In 1935, Italian Vittorio Erspamer showed that an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later Erspamer was able to show that it was a previously unknown amine, which he named enteramine .

Serotonin is a neurotransmitter, and is found in all bilateral animals , where it mediates gut movements and the animal's perception 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. In response to the perceived abundance or scarcity of resources, the 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. These genetic studies have demonstrated serotonin has strong associations with depression in regards to a negative environment.

Gauge of food availability

Serotonin functions as a neurotransmitter in the nervous systems of simple, as well as complex, animals. For example, in the roundworm C. 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 hermaphrodite 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.

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-HT_2C receptors make the body unable to shut off appetite, and are associated with increased weight gain,

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.

However, increasing insulin for a long period may trigger the onset of insulin resistance, obesity, type 2 diabetes, and lower serotonin levels.

Muscles use many of the amino acids except tryptophan, allowing men to have more serotonin than women.

In the digestive tract

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 that 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, 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 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.

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. The effect of 5-HT₁ receptor s predominates in subordinate animals, while 5-HT₂ receptor s 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.

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,

Effects on 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 is suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal.

Serotonin is necessary for normal male mating behavior,

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.

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.

In humans, though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones so that serotonin suppresses insulin release from the beta cells in the pancreas,

Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors.

5HT2B receptors also activate osteoblasts, which build up bone

Cardiovascular growth factor

Serotonin, in addition, evokes endothelial nitric oxide synthase activation and stimulates, through a 5-HT1B receptor-meditated mechanism, the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.

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. Free full text from the Australian Therapeutic Goods Administration

Two independent studies published in the New England Journal of Medicine in January 2007, implicated pergolide, along with cabergoline, in causing 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 for wasps, and deathstalkers to have serotonin in their venom may be to increase the pain of their sting on large animals, and also to cause lethal vasoconstriction on smaller prey.

Deficiency

Genetically altered C. elegans 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 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).

Low levels of serotonin may also be associated with intense spiritual experiences .

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.

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 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 ??m) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.

Receptors

The 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.

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 (TCAs) 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, there are no known pharmaceuticals which would 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 ??moles/L).

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.

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 .

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.

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.

Antidepressants

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 . 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 reuptake of serotonin, making it stay in the synapse 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.

Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases in serotonin. 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 , 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.

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

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.

Serotonin is used by a variety of single-cell organisms for various purposes. Selective serotonin reuptake inhibitors (SSRIs) have been found to be toxic to algae. 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, and hence also the serotonin concentration. Low serotonin signals to the entoamoebas they are outside a host and they become less virulent conserve energy. When they enter a new host, they multiply in the gut, and become more virulent as the serotonin concentration increases.

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 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 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 that 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.

• 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 .