Serotonin

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

**Serotonin** (pronounced /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.

## Function

In the central nervous system, serotonin plays an important role as a neurotransmitter in the modulation of anger, aggression, body temperature, mood, sleep, sexuality, appetite, and metabolism, as well as stimulating vomiting.

Serotonin has broad activities in the brain, and genetic variation in serotonin receptors and the serotonin transporter, which facilitates reuptake of serotonin into presynapses, have been implicated in neurological diseases. Drugs targeting serotonin-induced pathways are being used in the treatment of many psychiatric disorders, and one focus of clinical research is the influence of genetics on serotonin action and metabolism in psychiatric settings. Such studies have revealed that the variation in the promoter region of the serotonin transporter protein accounts for nearly 10% of total variance in anxiety-related personality , and the effect of this gene on depression was found to interact with the environment .

Levels of serotonin in the brain show association with aggression (Caspi et al. 2002), and a mutation in the gene which codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype.

Using the ultimatum game as model, it was shown that people whose serotonin levels have been artificially lowered will reject unfair offers more often than players with normal serotonin levels.

In addition, serotonin is also a peripheral signal mediator. It is found extensively in the human gastrointestinal tract as about 80-90% of the body's total serotonin is found in the enterochromaffin cells in the gut. In the blood, the major storage site is platelets, which collect serotonin for use in mediating post-injury vasoconstriction.[*citation needed*]

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

**Serotonin and SIDS**

Defective signalling of serotonin in the brain may be at the root cause of sudden infant death syndrome (SIDS), Italian researchers have found.

Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy genetically modified the lab mice to produce low levels of the brain signaling protein 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 that low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may have caused sudden death, researchers said in the July 4, 2008 issue of Science.

## Anatomy

### Gross anatomy

The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.
The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation.

Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching large areas of the brain. Axons of neurons in the *caudal* dorsal raphe nucleus terminate in the following locations:

* Deep cerebellar nuclei
* Cerebellar cortex
* Spinal cord

On the other hand, axons of neurons in the *rostral* dorsal raphe nucleus terminate in e.g.:

* Thalamus
* Striatum
* Hypothalamus
* Nucleus accumbens
* Neocortex
* Cingulate gyrus
* Cingulum
* Hippocampus
* Amygdala

Thus, activation of this serotonin system has effects on large areas of the brain.

### Microanatomy

Serotonin is released from serotonergic varicosities (swellings) into the extra neuronal space, but not from synaptic terminal boutons as other neurotransmitters.[*citation needed*] Serotonin diffuses over a relatively wide gap (>20µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.

#### Receptors

*Main article: 5-HT receptor*
5-HT receptors are the receptors for serotonin. They are located on the cell membrane of nerve cells and other cell types in animals and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or *heptahelical*) receptors that activate an intracellular second messenger cascade.[*citation needed*]

#### Termination

Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, 5-HT reuptake transporter, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).

### Endothelial cell function and Serotonin

5-hydroxytryptamine evokes endothelial nitric oxide synthase activation and stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.

## Synthesis

 File:Serotonin biosynthesis.svg
In the body, serotonin is synthesized from the amino acid tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a brain-specific isoform. There is evidence that genetic polymorphisms in both these subtypes influence susceptibility to anxiety and depression. There is also evidence that ovarian hormones can affect the expression of TPH in various species, suggesting a possible mechanism for postpartum depression and premenstrual stress syndrome.

Serotonin taken orally 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.

### Psychoactive drugs

The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD mimic the action of serotonin primarily at 5-HT2A receptor. The empathogen MDMA (ecstasy) releases serotonin from synaptic vesicles of neurons.

### Antidepressants

The MAOIs prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content and certain drugs.

Some drugs inhibit the re-uptake of serotonin, making it stay in the synapse longer. The tricyclic antidepressants (TCAs) inhibit the re-uptake of both serotonin and norepinephrine. The newer selective serotonin re-uptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs.

### Antiemetics

5-HT3 antagonists such as ondansetron, granisetron, and tropisetron are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in treatment of post-operative nausea and vomiting. Applications to the treatment of depression and other mental and psychological conditions have also been investigated with some positive results.

## Pathology

If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS). Low levels of serotonin may also be associated with intense religious experiences.

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

Obsessive-compulsive disorder (OCD) can be a debilitating disorder with the following two anxiety-related essential features: obsessions (undesirable, recurrent, disturbing thoughts) and compulsions (repetitive or ritualized behaviors). Some research shows that it may have to do with serotonin, which helps to keep people from repeating the same behaviors over and over again. A person who has OCD may not have enough serotonin. Therefore, many people who have OCD can function better when they take medicines that increase the amount of serotonin in their brain.

### Serotonin syndrome

*Main article: serotonin syndrome*
Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a condition known as serotonin syndrome. In practice, such toxic levels are essentially impossible to reach through an overdose of a single anti-depressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI. The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels. For example, recreational doses of MDMA (ecstasy) will generally cause such symptoms but only rarely lead to true toxicity.[*citation needed*]

### Chronic diseases resulting from serotonin 5-HT2B overstimulation

*Main article: Cardiac fibrosis*
In blood, serotonin stored in platelets is active wherever platelets bind, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic, to aid healing. Because of these effects, overdoses of serotonin, or serotonin agonist drugs, may cause acute or chronic pulmonary hypertension from pulmonary vasoconstriction, or else syndromes of retroperitoneal fibrosis or cardiac valve fibrosis (endocardial fibrosis) from overstimulation of serotonic growth receptors on fibrocytes.[*citation needed*]

Serotonin itself may cause a syndrome of cardiac fibrosis when it is eaten in large quantities in the diet (the Matoki banana of East Africa) or when it is over-secreted by certain mid-gut carcinoid tumors.[*citation needed*] The valvular fibrosis in such cases is typically on the right side of the heart, since excess serotonin in the serum outside platelets is metabolized in the lungs, and does not reach the left circulation.[*citation needed*]

Serotonergic agonist drugs in overdose in experimental animals not only cause acute (and sometimes fatal) pulmonary hypertension, but there is epidemiologic evidence that chronic use of certain of these drugs produce a chronic pulmonary hypertensive syndrome in humans.[*citation needed*] 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 epidemiolgically linked with these syndromes. They are the serotonergic vasoconstrictive anti-migraine drugs (ergotamine and methysergide), the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride. As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was in decreasing use since reported in 2003 to be associated with cardiac fibrosis. Two independent studies published in the New England Journal of Medicine in January 2007, implicated pergolide along with cabergoline in causing valvular heart disease. As a result of this, the FDA removed pergolide from the U.S. market in March, 2007. (Since cabergoline 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).

Because neither the amino acid L-tryptophan nor the SSRI-class antidepressants raise blood serotonin levels[*citation needed*], they are not under suspicion to cause the syndromes described. However, since 5-hydroxytryptophan (5-HTP) does raise blood serotonin levels, it is under some of the same scrutiny as actively serotonergic drugs.[*citation needed*]

## In unicellular organisms

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

## In plants

Serotonin is found in mushrooms and plants, including fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (*Juglans*) and hickory (*Carya*) genuses. Serotonin concentrations of 3–30 mg/kg have been found in plantain, pineapple, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables. Serotonin is one compound of the poison contained in the stinging hairs of the stinging nettle (*Urtica dioica*). It should be noted that serotonin, unlike its precursors 5-HTP and tryptophan, does not cross the blood–brain barrier.
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. Examples are plants from the *Anadenanthera* genus that are used in the hallucinogenic yopo snuff.

## In animals

Serotonin as a neurotransmitter is found in all animals, including insects. Several toad venoms, as well as that of the Brazilian wandering spider and stingray, contain serotonin and related tryptamines.

## History

Isolated and named in 1948 by Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic,
the name *serotonin* is something of a misnomer and reflects the circumstances of the compound's discovery. It was initially identified as a vasoconstrictor substance in blood serum – hence *serotonin*, a serum agent affecting vascular tone. This agent was later chemically identified as 5-hydroxytryptamine (5-HT) by Rapport, and, as the broad range of physiological roles were elucidated, 5-HT became the preferred name in the pharmacological field.

## References

1. ↑ http://drugs.emedtv.com/dolasetron/dolasetron.html
6. ↑ Indiana State University
7. ↑ [1] Serotonin tests info, Accessed May 6, 2008
9. ↑ Alan Frazer and Julie G. Hensler (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.”
10. ↑ |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.)
13. ↑ Sciencedaily Report *Anger and Aggression in Women: Blame It On Genetics*
14. ↑ Lars Farde & Jacqueline Borg, section of psychiatry at Karolinska Institutet in Stockholm, Sweden 2003, the study and a vulgarized article
16. ↑ 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.
17. ↑ 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.
18. ↑ books.google.com Accessed May 6, 2008
19. ↑ books.google.com Acessed May 6, 2008
20. ↑  Jähnichen S, Horowski R, Pertz H. "Pergolide and Cabergoline But not Lisuride Exhibit Agonist Efficacy at Serotonin 5-HT2B Receptors".PDF (515 KiB) Presentation. Retrieved on 2007-03-30.
21. ↑  Free full text from the Australian Therapeutic Goods Administration
22. ↑ Schade, Rene; Andersohn, Frank; Suissa, Samy; Haverkamp, Wilhelm & Garbe, Edeltraut (2007-01-04), "Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation", *New England Journal of Medicine* **356**(1): 29–38, PMID 17202453, <http://content.nejm.org/cgi/content/full/356/1/29>
23. ↑ Zanettini, Renzo; Antonini, Angelo; Gatto, Gemma; Gentile, Rosa; Tesei, Silvana & Pezzoli, Gianna (2007-01-04), "Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson's Disease", *New England Journal of Medicine* **356**(1): 39–46, PMID 17202454, <http://content.nejm.org/cgi/content/full/356/1/39>
24. ↑ Food and Drug Administration Public Health Advisory (2007-03-29). Retrieved on 2007-04-27.
25. ↑ MedWatch - 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents. U.S. Food and Drug Administration (March 29, 2007). Retrieved on 2007-03-30.
31. ↑ 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

## External links

* PsychoTropicalResearch Extensive reviews on serotonergic drugs and Serotonin Syndrome.
* Molecule of the Month: Serotonin at University of Bristol
* Scientific America 60-Second Psych: No Fair! My Serotonin Level Is Low.
* Serotonin Test Interpretation on ClinLab Navigator.

ar:سيروتونين
bg:Серотонин
ca:Serotonina
cs:Serotonin
da:Serotonin
de:Serotonin
el:Σεροτονίνη
es:Serotonina
fr:Sérotonine
hy:Սերոտոնին
hr:Serotonin
id:Serotonin
it:Serotonina
he:סרוטונין
la:Serotoninum
lt:Serotoninas
hu:Szerotonin
nl:Serotonine
ja:セロトニン
no:Serotonin
pl:Serotonina
pt:Serotonina
ru:Серотонин
sl:Serotonin
sr:Серотонин
fi:Serotoniini
sv:Serotonin
tr:Serotonin
uk:Серотонін
zh:血清張力素