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Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and
vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...
. Approximately 90% of the serotonin that the body produces is in the intestinal tract. Biochemically, the indoleamine molecule derives from the amino acid tryptophan, via the (rate-limiting)
hydroxylation In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...
of the 5 position on the ring (forming the intermediate
5-hydroxytryptophan 5-Hydroxytryptophan (5-HTP), also known as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin. Uses 5-HTP is sold over the cou ...
), and then decarboxylation to produce serotonin. Serotonin is primarily found in the enteric nervous system located in the gastrointestinal tract (GI tract). However, it is also produced in the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS), specifically in the raphe nuclei located in the brainstem, Merkel cells located in the skin, pulmonary neuroendocrine cells and taste receptor cells in the tongue. Additionally, serotonin is stored in blood platelets and is released during agitation and vasoconstriction, where it then acts as an
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...
to other platelets. Approximately 90% of the
human body The human body is the structure of a human being. It is composed of many different types of cells that together create tissues and subsequently organ systems. They ensure homeostasis and the viability of the human body. It comprises a hea ...
's total serotonin is located in the enterochromaffin cells in the GI tract, where it regulates intestinal movements. About 8% is found in platelets and 1–2% in the CNS. The serotonin is secreted luminally and basolaterally, which leads to increased serotonin uptake by circulating platelets and activation after stimulation, which gives increased stimulation of
myenteric The myenteric plexus (or Auerbach's plexus) provides motor innervation to both layers of the muscular layer of the gut, having both parasympathetic and sympathetic input (although present ganglion cell bodies belong to parasympathetic innervation ...
neurons and gastrointestinal motility. The remainder is synthesized in serotonergic
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s of the CNS, where it has various functions. These include the regulation of mood, appetite, and
sleep Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited Perception, sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefuln ...
. Serotonin also has some cognitive functions, including memory and learning. Several classes of antidepressants, such as the
SSRIs Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracellu ...
and the SNRIs among others, interfere with the normal reabsorption of serotonin after it is done with the transmission of the signal, therefore augmenting the neurotransmitter levels in the synapses. 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 release serotonin, where it can serve as a
vasoconstrictor Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...
or a vasodilator while regulating
hemostasis In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulatio ...
and blood clotting. In high concentrations, serotonin acts as a vasoconstrictor by contracting endothelial smooth muscle directly or by potentiating the effects of other vasoconstrictors (e.g. angiotensin II, norepinephrine). The vasoconstrictive property is mostly seen in pathologic states affecting the endotheliumsuch as atherosclerosis or chronic hypertension. In physiologic states, vasodilation occurs through the serotonin mediated release of nitric oxide from endothelial cells. Additionally, it inhibits the release of norepinephrine from adrenergic nerves. Serotonin is also a growth factor for some types of cells, which may give it a role in wound healing. There are various serotonin receptors. Serotonin is metabolized mainly to
5-HIAA 5-Hydroxyindoleacetic acid (5-HIAA) is the main metabolite of serotonin. In chemical analysis of urine samples, 5-HIAA is used to determine serotonin levels in the body. Clinical significance 5-HIAA is tested by 24-hour urine samples combined ...
, chiefly by the liver. Metabolism involves first
oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or ...
by monoamine oxidase to the corresponding
aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl gro ...
. The rate-limiting step is hydride transfer from serotonin to the flavin cofactor. There follows oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic-acid derivative. The latter is then excreted by the kidneys. Besides mammals, serotonin is found in all
bilateral animals The Bilateria or bilaterians are animals with bilateral symmetry as an embryo, i.e. having a left and a right side that are mirror images of each other. This also means they have a head and a tail (anterior-posterior axis) as well as a belly and ...
including worms and insects, as well as in
fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately fr ...
and in
plant Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae excl ...
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 amoebae, and its effect in the human gut is
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.


Biological role

Serotonin is involved in numerous physiological processes, including
sleep Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited Perception, sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefuln ...
,
thermoregulation Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperatur ...
, learning and
memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remember ...
,
pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
, (social) behavior, sex, feeding, motor activity, biological rhythms and possibly others. In less complex animals, such as some
invertebrates Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordat ...
, serotonin regulates feeding and other processes. In plants serotonin synthesis seems to be associated with stress signals.


Cellular effects

Serotonin primarily acts through its receptors and its effects depend on which cells and tissues express these receptors (see below).


Receptors

The
5-HT receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory n ...
s, the receptors for serotonin, are located on the cell membrane of
nerve cells A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
and other cell types in animals, and mediate the effects of serotonin as the
endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, ...
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...
and of a broad range of pharmaceutical and psychedelic drugs. Except for the 5-HT3 receptor, a ligand-gated
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...
, all other 5-HT receptors are G-protein-coupled receptors (also called seven-transmembrane, or heptahelical receptors) that activate an intracellular second messenger cascade.


Termination

Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including
cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...
,
dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with b ...
(an antitussive), tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). A 2006 study conducted by the
University of Washington The University of Washington (UW, simply Washington, or informally U-Dub) is a public research university in Seattle, Washington. Founded in 1861, Washington is one of the oldest universities on the West Coast; it was established in Seatt ...
suggested that a newly discovered monoamine transporter, known as PMAT, may account for "a significant percentage of 5-HT clearance". Contrasting with the high-affinity SERT, the PMAT has been identified as a low-affinity transporter, with an apparent 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 and
sertraline Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the diffe ...
anti-depressants, inhibit PMAT but at IC50 values which surpass the therapeutic plasma concentrations by up to four orders of magnitude. Therefore, SSRI monotherapy is "ineffective" in PMAT inhibition. At present, no known pharmaceuticals are known to 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's effects upon platelet-forming cells ( thrombocytes) in which it links to the modification of signaling enzymes called GTPases that then trigger the release of vesicle contents by exocytosis. A similar process underlies the pancreatic release of insulin. The effects of serotonin upon vascular smooth muscle tonethe biological function after which serotonin was originally nameddepend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.


Nervous system

The neurons of the raphe nuclei are the principal source of 5-HT release in the brain. There are nine raphe nuclei, designated B1–B9, which contain the majority of serotonin-containing neurons (some scientists chose to group the ''nuclei raphes lineares'' into one nucleus), all of which are located along the midline of the brainstem, and centered on the
reticular formation The reticular formation is a set of interconnected nuclei that are located throughout the brainstem. It is not anatomically well defined, because it includes neurons located in different parts of the brain. The neurons of the reticular formatio ...
. Axons from the neurons of the raphe nuclei form a
neurotransmitter system A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...
reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
, while the axons of the higher nuclei spread out in the entire brain.


Ultrastructure and function

The serotonin nuclei may also be divided into two main groups, the rostral and caudal containing three and four nuclei respectively. The rostral group consists of the caudal linear nuclei (B8), the dorsal raphe nuclei (B6 and B7) and the median raphe nuclei (B5, B8 and B9), that project into multiple cortical and subcortical structures. The caudal group consists of the nucleus raphe magnus (B3), raphe obscurus nucleus (B2), raphe pallidus nucleus (B1), and lateral medullary reticular formation, that project into the brainstem. The serotonergic pathway is involved in sensorimotor function, with pathways projecting both into cortical (Dorsal and Median Raphe Nuclei), subcortical, and spinal areas involved in motor activity. Pharmacological manipulation suggests that serotonergic activity increases with motor activity while firing rates of serotonergic neurons increase with intense visual stimuli. Animal models suggest that kainate signaling negatively regulates serotonin actions in the retina, with possible implications for the control of the visual system. The descending projections form a pathway that inhibits pain called the "descending inhibitory pathway" that may be relevant to a disorder such as fibromyalgia, migraine, and other pain disorders, and the efficacy of antidepressants in them. Serotonergic projections from the caudal nuclei are involved in regulating mood and emotion, and hypo- or hyper-serotonergic states may be involved in depression and sickness behavior.


Microanatomy

Serotonin is released into the synapse, or space between neurons, and diffuses over a relatively wide gap (>20 nm) to activate
5-HT receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory n ...
s located on the
dendrite Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the ...
s, cell bodies, and presynaptic terminals of adjacent neurons. When humans smell food, dopamine is released to increase the appetite. But, unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs that block 5-HT2C receptors make the body unable to recognize when it is no longer hungry or otherwise in need of nutrients, and are associated with weight gain, especially in people with a low number of receptors. The expression of 5-HT2C receptors in the
hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...
follows a
diurnal rhythm A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...
, just as the serotonin release in the
ventromedial nucleus The ventromedial nucleus of the hypothalamus (VMN, also sometimes referred to as the ventromedial hypothalamus, VMH) is a nucleus of the hypothalamus. "The ventromedial hypothalamus (VMH) is a distinct morphological nucleus involved in terminati ...
, which is characterised by a peak at morning when the motivation to eat is strongest. In macaques, alpha males have twice the level of serotonin in the brain as subordinate males and females (measured by the concentration of
5-HIAA 5-Hydroxyindoleacetic acid (5-HIAA) is the main metabolite of serotonin. In chemical analysis of urine samples, 5-HIAA is used to determine serotonin levels in the body. Clinical significance 5-HIAA is tested by 24-hour urine samples combined ...
in the
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...
(CSF)). Dominance status and CSF serotonin levels appear to be positively correlated. When dominant males were removed from such groups, subordinate males begin competing for dominance. Once new dominance hierarchies were established, serotonin levels of the new dominant individuals also increased to double those in subordinate males and females. The reason why serotonin levels are only high in dominant males, but not dominant females has not yet been established. In humans, levels of 5-HT1A receptor inhibition 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. Serotonin in the brain is not usually degraded after use, but is collected by serotonergic neurons by serotonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy.


Psychological influences

Serotonin has been implicated in cognition, mood, anxiety and psychosis, but strong clarity has not been achieved.


Autism spectrum disorder (ASD)

In regards to research for neurotransmitters and effects on patients with Autism Spectrum Disorder (ASD), 5-HT has been studied the most in terms of research efforts and investigations. As noted, 5-HT signaling does facilitate many neural processes including that of neurogenesis, cell migration and survival, synaptogenesis, and synaptic plasticity. It was noted that 45% of tested ASD subjects contained high levels of 5-HT in their blood. In addition, investigations performed on ASD-like animal models reported that hyperserotonemia significantly reduced the motivation for social interest through inhibition of separation distress, which could be related in the ASD patients that have social impairments.


Outside the nervous system


In the digestive tract (emetic)

Serotonin regulates gastrointestinal function. 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. There are often serotonin abnormalities in gastrointestinal disorders such as constipation and irritable bowel syndrome. 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 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 5-HT3 receptors in the chemoreceptor trigger zone that stimulate
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...
. Thus, drugs and toxins stimulate serotonin release from enterochromaffin cells in the gut wall. The enterochromaffin cells not only react to bad food but are also very sensitive to irradiation and
cancer chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothera ...
. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.


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 very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through 5-HT1B receptors, it negatively regulates bone mass, while it does so positively through 5-HT2B receptors and 5-HT2C receptors. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events. Very recently following the seminal finidings that gut serotonin regulates bone mass in 2008, the mechanistic investigations into what regulates serotonin synthesis from the gut in the regulation of bone mass have started. Piezo1 has been shown to sense RNA in the gut and relay this information through serotonin synthesis to the bone. This study by Sugisawa et al., showed that cation channel Piezo1 in the gut acts as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse ''Piezo1'' profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of ''Piezo1'' increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders. These studies of Yadav et al., Cell 2008, Nat Med 2010 and more recently Sugisawa et al., Cell 2019 have opened a new area of serotonin research in bone metabolism that can be potentially harnessed to treat bone mass disorders.


Organ development

Since serotonin signals resource availability it is not surprising that it affects organ development. Many human and animal studies have shown that nutrition in early life can influence, in adulthood, such things as body fatness, blood lipids, blood pressure, atherosclerosis, behavior, learning, and longevity. Rodent experiment shows that neonatal exposure to SSRIs makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants. By treating normal and knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period. Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors, mediating liver compensatory regrowth (see ) Serotonin present in the blood then stimulates cellular growth to repair liver damage. 5HT2B receptors also activate osteocytes, which build up bone However, serotonin also inhibits
osteoblast Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
s, through 5-HT1B receptors. *


Cardiovascular growth factor

Serotonin, in addition, evokes
endothelial The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
nitric oxide synthase Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and perist ...
activation and stimulates, through a 5-HT1B receptor-mediated 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.


Skin

Serotonin is also produced by
Merkel cell Merkel cells, also known as Merkel-Ranvier cells or tactile epithelial cells, are oval-shaped mechanoreceptors essential for light touch sensation and found in the skin of vertebrates. They are abundant in highly sensitive skin like that of the f ...
s which are part of the somatosensory system.


Lungs

Pulmonary neuroendocrine cells are specialized
epithelial cells Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
that occur as solitary cells or as clusters called neuroepithelial bodies in the lung. Pulmonary neuroendocrine cells are also known as ''Kulchitsky cells'' or ''K cells''.


Pharmacology

Several classes of drugs target the 5-HT system, including some antidepressants,
antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of ...
s, anxiolytics, antiemetics, and
antimigraine drugs Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks. Treatment of acute sy ...
, as well as, the
psychedelic drug Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips").Pollan, Michael (2018). ''How to Change Your Mind: What the New Science o ...
s and empathogens.


Mechanism of action

At rest, serotonin is stored within the vesicles of presynaptic neurons. When stimulated by nerve impulses, serotonin is released as a neurotransmitter into the synapse, reversibly binding to the postsynaptic receptor to induce a nerve impulse on the postsynaptic neuron. Serotonin can also bind to auto-receptors on the presynaptic neuron to regulate the synthesis and release of serotonin. Normally serotonin is taken back into the presynaptic neuron to stop its action, then reused or broken down by monoamine oxidase.


Psychedelic drugs

The serotonergic psychedelic drugs psilocin/ psilocybin,
DMT ''N'',''N''-Dimethyltryptamine (DMT or ''N'',''N''-DMT, SPL026) is a substituted tryptamine that occurs in many plants and animals, including human beings, and which is both a derivative and a structural analog of tryptamine. It is used as a ...
, mescaline, psychedelic mushroom and LSD are
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...
s, primarily at 5HT2A/ 2C receptors. The empathogen-entactogen
MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for recreational purposes. The desire ...
releases serotonin from synaptic vesicles of neurons.


Antidepressants

Drugs that alter serotonin levels are used in treating depression, generalized anxiety disorder, and social phobia. Monoamine oxidase inhibitors (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 synaptic cleft longer. The tricyclic antidepressants (TCAs) inhibit the reuptake of both serotonin and
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...
. The newer selective serotonin reuptake inhibitors ( SSRIs) have fewer side-effects and fewer interactions with other drugs. Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases. The ''
5-HTTLPR 5-HTTLPR (serotonin-transporter-linked promoter region) 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, it has been exten ...
'' 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.


Serotonin syndrome

Extremely high levels of serotonin can cause a condition known as serotonin syndrome, with toxic and potentially fatal effects. In practice, such toxic levels are essentially impossible to reach through an overdose of a single antidepressant drug, but require a combination of serotonergic agents, such as an SSRI with a MAOI, which may occur in therapeutic doses. The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at nontoxic levels. It is estimated that 14% of patients experiencing serotonin syndrome overdose on SSRIs; meanwhile the fatality rate is between 2% to 12%.


Antiemetics

Some 5-HT3 antagonists, such as ondansetron,
granisetron Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy and radiotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the ...
, and tropisetron, are important antiemetic agents. They are particularly important in treating the
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
and
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...
that occur during anticancer chemotherapy using
cytotoxic drugs Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
. Another application is in the treatment of postoperative nausea and vomiting.


Other

Some serotonergic agonist drugs 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. These are the serotonergic vasoconstrictive antimigraine drugs ( ergotamine and methysergide), the serotonergic appetite suppressant drugs (
fenfluramine Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome.https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212102s003l ...
, chlorphentermine, and
aminorex Aminorex (Menocil, Apiquel, aminoxaphen, aminoxafen, McN-742) is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension. In the U.S., it is an illegal Schedule I drug, mea ...
), and certain anti-Parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific
lisuride Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth. Side effects of lis ...
. As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was declining in use since it was reported in 2003 to be associated with cardiac fibrosis. Two independent studies published in ''
The New England Journal of Medicine ''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one. H ...
'' in January 2007 implicated pergolide, along with cabergoline, in causing valvular heart disease. As a result of this, the FDA removed pergolide from the United States market in March 2007. (Since cabergoline is not approved in the United States 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).


Methyl-tryptamines and hallucinogens

Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH2) and (OH) groups, are ''N''-oxides, or miss the OH group. These compounds do reach the brain, although some portion of them are metabolized by monoamine oxidase enzymes (mainly MAO-A) in the liver. Examples are plants from the genus '' Anadenanthera'' that are used in the hallucinogenic
yopo ''Anadenanthera peregrina'', also known as yopo, jopo, cohoba, parica or calcium tree, is a perennial tree of the genus ''Anadenanthera'' native to the Caribbean and South America. It grows up to tall, and has a horny bark. Its flowers grow ...
snuff. These compounds are widely present in the leaves of many plants, and may serve as deterrents for animal ingestion. Serotonin occurs in several mushrooms of the genus ''
Panaeolus ''Panaeolus'' is a genus of small, black-spored, saprotrophic agarics. The word ''Panaeolus'' is Greek for "all variegated", alluding to the spotted gills of the mushrooms produced. Characteristics These fungi are mostly dung and grasslan ...
''.


Comparative biology and evolution


Unicellular organisms

Serotonin is used by a variety of single-cell organisms for various purposes.
SSRIs Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracellu ...
have been found to be toxic to algae. The gastrointestinal parasite '' Entamoeba histolytica'' secretes serotonin, causing a sustained secretory diarrhea in some people. 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 serves to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing. Outside the gut of a host, there is nothing that the entoamoebas provoke to release serotonin, hence the serotonin concentration is very low. Low serotonin signals to the entoamoebas they are outside a host and they become less virulent to conserve energy. When they enter a new host, they multiply in the gut, and become more virulent as the enterochromaffine cells get provoked by them and the serotonin concentration increases.


Edible plants and mushrooms

In drying
seed A seed is an embryonic plant enclosed in a protective outer covering, along with a food reserve. The formation of the seed is a part of the process of reproduction in seed plants, the spermatophytes, including the gymnosperm and angiosper ...
s, serotonin production is a way to get rid of the buildup of poisonous
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous ...
. The ammonia is collected and placed in the indole part of L- tryptophan, which is then
decarboxylated Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...
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 in the fruits of plants 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,
fruit In botany, a fruit is the seed-bearing structure in flowering plants that is formed from the ovary after flowering. Fruits are the means by which flowering plants (also known as angiosperms) disseminate their seeds. Edible fruits in partic ...
s, 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
plantains Plantain may refer to: Plants and fruits * Cooking banana, banana cultivars in the genus ''Musa'' whose fruits are generally used in cooking ** True plantains, a group of cultivars of the genus ''Musa'' * ''Plantaginaceae'', a family of floweri ...
,
pineapple The pineapple (''Ananas comosus'') is a tropical plant with an edible fruit; it is the most economically significant plant in the family Bromeliaceae. The pineapple is indigenous to South America, where it has been cultivated for many centuri ...
s, banana,
kiwifruit Kiwifruit (often shortened to kiwi in North American, British and continental European English) or Chinese gooseberry is the edible berry of several species of woody vines in the genus ''Actinidia''. The most common cultivar group of kiwif ...
,
plum A plum is a fruit of some species in ''Prunus'' subg. ''Prunus'.'' Dried plums are called prunes. History Plums may have been one of the first fruits domesticated by humans. Three of the most abundantly cultivated species are not found ...
s, and
tomato The tomato is the edible berry of the plant ''Solanum lycopersicum'', commonly known as the tomato plant. The species originated in western South America, Mexico, and Central America. The Mexican Nahuatl word gave rise to the Spanish word ...
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 nettles (''Urtica dioica''), where it causes pain on injection in the same manner as its presence in insect venoms (see below). It is also naturally found in ''
Paramuricea clavata ''Paramuricea clavata'', the violescent sea-whip, is a species of colonial soft coral in the family Plexauridae. It is found in shallow seas of the north-eastern Atlantic Ocean and the north-western Mediterranean Sea as well as Ionian Sea. This ...
'', or the Red Sea Fan. Serotonin and tryptophan have been found in chocolate with varying cocoa contents. The highest serotonin content (2.93 µg/g) was found in chocolate with 85% cocoa, and the highest tryptophan content (13.27–13.34 µg/g) was found in 70–85% cocoa. The intermediate in the synthesis from tryptophan to serotonin, 5-hydroxytryptophan, was not found. Root development in '' Arabidopsis thaliana'' is stimulated and modulated by serotonin - in various ways at various concentrations. Serotonin serves as a plant defense chemical against fungi. When infected with Fusarium crown rot (''Fusarium pseudograminearum''),
wheat Wheat is a grass widely cultivated for its seed, a cereal grain that is a worldwide staple food. The many species of wheat together make up the genus ''Triticum'' ; the most widely grown is common wheat (''T. aestivum''). The archaeologi ...
(''Triticum aestivum'') greatly increases its production of tryptophan to synthesize new serotonin. The function of this is poorly understood but wheat also produces serotonin when infected by '' Stagonospora nodorum'' - in that case to retard spore production. The model
cereal A cereal is any grass cultivated for the edible components of its grain (botanically, a type of fruit called a caryopsis), composed of the endosperm, germ, and bran. Cereal grain crops are grown in greater quantities and provide more food ...
''
Brachypodium distachyon ''Brachypodium distachyon'', commonly called purple false brome or stiff brome, is a grass species native to southern Europe, northern Africa and southwestern Asia east to India. It is related to the major cereal grain species wheat, barley, ...
'' - used as a research substitute for wheat and other production cereals - also produces serotonin, coumaroyl-serotonin, and feruloyl-serotonin in response to '' F. graminearum''. This produces a slight antimicrobial effect. ''B. distachyon'' produces more serotonin (and conjugates) in response to deoxynivalenol (DON)-producing ''F. graminearum'' than non-DON-producing. '' Solanum lycopersicum'' produces many AA conjugates - including several of serotonin - in its leaves, stems, and roots in response to ''
Ralstonia solanacearum ''Ralstonia solanacearum'' is an aerobic non-spore-forming, Gram-negative, plant pathogenic bacterium. ''R. solanacearum'' is soil-borne and motile with a polar flagellar tuft. It colonises the xylem, causing bacterial wilt in a very wide range ...
'' infection.


Invertebrates

Serotonin functions as a neurotransmitter in the nervous systems of most animals.


Nematodes

For example, in the roundworm '' Caenorhabditis elegans'', which feeds on bacteria, serotonin is released as a signal in response to positive events, such as 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, 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.


Decapods

If lobsters are injected with serotonin, they behave like dominant individuals whereas octopamine causes subordinate behavior. A crayfish that is frightened may flip its tail to flee, and the effect of serotonin on this behavior depends largely 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 receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory ne ...
s (5-HT receptors) that have opposing effects on the
fight-or-flight response The fight-or-flight or the fight-flight-or-freeze response (also called hyperarousal or the acute stress response) is a physiological reaction that occurs in response to a perceived harmful event, attack, or threat to survival. It was first des ...
. The effect of 5-HT1 receptors predominates in subordinate animals, while 5-HT2 receptors predominates in dominants.


In venoms

Serotonin is a common component of invertebrate venoms, salivary glands, nervous tissues, and various other tissues, across molluscs, insects, crustaceans, scorpions, various kinds of worms, and jellyfish. Adult ''
Rhodnius prolixus ''Rhodnius prolixus'' is the principal triatomine vector of the Chagas parasite due to both its sylvatic and domestic populations in northern South America as well as to its exclusively domestic populations in Central America. It has a wide ra ...
'' - hematophagous on vertebrates - secrete lipocalins into the wound during feeding. These lipocalins were demonstrated to sequester serotonin to prevent vasoconstriction (and possibly coagulation) in the host by Andersen et al. 2003.


Insects

Serotonin is evolutionarily conserved and appears across the animal kingdom. It is seen in insect processes in roles similar to in the human central nervous system, such as memory, appetite, sleep, and behavior. Some circuits in mushroom bodies are serotonergic. (See specific ''Drosophila'' example below, Dipterans.)


=Acrididae

= Locust swarming is initiated ''but not maintained'' by serotonin, with release being triggered by tactile contact between individuals. This transforms social preference from aversion to a gregarious state that enables coherent groups. * Learning in flies and honeybees is affected by the presence of serotonin.


=Role in insecticides

= Insect 5-HT receptors have similar sequences to the vertebrate versions, but pharmacological differences have been seen. Invertebrate drug response has been far less characterized than mammalian pharmacology and the potential for species selective insecticides has been discussed.


=Hymenopterans

=
Wasp A wasp is any insect of the narrow-waisted suborder Apocrita of the order Hymenoptera which is neither a bee nor an ant; this excludes the broad-waisted sawflies (Symphyta), which look somewhat like wasps, but are in a separate suborder ...
s and hornets have serotonin in their venom, which causes pain and inflammation as do
scorpion Scorpions are predatory arachnids of the order Scorpiones. They have eight legs, and are easily recognized by a pair of grasping pincers and a narrow, segmented tail, often carried in a characteristic forward curve over the back and always en ...
s. ''
Pheidole dentata ''Pheidole dentata'' is a species of ant in the subfamily Myrmicinae. It is distributed in North America, from the Mid-Atlantic states and southeastern United States to Mexico. Neurochemistry ''P. dentata'' takes on more and more tasks in th ...
'' takes on more and more tasks in the colony as it gets older, which requires it to respond to more and more olfactory cues in the course of performing them. This olfactory response broadening was demonstrated by Seid and Traniello 2006 to go along with increased serotonin and dopamine, but not octopamine.


=Dipterans

= If flies are fed serotonin, they are more aggressive; flies depleted of serotonin still exhibit aggression, but they do so much less frequently. In their crops it plays a vital role in digestive motility produced by contraction. Serotonin that acts on the crop is exogenous to the crop itself and was shown by Liscia et al. 2012 to probably originate in the
serotonin neural plexus Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
in the thoracic-abdominal synganglion. A ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
'' serotonergic mushroom body was found by Lee et al. 2011 to work in concert with '' Amnesiac'' to form memories. Dierick and Greenspan 2007 found serotonin to promote aggression in '' Diptera'', which was counteracted by neuropeptide F - a surprising find given that they both promote
courtship Courtship is the period wherein some couples get to know each other prior to a possible marriage. Courtship traditionally may begin after a betrothal and may conclude with the celebration of marriage. A courtship may be an informal and private m ...
, which is usually similar to aggression in most respects.


Vertebrates

Serotonin, also referred to as 5-hydroxytryptamine (5-HT), is a neurotransmitter most known for its involvement in mood disorders in humans. It is also a widely present neuromodulator among vertebrates and invertebrates. Serotonin has been found having associations with many physiological systems such as cardiovascular,
thermoregulation Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperatur ...
, and behavioral functions, including:
circadian rhythm A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...
, appetite, aggressive and sexual behavior, sensorimotor reactivity and learning, and pain sensitivity. Serotonin's function in neurological systems along with specific behaviors among vertebrates found to be strongly associated with serotonin will be further discussed. Two relevant case studies are also mentioned regarding serotonin development involving
teleost fish Teleostei (; Greek ''teleios'' "complete" + ''osteon'' "bone"), members of which are known as teleosts ), is, by far, the largest infraclass in the class Actinopterygii, the ray-finned fishes, containing 96% of all extant species of fish. Tel ...
and mice. In mammals, 5-HT is highly concentrated in the
substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra ap ...
,
ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...
and raphe nuclei. Lesser concentrated areas include other brain regions and the spinal cord. 5-HT neurons are also shown to be highly branched, indicating that they are structurally prominent for influencing multiple areas of the CNS at the same time, although this trend is exclusive solely to mammals.


5-HT System in Vertebrates

Vertebrates are multicellular organisms in the phylum Chordata that possess a backbone and a
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
. This includes mammals, fish, reptiles, birds, etc. In humans, the nervous system is composed of the
central Central is an adjective usually referring to being in the center of some place or (mathematical) object. Central may also refer to: Directions and generalised locations * Central Africa, a region in the centre of Africa continent, also known a ...
and
peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brai ...
, with little known about the specific mechanisms of neurotransmitters in most other vertebrates. However, it is known that while serotonin is involved in stress and behavioral responses, it is also important in cognitive functions. Brain organization in most vertebrates includes 5-HT cells in the hindbrain. In addition to this, 5-HT is often found in other sections of the brain in non-placental vertebrates, including the basal forebrain and pretectum. Since location of serotonin receptors contribute to behavioral responses, this suggests serotonin is part of specific pathways in non-placental vertebrates that are not present in amniotic organisms. Teleost fish and mice are organisms most often used to study the connection between serotonin and vertebrate behavior. Both organisms show similarities in the effect of serotonin on behavior, but differ in the mechanism in which the responses occur.


= Dogs / Canine species

= There are few studies of serotonin in dogs. One study reported serotonin values were higher at dawn than at dusk. In another study, serum 5-HT levels did not seem to be associated with dogs' behavioural response to a stressful situation. Urinary serotonin/creatinine ratio in bitches tended to be higher 4 weeks after surgery. In addition, serotonin was positively correlated with both cortisol and progesterone but not with testosterone after ovariohysterectomy.


= Teleost Fish

= Like non-placental vertebrates, teleost fish also possess 5-HT cells in other sections of the brain, including the basal forebrain. '' Danio rerio'' (zebra fish) are a species of teleost fish often used for studying serotonin within the brain. Despite much being unknown about serotonergic systems in vertebrates, the importance in moderating stress and social interaction is known. It is hypothesized that AVT and CRF cooperate with serotonin in th
hypothalamic-pituitary-interrenal axis
These
neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like t ...
s influence the plasticity of the teleost, affecting its ability to change and respond to its environment. Subordinate fish in social settings show a drastic increase in 5-HT concentrations. High levels of 5-HT long term influence the inhibition of aggression in subordinate fish.


= Mice

= Researchers at the Department of Pharmacology and Medical Chemistry used serotonergic drugs on male mice to study the effects of selected drugs on their behavior. Mice in isolation exhibit increased levels of
agonistic behavior Agonistic behaviour is any social behaviour related to fighting. The term has broader meaning than aggressive behaviour because it includes threats, displays, retreats, placation, and conciliation. The term "agonistic behaviour" was first implemen ...
towards one another. Results found that serotonergic drugs reduce aggression in isolated mice while simultaneously increasing social interaction. Each of the treatments use a different mechanism for targeting aggression, but ultimately all have the same outcome. While the study shows that serotonergic drugs successfully target serotonin receptors, it does not show specifics of the mechanisms that affect behavior, as all types of drugs tended to reduce aggression in isolated male mice. Aggressive mice kept out of isolation may respond differently to changes in serotonin reuptake.


Behavior

Like in humans, serotonin is extremely involved in regulating behavior in most other vertebrates. This includes not only response and social behaviors, but also influencing mood. Defects in serotonin pathways can lead to intense variations in mood, as well as symptoms of mood disorders, which can be present in more than just humans.


= Social Interaction

= One of the most researched aspects of social interaction in which serotonin is involved is aggression. Aggression is regulated by the 5-HT system, as serotonin levels can both induce or inhibit aggressive behaviors, as seen in mice (see section on Mice) and crabs. While this is widely accepted, it is unknown if serotonin interacts directly or indirectly with parts of the brain influencing aggression and other behaviors. Studies of serotonin levels show that they drastically increase and decrease during social interactions, and they generally correlate with inhibiting or inciting aggressive behavior. The exact mechanism of serotonin influencing social behaviors is unknown, as pathways in the 5-HT system in various vertebrates can differ greatly.


= Response to Stimuli

= Serotonin is important in environmental response pathways, along with other
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...
s. Specifically, it has been found to be involved in auditory processing in social settings, as primary sensory systems are connected to social interactions. Serotonin is found in the IC structure of the midbrain, which processes specie specific and non-specific social interactions and vocalizations. It also receives acoustic projections that convey signals to auditory processing regions. Research has proposed that serotonin shapes the auditory information being received by the IC and therefore is influential in the responses to auditory stimuli. This can influence how an organism responds to the sounds of predatory or other impactful species in their environment, as serotonin uptake can influence aggression and/or social interaction.


= Mood

= We can describe mood not as specific to an emotional status, but as associated with a relatively long-lasting emotional state. Serotonin's association with mood is most known for various forms of depression and bipolar disorders in humans. Disorders caused by serotonergic activity potentially contribute to the many symptoms of major depression, such as overall mood, activity, suicidal thoughts and sexual and cognitive dysfunction. Selective serotonin reuptake inhibitors (SSRI's) are a class of drugs demonstrated to be an effective treatment in major depressive disorder and are the most prescribed class of antidepressants. SSRI's function is to block the reuptake of serotonin, making more serotonin available to absorb by the receiving neuron. Animals have been studied for decades in order to understand depressive behavior among species. One of the most familiar studies, the forced swimming test (FST), was performed to measure potential antidepressant activity. Rats were placed in an inescapable container of water, at which point time spent immobile and number of active behaviors (such as splashing or climbing) were compared before and after a panel of anti-depressant drugs were administered. Antidepressants that selectively inhibit NE reuptake were shown to reduce immobility and selectively increase climbing without affecting swimming. However, results of the SSRI's also show reduced immobility but increased swimming without affecting climbing. This study demonstrated the importance of behavioral tests for antidepressants, as they can detect drugs with an effect on core behavior along with behavioral components of species.


Growth and reproduction

In the nematode ''
C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...
'', artificial depletion of serotonin or the increase of octopamine cues behavior typical of a low-food environment: ''C. elegans'' becomes more active, and mating and egg-laying are suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal. Serotonin is necessary for normal nematode 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 (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism ...
-like signaling and the TGF beta signaling pathway, which control long-term adaption. In the fruit fly insulin both regulates
blood sugar Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the b ...
as well as acting as a growth factor. Thus, in the fruit fly, serotonergic neurons regulate the adult body size by affecting insulin secretion. Serotonin has also been identified as the trigger for
swarm behavior Swarm behaviour, or swarming, is a collective behaviour exhibited by entities, particularly animals, of similar size which aggregate together, perhaps milling about the same spot or perhaps moving ''en masse'' or migrating in some direction. ...
in locusts. In humans, though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones, modulating insulin release from the
beta cell Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are di ...
s in the
pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an ...
through serotonylation of GTPase signaling proteins. Exposure to SSRIs during
Pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...
reduces fetal growth. Genetically altered ''C. elegans'' worms that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a dormant larval state.


Aging and age-related phenotypes

Serotonin is known to regulate aging, learning and memory. The first evidence comes from the study of longevity in ''C. elegans''. During early phase of aging, the level of serotonin increases, which alters locomotory behaviors and associative memory. The effect is restored by mutations and drugs (including
mianserin Mianserin, sold under the brand name Tolvon among others, is an atypical antidepressant that is used primarily in the treatment of depression in Europe and elsewhere in the world. It is a tetracyclic antidepressant (TeCA). Mianserin is closel ...
and methiothepin) that inhibit serotonin receptors. The observation does not contradict with the notion that the serotonin level goes down in mammals and humans, which is typically seen in late but not early phase of aging.


Biochemical mechanisms


Biosynthesis

In animals including humans, serotonin is synthesized from the
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
L- tryptophan by a short
metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical ...
consisting of two
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s, tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase (DDC), and the coenzyme
pyridoxal phosphate Pyridoxal phosphate (PLP, pyridoxal 5'- phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent ...
. The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and
TPH2 Tryptophan hydroxylase 2 (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. Until ...
, which is a neuron-specific
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...
. Serotonin can be synthesized from tryptophan in the lab using '' Aspergillus niger'' and ''
Psilocybe coprophila ''Deconica coprophila'', commonly known as the dung-loving psilocybe, or dung demon, is a species of mushroom in the family Strophariaceae. First described as ''Agaricus coprophilus'' by Jean Baptiste François Pierre Bulliard in 1793, it was t ...
'' as catalysts. The first phase to 5-hydroxytryptophan would require letting tryptophan sit in ethanol and water for 7 days, then mixing in enough HCl (or other acid) to bring the pH to 3, and then adding NaOH to make a pH of 13 for 1 hour. ''Asperigillus niger'' would be the catalyst for this first phase. The second phase to synthesizing tryptophan itself from the 5-hydroxytryptophan intermediate would require adding ethanol and water, and letting sit for 30 days this time. The next two steps would be the same as the first phase: adding HCl to make the pH = 3, and then adding NaOH to make the pH very basic at 13 for 1 hour. This phase uses the ''Psilocybe coprophila'' as the catalyst for the reaction. Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system, because it does not cross the blood–brain barrier. However, tryptophan and its metabolite
5-hydroxytryptophan 5-Hydroxytryptophan (5-HTP), also known as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin. Uses 5-HTP is sold over the cou ...
(5-HTP), from which serotonin is synthesized, do cross the blood–brain barrier. These agents are available as dietary supplements and in various foods, and may be effective serotonergic agents. One product of serotonin breakdown is 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the
urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellul ...
. Serotonin and 5-HIAA are sometimes produced in excess amounts by certain
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s or
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s, and levels of these substances may be measured in the urine to test for these tumors.


Analytical chemistry

Indium tin oxide is recommended for the
electrode An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit (e.g. a semiconductor, an electrolyte, a vacuum or air). Electrodes are essential parts of batteries that can consist of a variety of materials ...
material in electrochemical investigation of concentrations produced, detected, or consumed by microbes. A laser desorption ionization mass spectrometry technique was developed by Bertazzo et al. 1994 to measure the
molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bio ...
of both natural and synthetic serotonins.


History and etymology

It had been known to physiologists for over a century that a vasoconstrictor material appears in serum when blood was allowed to clot. In 1935, Italian Vittorio Erspamer showed an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later, Erspamer was able to show it was a previously unknown
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
, which he named "enteramine". In 1948, Maurice M. Rapport, Arda Green, and
Irvine Page Irvine Heinly Page (January 7, 1901 – June 10, 1991) was an American physiologist who played an important part in the field of hypertension for almost 60 years while working at the Cleveland Clinic as the first Chair of Research.Frohlich ED, Du ...
of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin. In 1952, enteramine was shown to be the same substance as serotonin, and as the broad range of physiological roles was elucidated, the abbreviation 5-HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field. Synonyms of serotonin include: 5-hydroxytriptamine, thrombotin, enteramin, substance DS, and 3-(β-Aminoethyl)-5-hydroxyindole. In 1953,
Betty Twarog Betty Mack Twarog (August 28, 1927 – February 6, 2013) was an American biochemist who was the first to find serotonin in mammalian brain. Life and career Betty M Twarog was born on August 28, 1927, in New York City. She attended Swarthmore ...
and Page discovered serotonin in the central nervous system. Page regarded Erspamer's work on '' Octopus vulgaris'', ''
Discoglossus pictus The Mediterranean painted frog or simply painted frog (''Discoglossus pictus'') is a species of frog in the family Alytidae (formerly Discoglossidae). Distribution ''Discoglossus pictus'' is found Mediterranean Africa in northeast Morocco, nort ...
'', '' Hexaplex trunculus'', '' Bolinus brandaris'', '' Sepia'', '' Mytilus'', and '' Ostrea'' as valid and fundamental to understanding this newly identified substance, but regarded his earlier results in various models - especially those from rat blood - to be too confounded by the presence of other MAs, including some other vasoactives.


See also

*
HIOC HIOC is a small-molecule agent which acts as a selective TrkB receptor agonist (active at at least 100 nM; prominent activation at 500 nM). It was derived from N-acetylserotonin (NAS). Relative to NAS, HIOC possesses greater potency and a longe ...


Notes


References


Further reading

*


External links


5-Hydroxytryptamine MS Spectrum

Serotonin bound to proteins
in the PDB
PsychoTropicalResearch
Extensive reviews on serotonergic drugs and Serotonin Syndrome.

at
University of Bristol , mottoeng = earningpromotes one's innate power (from Horace, ''Ode 4.4'') , established = 1595 – Merchant Venturers School1876 – University College, Bristol1909 – received royal charter , type ...
* 60-Second Psych
No Fair! My Serotonin Level Is Low
Scientific American ''Scientific American'', informally abbreviated ''SciAm'' or sometimes ''SA'', is an American popular science magazine. Many famous scientists, including Albert Einstein and Nikola Tesla, have contributed articles to it. In print since 1845, it ...

Serotonin Test Interpretation on ClinLab Navigator
{{Portal bar, Chemistry, Biology, Medicine Tryptamine alkaloids Biogenic amines Neurotransmitters TAAR1 agonists Hydroxyarenes Peripherally selective drugs X