Serotonin
Overview
 
Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter
Monoamine neurotransmitter
thumb|right|350px| A phylogenetic tree showing how a number of monoamine receptors are related to each other.Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain...

. Biochemically derived from tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...

, serotonin is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 (CNS) of animals including humans. It is popularly thought to be a contributor to feelings of well-being and happiness
Happiness
Happiness is a mental state of well-being characterized by positive emotions ranging from contentment to intense joy. A variety of biological, psychological, religious, and philosophical approaches have striven to define happiness and identify its sources....

.

Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the gut
Gut (zoology)
In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...

, where it is used to regulate intestinal movements.
Encyclopedia
Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter
Monoamine neurotransmitter
thumb|right|350px| A phylogenetic tree showing how a number of monoamine receptors are related to each other.Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain...

. Biochemically derived from tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...

, serotonin is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 (CNS) of animals including humans. It is popularly thought to be a contributor to feelings of well-being and happiness
Happiness
Happiness is a mental state of well-being characterized by positive emotions ranging from contentment to intense joy. A variety of biological, psychological, religious, and philosophical approaches have striven to define happiness and identify its sources....

.

Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the gut
Gut (zoology)
In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...

, where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic
Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...

 neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

s in the CNS where it has various functions. These include the regulation of mood
Mood (psychology)
A mood is a relatively long lasting emotional state. Moods differ from emotions in that they are less specific, less intense, and less likely to be triggered by a particular stimulus or event....

, appetite, and sleep. Serotonin also has some cognitive functions, including in 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 platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

s, which store it. When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis
Hemostasis
Hemostasis or haemostasis is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel . Most of the time this includes blood changing from a liquid to a solid state. Intact blood vessels are central to moderating blood's tendency to clot...

 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
Monoamine oxidase
L-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...

 ( MAO ) to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase
Aldehyde dehydrogenase
Aldehyde dehydrogenases are a group of enzymes that catalyse the oxidation of aldehydes.- Function :Aldehyde dehydrogenase is a polymorphic enzyme responsible for the oxidation of aldehydes to carboxylic acids, which leave the liver and are metabolized by the body’s muscle and heart...

 to 5-HIAA, the indole acetic acid derivative. The latter is then excreted by the kidneys. One type of tumor, called carcinoid
Carcinoid
Carcinoid is a slow-growing type of neuroendocrine tumor, originating in the cells of the neuroendocrine system.In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners. This has led to some complexity in distinguishing...

, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome
Carcinoid syndrome
Carcinoid syndrome refers to the array of symptoms that occur secondary to carcinoid tumors. The syndrome includes flushing and diarrhea, and, less frequently, heart failure and bronchoconstriction...

 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 plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...

s. 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.

Functions

Serotonin is a neurotransmitter, and is found in all bilateral animals
Bilateria
The bilateria are all animals having a bilateral symmetry, i.e. they have a front and a back end, as well as an upside and downside. Radially symmetrical animals like jellyfish have a topside and downside, but no front and back...

, 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 arthropod
Arthropod
An arthropod is an invertebrate animal having an exoskeleton , a segmented body, and jointed appendages. Arthropods are members of the phylum Arthropoda , and include the insects, arachnids, crustaceans, and others...

s and vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...

s, resources also can mean social dominance. In response to the perceived abundance or scarcity of resources, the animal's growth, reproduction or mood
Mood (psychology)
A mood is a relatively long lasting emotional state. Moods differ from emotions in that they are less specific, less intense, and less likely to be triggered by a particular stimulus or event....

 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
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...

, 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
Cuticle
A cuticle , or cuticula, is a term used for any of a variety of tough but flexible, non-mineral outer coverings of an organism, or parts of an organism, that provide protection. Various types of "cuticles" are non-homologous; differing in their origin, structure, function, and chemical composition...

, dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 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
Octopamine
Octopamine is an endogenous biogenic amine that is closely related to norepinephrine, and has effects on the adrenergic and dopaminergic systems. It is also found naturally in numerous plants, including bitter orange. Biosynthesis of the D--enantiomer of octopamine is by β-hydroxylation of...

 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
Incentive salience
Incentive salience is a motivational "wanting" attribute given by the brain to reward-predicting stimuli. This "wanting" is unlike "liking" in that liking is a pleasure immediately gained from consumption or other contact with stimuli, while the "wanting" of incentive salience is a motivational...

. But unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates 5-HT2C receptor
5-HT2C receptor
The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...

s 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, especially in people who have a low number of receptors. The expression of 5-HT2C receptors in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...

 follows a diurnal rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...

, just as the serotonin release in the ventromedial nucleus
Ventromedial nucleus
The ventromedial nucleus is a nucleus of the hypothalamus.-Division:It has four subdivisions:* anterior * dorsomedial * ventrolateral * central ....

, which is characterised by a peak at morning when the motivation to eat is strongest.

Effects of food content

In humans, serotonin levels are affected by diet. An increase in the ratio of tryptophan to phenylalanine and leucine will increase serotonin levels. Fruits with a good ratio include dates, papayas and bananas. Foods with a lower ratio inhibit the production of serotonin. These include whole wheat and rye bread. Research also suggests eating a diet rich in carbohydrates and low in protein will increase serotonin by secreting insulin, which helps in amino acid competition.
However, increasing insulin for a long period may trigger the onset of insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

, obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...

, type 2 diabetes, and lower serotonin levels.
Muscles use many of the amino acids except tryptophan, allowing men to have more serotonin than women. Myo-inositol
Inositol
Inositol or cyclohexane-1,2,3,4,5,6-hexol is a chemical compound with formula 6126 or 6, a sixfold alcohol of cyclohexane. It exists in nine possible stereoisomers, of which the most prominent form, widely occurring in nature, is cis-1,2,3,5-trans-4,6-cyclohexanehexol, or myo-inositol...

, a carbocyclic polyol
Polyol
A polyol is an alcohol containing multiple hydroxyl groups. In two technological disciplines the term "polyol" has a special meaning: food science and polymer chemistry.- Polyols in food science :...

 present in many foods, is known to play a role in serotonin modulation.

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
Chemoreceptor trigger zone
The chemoreceptor trigger zone , is an area of the medulla that receives inputs from blood-borne drugs or hormones, and communicates with the vomiting center, to initiate vomiting. The CTZ is close to the area postrema on the floor of the fourth ventricle and is outside of the blood-brain barrier...

 that stimulate vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

. The enterochromaffin cells not only react to bad food, they are also very sensitive to irradiation
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...

 and cancer chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

. Drugs that block 5HT3
5-HT3 antagonist
The 5-HT3 antagonists are a class of medications that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain....

 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
Lobster
Clawed lobsters comprise a family of large marine crustaceans. Highly prized as seafood, lobsters are economically important, and are often one of the most profitable commodities in coastal areas they populate.Though several groups of crustaceans are known as lobsters, the clawed lobsters are most...

 is injected with serotonin, it behaves like a dominant animal
Alpha (biology)
In social animals, the alpha is the individual in the community with the highest rank. Where one male and one female fulfill this role, they are referred to as the alpha pair...

, while octopamine
Octopamine
Octopamine is an endogenous biogenic amine that is closely related to norepinephrine, and has effects on the adrenergic and dopaminergic systems. It is also found naturally in numerous plants, including bitter orange. Biosynthesis of the D--enantiomer of octopamine is by β-hydroxylation of...

 causes subordinate behavior.
A frightened crayfish
Crayfish
Crayfish, crawfish, or crawdads – members of the superfamilies Astacoidea and Parastacoidea – are freshwater crustaceans resembling small lobsters, to which they are related...

 flips its tail
Caridoid escape reaction
The Caridoid Escape Reaction, also known as lobstering or tail-flipping, refers to an innate escape mechanism in marine and freshwater crustaceans such as lobsters, krill, shrimp and crayfish....

 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
Fight-or-flight response
The fight-or-flight response was first described by Walter Bradford Cannon....

. The effect of 5-HT1 receptor
5-HT1 receptor
The 5-HT1 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin . The 5-HT1 subfamily consists of five G protein-coupled receptors that are coupled to Gi/Go and mediate inhibitory neurotransmission, including 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F...

s predominates in subordinate animals, while 5-HT2 receptor
5-HT2 receptor
The 5-HT2 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin . The 5-HT2 subfamily consists of three G protein-coupled receptors which are coupled to Gq/G11 and mediate excitatory neurotransmission, including 5-HT2A, 5-HT2B, and 5-HT2C...

s predominates in dominants.
In humans, levels of 5-HT1A receptor activation in the brain show negative correlation with aggression, and a mutation in the gene that codes for the 5-HT2A
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...

 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 transporter
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...

s 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
5-HTTLPR
5-HTTLPR is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter.Since the polymorphism was identified in the middle of the 1990s,...

 serotonin transporters the neurons should deploy, and the effect of this variation was found to interact with the environment in depression.

Effects on growth and reproduction

In C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...

, 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, and the inclination to leave food to search for a mate.
The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

-like signaling and the TGF beta signaling pathway
TGF beta signaling pathway
The Transforming growth factor beta signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. In spite of the wide range of cellular...

, which control long-term adaption.

Bone metabolism

In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass. Mice that lack brain serotonin have osteopenia while mice that lack gut serotonin have high bone density. In humans increased blood serotonin levels have been shown to be significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at a very low levels, in the bone cells. Serotonin mediates its actions on bone cells using three different receptors. Through Htr1b receptor it negatively regulates bone mass while it does so positively through Htr2b and Htr2c. These studies have opened up a new area of research in bone metabolism that can be potentially harnessed to treat bone mass disorders.

Behavior

Serotonin is necessary for normal male mating behavior, and the inclination to leave food to search for a mate.
The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

-like signaling and the TGF beta signaling pathway
TGF beta signaling pathway
The Transforming growth factor beta signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. In spite of the wide range of cellular...

, which control long-term adaption.
In the fruitfly
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...

, where insulin both regulates blood sugar
Blood sugar
The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...

 and acts as a growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....

, serotonergic neurons regulate the adult body size by affecting insulin secretion. Serotonin has also been identified as the trigger for swarm behavior in locusts.
In humans, though insulin regulates blood sugar and IGF
Insulin-like growth factor
The insulin-like growth factors are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment...

 regulates growth, serotonin controls the release of both hormones so that serotonin suppresses insulin release from the beta cell
Beta cell
Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...

s in the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...

, and exposure to SSRIs reduces fetal growth.
Human serotonin can also act as a growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....

 directly. Liver damage increases cellular expression of 5-HT2A
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...

 and 5-HT2B receptor
5-HT2B receptor
5-hydroxytryptamine receptor 2B, also known as HTR2B, is a 5-HT2 receptor, but also denotes the human gene encoding it.-Function:...

s. Serotonin present in the blood then stimulates cellular growth to repair liver damage.
5HT2B receptors also activate osteocyte
Osteocyte
An osteocyte, a star-shaped cell, is the most abundant cell found in compact bone. Cells contain a nucleus and a thin ring of cytoplasm. When osteoblasts become trapped in the matrix they secrete, they become osteocytes...

s, which build up bone However, serotonin also inhibits osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...

s, through 5-HT1B receptor.

Cardiovascular growth factor

Serotonin, in addition, evokes endothelial
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

 nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...

 activation and stimulates, through a 5-HT1B receptor
5-HT1B receptor
5-hydroxytryptamine receptor 1B also known as the 5-HT1B receptor is a protein that in humans is encoded by the HTR1B gene. The 5-HT1B receptor is a 5-HT receptor subtype.-Tissue distribution and function:...

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

Some serotonergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis
Retroperitoneal fibrosis
Retroperitoneal fibrosis or Ormond's disease is a disease featuring the proliferation of fibrous tissue in the retroperitoneum, the compartment of the body containing the kidneys, aorta, renal tract and various other structures. It may present with lower back pain, renal failure, hypertension, deep...

, as well as cardiac valve fibrosis
Cardiac fibrosis
Cardiac fibrosis refers to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts.Fibrocyte cells normally secrete collagen, and function to provide structural support for the heart...

.
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
Methysergide
Methysergide is a prescription drug used for prophylaxis of migraine headaches and is sold under the brand names Sansert and Deseril in 2 mg dosages.-Pharmacology:Methysergide interacts with serotonin receptors...

), the serotonergic appetite suppressant drugs (fenfluramine
Fenfluramine
Fenfluramine is a drug that was part of the Fen-Phen anti-obesity medication . Fenfluramine was introduced on the U.S. market in 1973. It is the racemic mixture of two enantiomers, dextrofenfluramine and levofenfluramine...

, chlorphentermine
Chlorphentermine
Chlorphentermine is an appetite suppressant of the phenethylamine class. Developed in 1962, it is the 4-chloro derivative of the better known appetite suppressant phentermine, which is still in current use.Chlorphentermine itself is a relatively weak stimulant with little abuse potential, but is...

, and aminorex
Aminorex
Aminorex is an anorectic stimulant drug of the 2-amino-5-aryl oxazoline class developed by a team at McNeil in 1962. It is closely related to 4-methylaminorex. Aminorex has been shown to have locomotor stimulant effects, lying midway between dextroamphetamine and methamphetamine...

), and certain anti-Parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide
Pergolide
Pergolide is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease....

 and cabergoline
Cabergoline
Cabergoline , an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. In vitro, rat studies show cabergoline has a direct inhibitory effect on pituitary lactotroph cells...

, but not the more dopamine-specific lisuride
Lisuride
Lisuride is an antiparkinson agent of the iso-ergoline class, chemically related to the dopaminergic ergoline Parkinson's drugs. Lisuride is described as free base and as hydrogen maleate salt.Lisuride is used to lower prolactin and, in low doses, to prevent migraine attacks...

.
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
Pergolide
Pergolide is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease....

. The drug was declining in use since reported in 2003 to be associated with cardiac fibrosis.
Two independent studies published in the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...

 in January 2007, implicated pergolide, along with cabergoline
Cabergoline
Cabergoline , an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. In vitro, rat studies show cabergoline has a direct inhibitory effect on pituitary lactotroph cells...

, in causing valvular heart disease
Valvular heart disease
Valvular heart disease is any disease process involving one or more of the valves of the heart . Valve problems may be congenital or acquired...

. As a result of this, the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 removed pergolide from the U.S. market in March, 2007. (Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).

Local effects of injection: venoms and pain

Since serotonin is an indicator of bleeding, a sudden large increase in peripheral levels causes pain. The reason for wasp
Wasp
The term wasp is typically defined as any insect of the order Hymenoptera and suborder Apocrita that is neither a bee nor an ant. Almost every pest insect species has at least one wasp species that preys upon it or parasitizes it, making wasps critically important in natural control of their...

s and deathstalker
Deathstalker
The deathstalker , is a species of scorpion, a member of the Buthidae family. It is also known as Palestine yellow scorpion, Omdurman scorpion, Israeli desert scorpion and numerous other colloquial names, which generally originate from the commercial captive trade of the animal...

 scorpions to have serotonin in their venom may be to increase the pain of their sting on large animals, and also to cause lethal vasoconstriction in smaller prey.

Deficiency

Genetically altered C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...

that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a dormant larval state
Dauer larva
Dauer describes an alternative developmental stage of nematode worms, particularly Caenorhabditis elegans whereby the larva goes into a type of stasis and can survive harsh conditions. It may also be equivalent to the infective stage of parasitic nematode larvae...

.

Serotonin in mammals is made by two different tryptophan hydroxylase
Tryptophan hydroxylase
Tryptophan hydroxylase is an enzyme involved in the synthesis of the neurotransmitter serotonin. TPH catalyzes the following chemical reactionIt employs one cofactor, iron.- Function :...

s: TPH1
TPH1
Tryptophan hydroxylase 1 , also known as TPH1, is an enzyme which in humans is encoded by the TPH1 gene.Until 2003 it was thought that there only was a single TPH gene, but then...

 produces serotonin in the pineal gland
Pineal gland
The pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...

and the enterochromaffin cells, while TPH2
TPH2
The enzyme Tryptophan hydroxylase 2, also known as TPH2, is an isozyme of Tryptophan hydroxylase found in vertebrates. In humans TPH2 is primarily expressed in the serotonergic neurons of the brain, with the highest expression in the raphe nucleus of the midbrain...

 produces it in the raphe nuclei
Raphe nuclei
The raphe nuclei are a moderate-size cluster of nuclei found in the brain stem. Their main function is to release serotonin to the rest of the brain...

 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
Purebred
Purebreds, also called purebreeds, are cultivated varieties or cultivars of an animal species, achieved through the process of selective breeding...

 strain, 50% of the mutants died during the first four weeks, but in a mixed strain, 90% survived. Normally, the mother weans
Weaning
Weaning is the process of gradually introducing a mammal infant, either human or animal, to what will be its adult diet and withdrawing the supply of its mother's milk.The process takes place only in mammals, as only mammals produce milk...

 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
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...

 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
Sudden infant death syndrome
Sudden infant death syndrome is marked by the sudden death of an infant that is unexpected by medical history, and remains unexplained after a thorough forensic autopsy and a detailed death scene investigation. An infant is at the highest risk for SIDS during sleep, which is why it is sometimes...

 (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
Sudden infant death syndrome
Sudden infant death syndrome is marked by the sudden death of an infant that is unexpected by medical history, and remains unexplained after a thorough forensic autopsy and a detailed death scene investigation. An infant is at the highest risk for SIDS during sleep, which is why it is sometimes...

 (SIDS).

Recent research conducted at Rockefeller University
Rockefeller University
The Rockefeller University is a private university offering postgraduate and postdoctoral education. It has a strong concentration in the biological sciences. It is also known for producing numerous Nobel laureates...

 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.

In the Brain

Gross anatomy

The neurons of the raphe nuclei
Raphe nuclei
The raphe nuclei are a moderate-size cluster of nuclei found in the brain stem. Their main function is to release serotonin to the rest of the brain...

 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
Reticular formation
The reticular formation is a part of the brain that is involved in actions such as awaking/sleeping cycle, and filtering incoming stimuli to discriminate irrelevant background stimuli...

.
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
Raphe nuclei
The raphe nuclei are a moderate-size cluster of nuclei found in the brain stem. Their main function is to release serotonin to the rest of the brain...

 terminate in the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...

 and spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

, 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 receptor
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...

s located on the dendrite
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...

s, cell bodies and presynaptic terminals of adjacent neurons.

Receptors

The 5-HT receptor
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...

s are the receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

 for serotonin. They are located on the cell membrane of nerve cells
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

 and other cell types in animals, and mediate the effects of serotonin as the endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...

 ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

 and of a broad range of pharmaceutical and hallucinogenic drugs
Psychedelics, dissociatives and deliriants
This general group of pharmacological agents can be divided into three broad categories: psychedelics, dissociatives, and deliriants. These classes of psychoactive drugs have in common that they can cause subjective changes in perception, thought, emotion and consciousness...

. With the exception of the 5-HT3 receptor, a ligand-gated ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...

, all other 5-HT receptors are G protein-coupled, seven transmembrane (or heptahelical) receptors that activate an intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...

 second messenger cascade.

Termination

Serotonergic action is terminated primarily via uptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....

 of 5-HT from the synapse. This is accomplished through the specific monoamine transporter
Monoamine transporter
Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...

 for 5-HT, SERT
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...

, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including MDMA (ecstasy), amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...

, cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

, dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...

 (an antitussive), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...

s (SSRIs).
Interestingly, a 2006 study conducted by the University of Washington
University of Washington
University of Washington is a public research university, founded in 1861 in Seattle, Washington, United States. The UW is the largest university in the Northwest and the oldest public university on the West Coast. The university has three campuses, with its largest campus in the University...

 suggested a newly discovered monoamine transporter, known as PMAT
Plasma membrane monoamine transporter
The plasma membrane monoamine transporter is a low-affinity monoamine transporter protein. It is also known as human equilibrative nucleoside transporter-4...

, 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 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
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...

 and sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...

, inhibit PMAT but at IC50
IC50
The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half...

 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 Km values even higher than that of 5-HT (330–15,000 μmoles/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 GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...

s that then trigger the release of vesicle contents by exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...

. A similar process underlies the pancreatic release of insulin.
The effects of serotonin upon vascular smooth muscle "tone" (this is the biological function from which serotonin originally got its name) depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.

Biosynthesis

In animals including humans, serotonin is synthesized
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...

 from the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 L-tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...

 by a short metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...

 consisting of two enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s: tryptophan hydroxylase
Tryptophan hydroxylase
Tryptophan hydroxylase is an enzyme involved in the synthesis of the neurotransmitter serotonin. TPH catalyzes the following chemical reactionIt employs one cofactor, iron.- Function :...

 (TPH) and amino acid decarboxylase
Aromatic L-amino acid decarboxylase
Aromatic L-amino acid decarboxylase is a lyase enzyme.-Reactions:It catalyzes several different decarboxylation reactions:* L-DOPA to dopamine - a neurotransmitter* 5-HTP to serotonin - also a neurotransmitter...

 (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway.
TPH has been shown to exist in two forms: TPH1
TPH1
Tryptophan hydroxylase 1 , also known as TPH1, is an enzyme which in humans is encoded by the TPH1 gene.Until 2003 it was thought that there only was a single TPH gene, but then...

, found in several tissues
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...

, and TPH2
TPH2
The enzyme Tryptophan hydroxylase 2, also known as TPH2, is an isozyme of Tryptophan hydroxylase found in vertebrates. In humans TPH2 is primarily expressed in the serotonergic neurons of the brain, with the highest expression in the raphe nucleus of the midbrain...

, which is a brain-specific isoform
Protein isoform
A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...

.

Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system, because it does not cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

. However, tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...

 and its metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...

 5-hydroxytryptophan
5-Hydroxytryptophan
5-Hydroxytryptophan , also known as oxitriptan , is a naturally occurring amino acid and chemical precursor as well as metabolic intermediate in the biosynthesis of the neurotransmitters serotonin and melatonin from tryptophan....

 (5-HTP), from which serotonin is synthesized, can and does cross the blood-brain barrier. These agents are available as dietary supplement
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...

s, and may be effective serotonergic agents.
One product of serotonin breakdown is 5-hydroxyindoleacetic acid
5-Hydroxyindoleacetic acid
5-Hydroxyindoleacetic acid is the main metabolite of serotonin in the human body. In chemical analysis of urine samples, 5-HIAA is used to determine the body's levels of serotonin.- Clinical significance :...

 (5 HIAA), which is excreted in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

s or cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

s, 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
DRUGS
Destroy Rebuild Until God Shows are an American post-hardcore band formed in 2010. They released their debut self-titled album on February 22, 2011.- Formation :...

 target the 5-HT system, including some antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...

s, antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...

s, anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...

s, antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....

s, and antimigraine drugs
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...

, as well as the psychedelic drug
Psychedelic drug
A psychedelic substance is a psychoactive drug whose primary action is to alter cognition and perception. Psychedelics are part of a wider class of psychoactive drugs known as hallucinogens, a class that also includes related substances such as dissociatives and deliriants...

s and empathogens.

Psychedelic drugs

The psychedelic drug
Psychedelic drug
A psychedelic substance is a psychoactive drug whose primary action is to alter cognition and perception. Psychedelics are part of a wider class of psychoactive drugs known as hallucinogens, a class that also includes related substances such as dissociatives and deliriants...

s psilocin
Psilocin
Psilocin , an aromatic compound, sometimes also spelled psilocine, psilocyn, or psilotsin, is a psychedelic mushroom alkaloid. It is found in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin...

/psilocybin
Psilocybin
Psilocybin is a naturally occurring psychedelic prodrug, with mind-altering effects similar to those of LSD and mescaline, after it is converted to psilocin. The effects can include altered thinking processes, perceptual distortions, an altered sense of time, and spiritual experiences, as well as...

, DMT
Dimethyltryptamine
N,N-Dimethyltryptamine is a naturally occurring psychedelic compound of the tryptamine family. DMT is found in several plants, and also in trace amounts in humans and other mammals, where it is originally derived from the essential amino acid tryptophan, and ultimately produced by the enzyme INMT...

, mescaline
Mescaline
Mescaline or 3,4,5-trimethoxyphenethylamine is a naturally occurring psychedelic alkaloid of the phenethylamine class used mainly as an entheogen....

, and LSD
LSD
Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...

 are agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...

s, primarily at 5HT2A
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...

/2C receptors. The empathogen-entactogen
Empathogen-entactogen
The terms empathogen and entactogen are used to describe a class of psychoactive drugs that produce distinctive emotional and social effects similar to those of MDMA. Putative members of this class include 2C-B, 2C-I, MDMA, MDA, MDEA, MBDB, 2C-T-7, and 2C-T-2, among others...

 MDMA (ecstasy) and Mephedrone, also known as 4-methylmethcathinone
4-Methylmethcathinone
Mephedrone, also known as 4-methylmethcathinone , or 4-methylephedrone, is a synthetic stimulant and entactogen drug of the amphetamine and cathinone classes. Slang names include meph, drone, and MCAT. It is reportedly manufactured in China and is chemically similar to the cathinone compounds found...

, or 4-methylephedrone release serotonin from synaptic vesicles of neurons.

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
Social anxiety disorder
Social anxiety disorder , also known as social phobia, is an anxiety disorder characterized by intense fear in social situations causing considerable distress and impaired ability to function in at least some parts of daily life...

. Monoamine oxidase inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....

s (MAOI) prevent the breakdown of monoamine neurotransmitter
Monoamine neurotransmitter
thumb|right|350px| A phylogenetic tree showing how a number of monoamine receptors are related to each other.Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain...

s (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
Hypertensive emergency
Malignant hypertension or hypertensive emergency is severe hypertension with acute impairment of an organ system and the possibility of irreversible organ-damage...

 triggered by foods with high tyramine
Tyramine
Tyramine is a naturally occurring monoamine compound and trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent...

 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
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

. 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
Tianeptine
Tianeptine was discovered by The French Society of Medical Research in the 1960s. Under the trade-names it is a drug used for treating major depressive episodes ....

, 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
5-HTTLPR
5-HTTLPR is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter.Since the polymorphism was identified in the middle of the 1990s,...

 gene codes for the number of serotonin transporters in the brain, with more serotonin transporters causing decreased duration and magnitude of serotonergic signaling. The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety. Therefore, increasing levels of extracellular serotonin may be associated with increased affect
Affect
When used as a descriptor or adjective, affect means to change, and usually refers to an emotion or symptom. Affected, when used in a description, refers to fake or intentionally assumed behaviour , i.e., an affected accent...

, 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
Ultimatum game
The ultimatum game is a game often played in economic experiments in which two players interact to decide how to divide a sum of money that is given to them. The first player proposes how to divide the sum between the two players, and the second player can either accept or reject this proposal. ...

, 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
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...

, 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
5-HT3 antagonist
The 5-HT3 antagonists are a class of medications that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain....

, such as ondansetron
Ondansetron
Ondansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...

, granisetron
Granisetron
Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect...

, and tropisetron
Tropisetron
Tropisetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia. The drug is available in a 5 mg oral preparation or in 2 mg...

, are important antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....

 agents. They are particularly important in treating the nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

 and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

 that occur during anticancer chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

 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. Selective serotonin reuptake inhibitors (SSRIs) have been found to be toxic to algae. The gastrointestinal parasite Entamoeba histolytica
Entamoeba histolytica
Entamoeba histolytica is an anaerobic parasitic protozoan, part of the genus Entamoeba. Predominantly infecting humans and other primates, E. histolytica is estimated to infect about 50 million people worldwide...

secretes serotonin, causing a sustained secretory diarrhea in some patients. Patients infected with E. histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection. E. histolytica also responds to the presence of serotonin by becoming more virulent. This means serotonin secretion not only serves to increase the spread of enteamoebas by giving the host diarrhea, but also to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing
Quorum sensing
Quorum sensing is a system of stimulus and response correlated to population density. Many species of bacteria use quorum sensing to coordinate gene expression according to the density of their local population. In similar fashion, some social insects use quorum sensing to determine where to nest...

. 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 in order 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
SEEDS
SEEDS is a voluntary organisation registered under the Societies Act of India....

 serotonin production is a way to get rid of the buildup of poisonous ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...

. The ammonia is collected and placed in the indole
Indole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...

 part of L-tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...

, which is then decarboxylated
Decarboxylation
Decarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...

 by tryptophan decarboxylase
Aromatic L-amino acid decarboxylase
Aromatic L-amino acid decarboxylase is a lyase enzyme.-Reactions:It catalyzes several different decarboxylation reactions:* L-DOPA to dopamine - a neurotransmitter* 5-HTP to serotonin - also a neurotransmitter...

 to give tryptamine, which is then hydroxylated
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...

 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 mushroom
Mushroom
A mushroom is the fleshy, spore-bearing fruiting body of a fungus, typically produced above ground on soil or on its food source. The standard for the name "mushroom" is the cultivated white button mushroom, Agaricus bisporus; hence the word "mushroom" is most often applied to those fungi that...

s, fruits and vegetable
Vegetable
The noun vegetable usually means an edible plant or part of a plant other than a sweet fruit or seed. This typically means the leaf, stem, or root of a plant....

s. The highest values of 25–400 mg/kg have been found in nuts of the walnut
Walnut
Juglans is a plant genus of the family Juglandaceae, the seeds of which are known as walnuts. They are deciduous trees, 10–40 meters tall , with pinnate leaves 200–900 millimetres long , with 5–25 leaflets; the shoots have chambered pith, a character shared with the wingnuts , but not the hickories...

 (Juglans) and hickory
Hickory
Trees in the genus Carya are commonly known as hickory, derived from the Powhatan language of Virginia. The genus includes 17–19 species of deciduous trees with pinnately compound leaves and big nuts...

 (Carya) genera. Serotonin concentrations of 3–30 mg/kg have been found in plantain
Plantain
Plantain is the common name for herbaceous plants of the genus Musa. The fruit they produce is generally used for cooking, in contrast to the soft, sweet banana...

, pineapple
Pineapple
Pineapple is the common name for a tropical plant and its edible fruit, which is actually a multiple fruit consisting of coalesced berries. It was given the name pineapple due to its resemblance to a pine cone. The pineapple is by far the most economically important plant in the Bromeliaceae...

, banana
Banana
Banana is the common name for herbaceous plants of the genus Musa and for the fruit they produce. Bananas come in a variety of sizes and colors when ripe, including yellow, purple, and red....

, kiwifruit
Kiwifruit
The kiwifruit, often shortened to kiwi in many parts of the world, is the edible berry of a cultivar group of the woody vine Actinidia deliciosa and hybrids between this and other species in the genus Actinidia....

, plum
Plum
A plum or gage is a stone fruit tree in the genus Prunus, subgenus Prunus. The subgenus is distinguished from other subgenera in the shoots having a terminal bud and solitary side buds , the flowers in groups of one to five together on short stems, and the fruit having a groove running down one...

s, and tomato
Tomato
The word "tomato" may refer to the plant or the edible, typically red, fruit which it bears. Originating in South America, the tomato was spread around the world following the Spanish colonization of the Americas, and its many varieties are now widely grown, often in greenhouses in cooler...

es. 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 nettle
Stinging nettle
Stinging nettle or common nettle, Urtica dioica, is a herbaceous perennial flowering plant, native to Europe, Asia, northern Africa, and North America, and is the best-known member of the nettle genus Urtica...

s (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
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

, 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 tryptamine
Tryptamine
Tryptamine is a monoamine alkaloid found in plants, fungi, and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived...

s that are methylated
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...

 at the amino
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...

 (NH2) and (OH) groups
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...

, are N-oxides
Amine oxide
An amine oxide, also known as amine-N-oxide and N-oxide, is a chemical compound that contains the functional group R3N+-O−, an N-O bond with three additional hydrogen and/or hydrocarbon side chains attached to N. Sometimes it is written as R3N→O or, wrongly, as R3N=O.In the strict sense the...

, 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
Anadenanthera
Anadenanthera is a genus of South American trees in the Legume family, Fabaceae. The genus contains two to four species, including A. colubrina and A. peregrina...

genus that are used in the hallucinogenic yopo
Yopo
"Ebene" redirects here. For the city in Mauritius, see Ebene City.Anadenanthera peregrina, also known as Yopo, Jopo, Cohoba, Mopo, Nopo, Parica or Calcium Tree, is a perennial tree of the Anadenanthera genus native to the Caribbean and South America. It grows up to 20 m tall, having a thorny bark...

 snuff. These compounds are widely present in the leaves of many plants, and may serve as deterrents for animal ingestion.

History

In 1935, Italian Vittorio Erspamer
Vittorio Erspamer
Vittorio Erspamer was an Italian pharmacologist and chemist, known for the identification, synthesis and pharmacological studies of more than sixty new chemical compounds, most notably serotonin and octopamine.-Biography:...

 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
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...

, which he named enteramine. In 1948, Maurice M. Rapport
Maurice M. Rapport
Maurice M. Rapport was leading biochemist who described the structure of serotonin...

, Arda Green, and Irvine Page
Irvine Page
Irvine Heinly Page was born in Indianapolis, Indiana and was an American physiologist who played an important part in the field of hypertension for almost 60 years....

 of the Cleveland Clinic
Cleveland Clinic
The Cleveland Clinic is a multispecialty academic medical center located in Cleveland, Ohio, United States. The Cleveland Clinic is currently regarded as one of the top 4 hospitals in the United States as rated by U.S. News & World Report...

 discovered a vasoconstrictor substance in blood serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

, and since it was a serum agent affecting vascular tone, they named it serotonin. In 1952 it was shown that enteramine was the same substance as serotonin, and as the broad range of physiological roles were elucidated, the abbreviation 5HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field.

External links

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