nuclei in the mid-brain and their fibres project in a diffuse way to the cerebral cortex, hippocampus, limbic system, and hypothalamus as well as down the spinal cord — a distribution not dissimilar to that of noradrenergic fibres.

Modern molecular biological studies have shown that there are many different types of receptors for 5HT — perhaps as many as ten — whose precise functional responsibilities are not yet clear. There is clear evidence that 5HT is involved in sleep, wakefulness, and mood. Descending 5HT pathways (from the brain down the spinal cord) affect the excitability of spinal motorneurons, activating those involved in simple reflexes and inhibiting more complex reflexes. Animals deprived of 5HT (by giving agents that prevent its synthesis) show exaggerated responses to many types of sensory stimulus, indicating that 5HT normally exerts a modifying effect, allowing irrelevant stimuli to be ignored and the response to pain palliated. 5HT is also involved at the level of the hypothalamus in temperature regulation and in the control of factors which release hormones from the anterior pituitary gland; also in the central control of vomiting.

There is much evidence to suggest that major changes in the blood vessels on the surface of the brain, which underlie migraine, are caused by release of 5HT. After an initial vasoconstrictor phase has passed the brain vessels dilate, and it is thought this is responsible for the pain. Drugs used to treat this condition, such as Sumatriptan, are antagonists at the receptor sub-type 5HT_1d.

Lysergic acid diethylamide (LSD) is one of the most notorious mood-altering (psychomimetic/hallucinogenic) drugs, producing bizarre visual experiences together with marked motor unrest and vocalization of extraordinary utterances. Mental function is altered so that perception of all sensory input — visual, auditory, tactile or olfactory — is distorted. In the brain LSD is able to activate 5HT receptors although elsewhere LSD is an antagonist. The psychomimetic effects of LSD certainly involve interference with the multiple actions of 5HT in the brain. Users of LSD describe both good and bad ‘trips’, which may mean that the response to LSD is dependent on the state of the 5HT system when the drug is taken. With 5HT, as with many neurotransmitters, the body economizes by using reuptake mechanisms: after a neurotransmitter has been released and has acted on post synaptic receptors the transmitter in the vicinity of the nerve terminal is taken up, stored, and recycled when the next nerve impulse arrives. In recent years drugs have been developed which specifically block the reuptake of 5HT. Clearly this is useful if reduction in the effectiveness of 5HT transmission in the brain has led to depression. Selective serotonin reuptake inhibitors (SSRIs) have proved useful mood-improving drugs; the best known is fluoxetine (Prozac), although there have been adverse criticisms of its use as many patients are reluctant to give it up, even when the condition precipitating the depression has passed.

— Alan W. Cuthbert

See also neurotransmitters; membrane receptors.

Serotonin is a chemical derived from the amino acid tryptophan. It plays a key part in a number of reactions in the brain and other tissues. In the blood, it acts as a vasoconstrictor, narrowing blood vessels, and is involved in the inflammation response. In the brain, serotonin is a neurotransmitter, affecting the activity of nerve cells. Brain concentrations are affected by diet in quite a complex way depending on the ability of tryptophan to cross the barrier between blood and the brain. Generally, carbohydrate-rich diets increase tryptophan levels, accelerating serotonin production. Some protein-rich diets (those containing the amino acids tyrosine, phenylalanine, leucine, isoleucine, and valine) compete with tryptophan to get across the blood-brain barrier, depress tryptophan uptake into the brain, and reduce serotonin levels.

Changes in serotonin levels can alter mood: increases have a calming effect, relieving depression, insomnia, and irritability; decreases are associated with wakefulness and greater sensitivity to pain. There is also a link between high serotonin levels and the early onset of fatigue: elevated levels induce lethargy and reduce the desire to exercise. Attempts have been made by some sports scientists to see if reducing serotonin levels can improve physical performance, but the results so far are inconclusive. See also branched chain amino acids.

For the professional wrestling stable, see Raven's Nest.

Serotonin
IUPAC name	5-Hydroxytryptamine or 3-(2-aminoethyl)-1H-indol-5-ol
Identifiers
CAS number	50-67-9
PubChem	5202
MeSH	Serotonin
SMILES	NCCc1c[nH]c2ccc(O)cc12
InChI	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
Properties
Molecular formula	N2OC10H12
Molar mass	176.215
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references

Serotonin (pronounced IPA: /ˌsɛrəˈtoʊnən/) (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.

Explanation

In the central nervous system, serotonin is believed to play an important role in the regulation of anger, aggression, body temperature, mood, sleep, vomiting, sexuality, and appetite. Low levels of serotonin may be associated with several disorders, namely increase in aggressive and angry behaviors, clinical depression, obsessive-compulsive disorder (OCD), migraine, irritable bowel syndrome, tinnitus, fibromyalgia, bipolar disorder, anxiety disorders^{[citation needed]} and intense religious experiences.^[1] If neurons of the brainstem that make serotonin—serotonergic neurons—are abnormal, there is a risk of sudden infant death syndrome (SIDS).^[2][3]

Isolated and named in 1948 by Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic,^[4] 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.

The pathway for the synthesis of serotonin from tryptophan

Serotonin is synthesized extensively in the human gastrointestinal tract (about 90%),^[1] and the major storage place is platelets in the blood stream.

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 (Nash et al 2005; Zhang et al 2005). 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 (Hiroi et al 2006).

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.

Neurotransmission

The neurons of the Raphe nuclei are the principal source of 5-HT release in the brain.^[5] The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation.^[6] 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 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, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).

Recent research suggests that serotonin plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout the body.^[7]

Pharmacology

The pharmacology of 5-HT is extremely complex, with its actions being mediated by a large and diverse range of 5-HT receptors. At least seven different receptor "families" are known to exist, each located in different parts of the body and triggering different responses. 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.

Receptors

Main article: 5-HT receptor

In the field of neurochemistry, 5-HT receptors are receptors for the neurotransmitter and peripheral signal mediator serotonin (5-HT). 5-HT receptors 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.

Psychedelic modulation

There exist many drugs that innately modulate the 5-HT system in such a way to produce alterations in perception, emotional response, and thought process. These include psilocin/psilocybin, DMT, mescaline, LSD, MDMA (ecstasy), and ibogaine. These and many more have been described in the books TiHKAL and PiHKAL by Alexander Shulgin.

Therapeutic modulation

Various drugs are used to modulate the 5-HT system including some antidepressants, anxiolytics, antiemetics, and triptans.

Modulating levels

A variety of psychiatric medications affect serotonin levels, including the monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), atypical antipsychotics, the selective serotonin reuptake inhibitors (SSRIs), and amphetamines. Recreational substances such as MDA, MDMA, and MDEA also affect serotonin levels. Research by GW Pharma in the UK has shown that cannabis modulates serotonin levels through g-proteins, also resulting in an anti-nauseant effect.

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.^[8]

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.^[9] The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels.^[10] For example, recreational doses of MDMA (ecstasy) will generally cause such symptoms but only rarely lead to true toxicity.

Bacteria, Yeast, Algae, Parasites

Serotonin is used by a variety of single celled organisms for various purposes. Selective serotonin re-uptake inhibitors (SSRI's) have been found to be toxic to algae.^[11] The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.^[12][13] Patients infected with Entamoeba histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.^[14]Entamoeba histolytica also responds to the presence of serotonin by becoming more virulent.^[15]

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) genus. 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.^[16] Serotonin is one compound of the poison contained in the stinging hairs of the stinging nettle (Urtica dioica). It should be noted serotonin does not cross the blood-brain barrier unlike its precursors 5-HTP or tryptophan. Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH₂) and hydroxy (OH) groups, are N-oxides, or miss the OH group. Example are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff.

Animals

Serotonin as a neurotransmitter is found in all animals, including insects. Several toad venoms contain serotonin and related tryptamines.

References

1. ^ Dr. Lars Farde Ph.D, professor of psychiatry at Karolinska Institutet in Stockholm, Sweden 2003, the study and a vulgarized article
2. ^ Paterson D.S. et al (2006). "Multiple Serotonergic Brainstem Abnormalities in Sudden Infant Death Syndrome". Journal of the American Medical Association 296: 2124–2132. 
3. ^ Sciencedaily Report Anger and Aggression in Women: Blame It On Genetics
4. ^ Rapport MM, Green AA, Page IH (1948). "Serum vasoconstrictor (serotonin). IV. Isolation and characterization". J Biol Chem 176 (3): 1243–1251.
5. ^ (1999) "Understanding the neuroanatomical organization of serotonergic cells in the brain provides insight into the functions of this neurotransmitter", in George J. Siegel: Basic Neurochemistry, Bernard W. Agranoff, Stephen K. Fisher, R. Wayne Albers, Michael D. Uhler, Sixth, Lippincott Williams and Wilkins. ISBN 0-397-51820-X. “In 1964, Dahlstrom and Fuxe (discussed in [2]), using the Falck-Hillarp technique of histofluorescence, observed that the majority of serotonergic soma are found in cell body groups, which previously had been designated as the raphe nuclei.” 
6. ^ |The Raphe nuclei group of neurons are located along the brain stem from the labels 'Mid Brain' to 'Oblongata', centered on the pons. (See relevant image.)
7. ^ Lesurtel M. et al (2006). "Platelet-derived serotonin mediates liver regeneration". Science 312 (5770): 104–7. PMID 16601191. 
8. ^ Svenningsson P, et al (2006). "Alterations in 5-HT1B receptor function by p11 in depression-like states". Science 311 (5757): 77–80. PMID 16400147. 
9. ^ Isbister, G.K., et al., Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. Journal of Toxicology. Clinical Toxicology, 2004. 42(3): p. 277-85.
10. ^ Dunkley, E.J.C., et al., Hunter Serotonin Toxicity Criteria: a simple and accurate diagnostic decision rule for serotonin toxicity. Quarterly Journal of Medicine, 2003. 96: p. 635-642.
11. ^ Johnson DJ, Sanderson H, Brain RA, Wilson CJ, Solomon KR (2007). "Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae". Ecotoxicol. Environ. Saf. 67 (1): 128-39. DOI:10.1016/j.ecoenv.2006.03.016. PMID 16753215. 
12. ^ McGowan K, Kane A, Asarkof N, et al (1983). "Entamoeba histolytica causes intestinal secretion: role of serotonin". Science 221 (4612): 762-4. PMID 6308760. 
13. ^ McGowan K, Guerina V, Wicks J, Donowitz M (1985). "Secretory hormones of Entamoeba histolytica". Ciba Found. Symp. 112: 139-54. PMID 2861068. 
14. ^ Banu, Naheed, et al. (2005). "Neurohumoral alterations and their role in amoebiasis.". Indian J. Clin Biochem 20 (2): 142-5. 
15. ^ Acharya DP, Sen MR, Sen PC (1989). "Effect of exogenous 5-hydroxytryptamine on pathogenicity of Entamoeba histolytica in experimental animals". Indian J. Exp. Biol. 27 (8): 718-20. PMID 2561282. 
16. ^ Jerome M. Feldman,Ellen M. Lee, Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid. Am. J. Clin. Nutr. 42(4):639-43 (1985) PMID 2413754 http://www.ajcn.org/cgi/reprint/42/4/639.pdf

See also

• 5-HTP a serotonin precursor, found in food and sold as a dietary supplement

External links

• PsychoTropicalResearch Extensive reviews on serotonergic drugs and Serotonin Syndrome.
• Molecule of the Month: Serotonin at University of Bristol

Tryptamines

4-Acetoxy-DET • 4-Acetoxy-DIPT • 4-Acetoxy-DMT • 4-HO-DIPT • 5-Bromo-DMT • 5-Fluoro-α-MT • 5-MeO-α-ET  • 5-MeO-α-MT • 5-MeO-DALT • 5-MeO-DET • 5-MeO-DIPT • 5-MeO-DMT • 5-MeO-DPT • 5-MeO-MIPT • α-ET • α-MT • Baeocystin • Bufotenin • DET • DiPT • DMT • DPT • Ethocybin • EiPT • Ethocin • Ibogaine • Iprocin • MET • MiPT • Miprocin • Melatonin • NMT • Norbaeocystin • Normelatonin • PiPT • Psilocin • Psilocybin • Rizatriptan • Serotonin • Sumatriptan • Tryptamine • Tryptophan

Autacoids
Angiotensin - Eicosanoid - Histamine - Kinin - Platelet-activating factor - Serotonin

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