~ a monoamine neurotransmitter, biochemically derived from 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
. Only the L-stereoisomer of tryptophan is used in structural or enzyme proteins, but the D-stereoisomer is occasionally found in naturally produced peptides (for example, the marine venom peptide contryphan).
The distinguishing structural characteristic of tryptophan is that it contains an indole functional group. It is an essential amino acid as defined by its growth effects on rats.
that is primarily found in the gastrointestinal (GI) tract, platelets, and central nervous system (CNS) of humans and animals.Approximately 80 percent of the
human body's total serotonin is located
in the enterochromaffin cells in the gut
, where it is used to regulate intestinal movements. The remainder is synthesized
in serotonergic neurons in the CNS where it has various functions, including the regulation of mood, appetite, sleep, muscle contraction, and some cognitive functions including memory and learning.
Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.
Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing.
Serotonin is eventually metabolized
to 5-HIAA by the liver
, and excreted by the kidneys. One type of tumor, called carcinoid, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing
, diarrhea, and heart problems. In addition to animals, serotonin is also found in fungi and plants
. 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 has been used as a neurotransmitter since very early in nerve system evolution, and is found in all bilateral animals
where it mediates gut movements and the animal's perception of resource
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. Gauge of food availability
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. 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. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals.
The reason for this is that 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 receptors predominates in subordinate animals while 5-HT2 receptors 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 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 surface.
Studies have revealed that 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, and the effect of this variation was found to interact with the environment in depression.Effects on growth and reproduction
Serotonin is necessary for normal male mating behavior, and the inclination to leave food to search for a mate.
In humans though insulin regulates blood sugar(dostupnost) and IGF regulates growth(nadogradnja), 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. Serotonin present in the blood then stimulates cellular growth to repair liver damage.5HT2B receptors also activate osteoblasts, which build up bone. However, serotonin also activates osteoclasts, which degrade bone.Cardiovascular growth factorIn 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, as well as cardiac valve fibrosis. In the past, three groups of serotonergic drugs have been epidemiologically linked with these syndromes. Local effects of injection: venoms and painSince 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.
(otrov ose je osam puta jaci od otrova najotrovnije zmije na svijetu, ali je kolicinski naravno puno manji)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 that lack 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.
(vece kolektivno polje i kriticna masa)
Normally the mother weans the litter for 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.In humans, defective signaling of serotonin in the brain may be the root cause of sudden infant death syndrome
. 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
Serotonin is released into the space between neurons, and diffuses over a relatively wide gap
(>20 µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.Receptors
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. SerotonylationSerotonin can also signal through a nonreceptor mechanism called serotonylation.
In this serotonin modifies proteins. This process underlies serotonin effects upon thrombocyte cells in which it links to the modification of signaling enzymes 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.BiosynthesisSerotonin 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. Drugs targeting the 5-HT system
Several classes of drugs target the 5-HT system including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs as well as the psychedelic drugs and empathogens.Psychedelic drugs
The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD are agonists primarily at 5HT2A/2C receptors. The Empathogen-entactogen MDMA (ecstasy) releases serotonin from synaptic vesicles of neurons.AntidepressantsThe 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 re-uptake of serotonin, making it stay in the synapse longer. The tricyclic antidepressants (TCAs) inhibit the re-uptake of both serotonin and norepinephrine. The newer selective serotonin re-uptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs. The side effects that have become apparent in recent times 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 SSRI's 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.
Although phobias and depression might be attenuated by serotonin-altering-drugs this does not mean that 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.In unicellular organisms
Patients infected with Entamoeba histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection. Entamoeba histolytica also responds to the presence of serotonin by becoming more virulent. This means that the 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. In plants
In drying seeds serotonin production is a way to get rid of the buildup of poisonous ammonia. The ammonia is collected and placed in the indole part of L-tryptophan, which is then decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by a cytochrome P450 monooxygenase, yielding serotonin.However, since serotonin is a major gastrointestinal tract modulator, it may be produced by plants in fuits 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).(Kopriva!!)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.