Product Code Database
Serotonin (), also known as 5-hydroxytryptamine ( 5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, memory, and physiological processes such as vomiting and vasoconstriction. In the CNS, serotonin regulates mood, appetite, and sleep.
Most of the body's serotonin—about 90%—is synthesized in the gastrointestinal tract by enterochromaffin cells, where it regulates intestinal movements. It is also produced in smaller amounts in the brainstem's raphe nuclei, the skin's Merkel cells, pulmonary neuroendocrine cells, and taste receptor cells of the tongue. Once secreted, serotonin is taken up by in the blood, which release it during clotting to promote vasoconstriction and platelet aggregation. Around 8% of the body's serotonin is stored in platelets, and 1–2% is found in the CNS.
Serotonin acts as both a vasoconstrictor and vasodilator depending on concentration and context, influencing hemostasis and blood pressure regulation. It plays a role in stimulating myenteric neurons and enhancing gastrointestinal motility through uptake and release cycles in platelets and surrounding tissue. Biochemically, serotonin is an indoleamine synthesized from tryptophan and metabolized primarily in the liver to 5-hydroxyindoleacetic acid (5-HIAA).
Serotonin is targeted by several classes of , including selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), which block reabsorption in the synapse to elevate its levels. It is found in nearly all bilateral animals, including insects, spiders and worms, and also occurs in fungi and . In plants and insect venom, it serves a defensive function by inducing pain.
Metabolism involves first oxidation by monoamine oxidase to 5-hydroxyindoleacetaldehyde (5-HIAL).
In addition to the serotonin receptors, serotonin is an agonist of the trace amine-associated receptor 1 (TAAR1) in some species. It is a weak TAAR1 partial agonist in rats, but is inactive at the TAAR1 in mice and humans.
The cryo-EM structures of the serotonin 5-HT2A receptor with serotonin, as well as with various serotonergic psychedelics, have been solved and published by Bryan L. Roth and colleagues.
In contrast to the high affinity of SERT, the PMAT has been identified as a low-affinity transporter, with an apparent Km of 114 micromoles/l for serotonin, which is 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 that the administration of SSRIs such as fluoxetine and sertraline may be associated with an inhibitory effect on PMAT activity when used at higher than normal dosages (IC50 test values used in trials were 3–4 fold higher than typical prescriptive dosage).
The effects of serotonin upon vascular smooth biological function after which serotonin was originally nameddepend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.
| + Binding profile of serotonin ! Receptor !! Ki (nM) !! Receptor functionReferences for the functions of these receptors are available on the wikipedia pages for the specific receptor in question | ||
| 5-HT1 receptor family signals via Gi/o inhibition of adenylyl cyclase. | ||
| Memory (agonists ↓); learning (agonists ↓); anxiety (agonists ↓); depression (agonists ↓); positive, negative, and cognitive symptoms of schizophrenia (partial agonists ↓); analgesia (agonists ↑); aggression (agonists ↓); dopamine release in the prefrontal cortex (agonists ↑); serotonin release and synthesis (agonists ↓) | ||
| Vasoconstriction (agonists ↑); aggression (agonists ↓); bone mass (↓). Serotonin autoreceptor. | ||
| Vasoconstriction (agonists ↑) | ||
| 5-HT2 receptor family signals via Gq activation of phospholipase C. | ||
| Psychedelia (agonists ↑); depression (agonists & antagonists ↓); anxiety (antagonists ↓); positive and negative symptoms of schizophrenia (antagonists ↓); norepinephrine release from the locus coeruleus (antagonists ↑); glutamate release in the prefrontal cortex (agonists ↑); dopamine in the prefrontal cortex (agonists ↑); urinary bladder contractions (agonists ↑) | ||
| Cardiovascular functioning (agonists increase risk of pulmonary hypertension), empathy (via von Economo neurons) | ||
| Dopamine release into the mesocorticolimbic pathway (agonists ↓); acetylcholine release in the prefrontal cortex (agonists ↑); dopaminergic and noradrenergic activity in the frontal cortex (antagonists ↑); appetite (agonists ↓); antipsychotic effects (agonists ↑); antidepressant effects (agonists & antagonists ↑) | ||
| Other 5-HT receptors | ||
| Emesis (agonists ↑); anxiolysis (antagonists ↑). | ||
| Movement of food across the GI tract (agonists ↑); memory & learning (agonists ↑); antidepressant effects (agonists ↑). Signalling via Gαs activation of adenylyl cyclase. | ||
| Memory consolidation. Signals via Gi/o inhibition of adenylyl cyclase. | ||
| Cognition (antagonists ↑); antidepressant effects (agonists & antagonists ↑); anxiogenic effects (antagonists ↑). Gs signalling via activating adenylyl cyclase. | ||
| Cognition (antagonists ↑); antidepressant effects (antagonists ↑). Acts by Gs signalling via activating adenylyl cyclase. | ||
It is the dorsal part of the raphe nucleus that contains neurons projecting to the central nervous system. Serotonin-releasing neurons in this area receive input from a large number of areas, notably from prefrontal cortex, lateral habenula, preoptic area, substantia nigra and amygdala. These neurons are thought to communicate the expectation of rewards in the near future, a quantity called state value in reinforcement learning.
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-
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 follows a circadian rhythm, just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest.
In , alpha males have twice the level of serotonin in the brain as subordinate males and females (measured by the concentration of 5-HIAA in the cerebrospinal fluid (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.McGuire, Michael (2013) "Believing, the neuroscience of fantasies, fears, and confictions" (Prometius Books)
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.
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.
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.
5-HT2B receptors also activate , which build up bone However, serotonin also inhibits , through 5-HT1B receptors.
Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases. The 5-HTTLPR 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.
Besides their use in treating depression and anxiety, certain serotonergic antidepressants are also approved and used to treat fibromyalgia, neuropathic pain, and chronic fatigue syndrome.
Serotonin itself, despite acting as a serotonin 5-HT2A receptor agonist, is thought to be non-hallucinogenic. The hallucinogenic effects of serotonergic psychedelics appear to be mediated by activation of serotonin 5-HT2A receptors expressed in a population of Cerebral cortex in the medial prefrontal cortex (mPFC). These serotonin 5-HT2A receptors, unlike most serotonin and related receptors, are expressed . In addition, the neurons containing them lack gene expression of the serotonin transporter (SERT), which normally active transport serotonin from the extracellular space to the intracellular space within neurons. Serotonin itself is too hydrophilic to enter serotonergic neurons without the SERT, and hence these serotonin 5-HT2A receptors are inaccessible to serotonin. Conversely, serotonergic psychedelics are more lipophilic than serotonin and readily enter these neurons. In addition to explaining why serotonin does not show psychedelic effects, these findings may explain why drugs that increase serotonin levels, like selective serotonin reuptake inhibitors (SSRIs) and various other types of serotonergic agents, do not produce psychedelic effects. Artificial expression of the SERT in these medial prefrontal cortex neurons resulted in the serotonin releasing agent para-chloroamphetamine (PCA), which does not normally show psychedelic-like effects, being able to produce psychedelic-like effects in animals.
Although serotonin itself is non-hallucinogenic, administration of very high doses of a serotonin precursor, like tryptophan or 5-hydroxytryptophan (5-HTP), or intracerebroventricular injection of high doses of serotonin directly into the brain, can produce psychedelic-like effects in animals.
DMT is a natural product endogenous compound in the body. In relation to the fact that serotonin itself is unable to activate intracellular serotonin 5-HT2A receptors, it is possible that DMT might be the endogenous ligand of these receptors rather than serotonin.
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% and 12%.
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, chlorphentermine, and aminorex), and certain anti-Parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride.
As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was 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 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).
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 Edible mushroom, , and . 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, , banana, kiwifruit, , and . 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 ( Urtica dioica), where it causes pain on injection in the same manner as its presence in insect venoms. It is also naturally found in Paramuricea clavata, 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 ( 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 Brachypodium distachyon – 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 amino acid conjugates – including several of serotonin – in its leaves, stems, and roots in response to Ralstonia solanacearum infection.
Serotonin occurs in several hallucinogenic mushrooms of the genus Panaeolus.
In mammals, 5-HT is highly concentrated in the substantia nigra, ventral tegmental area 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.
In the fruit fly insulin both regulates blood sugar 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 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 in the pancreas through serotonylation of GTPase signaling proteins. Exposure to during gestation 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 dauer larva.
TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a neuron-specific Protein isoform.
Serotonin can be synthesized from tryptophan in the lab using Aspergillus niger and Psilocybe coprophila 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. Aspergillus 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-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. Serotonin and 5-HIAA are sometimes produced in excess amounts by certain or , and levels of these substances may be measured in the urine to test for these tumors.
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, enteramine, substance DS, and 3-(β-aminoethyl)-5-hydroxyindole.SciFinder – Serotonin Substance Detail. Accessed (4 November 2012). In 1953, Betty Twarog and Page discovered serotonin in the central nervous system. Page regarded Erspamer's work on Octopus vulgaris, Discoglossus pictus, 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 bioactive chemicals, including some other vasoactives.
It is thought that exogenous serotonin is too hydrophilic to cross the blood–brain barrier and has too poor of metabolic stability due to rapid drug metabolism by monoamine oxidase (MAO) such that it cannot produce drug-like central effects in humans with peripheral administration.
However, close analogues of serotonin that are more lipophilic and metabolically stable, like bufotenin ( N, N-dimethylserotonin), 5-MeO-DMT ( N, N, O-trimethylserotonin), and 5-MeO-AMT (α, O-dimethylserotonin), among many others, are active and produce pronounced centrally mediated effects in humans. These drugs are non-selective serotonin receptor agonists like serotonin and are serotonergic psychedelics due to activation of the serotonin 5-HT2A receptor. α-Methylserotonin is well-studied in preclinical research, but is not known to have been tested in humans.
|
|
