Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract (GI tract), blood platelets, and the central nervous system (CNS) of animals, including humans. It is poplularly thought to be a contributor to feelings of well-being and happiness.
Approximately 90% of the human body’s total serotonin is located in the enterochromaffin cells in the GI tract, where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.
Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they release serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing. There are various serotonin receptors.
Serotonin is metabolized mainly to 5-HIAA, chiefly by the liver. Metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic acid derivative. The latter is then excreted by the kidneys. One type of tumor, called carcinoid, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing (serotonin itself does not cause flushing).
Potential causes of flushing in carcinoid syndrome include bradykinins, prostaglandins, tachykinins, substance P, and/or histamine, diarrhea, and heart problems.
In addition to animals, serotonin is found in fungi and plants. Serotonin’s presence in insect venoms and plant spines serves to cause pain, which is a side-effect of serotonin injection. Serotonin is produced by pathogenic amoebae, and its effect on the gut causes diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.
Serotonin is a neurotransmitter and is found in all bilateral animals, where it mediates gut movements and the animal’s perceptions of resource availability. In less complex animals, such as some invertebrates, resources simply mean food availability. In more complex animals, such as arthropods and vertebrates, resources also can mean social dominance.
In response to the perceived abundance or scarcity of resources, an animal’s growth, reproduction or mood may be elevated or lowered. This may somewhat depend on how much serotonin the organism has at its disposal.
Serotonin functions as a neurotransmitter in the nervous systems of simple, as well as complex, animals. For example, in the roundworm Caenorhabditis elegans, which feeds on bacteria, serotonin is released as a signal in response to positive events, e.g., finding a new source of food or in male animals finding a 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.
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 increased weight gain, especially in people with a low number of receptors. The expression of 5-HT2C receptors in the hippocampus follows a diurnal 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.
Effects of Food Content
Consuming purified tryptophan increases brain serotonin whereas eating foods containing tryptophan does not. This is because the transport system which brings tryptophan across the blood-brain barrier is also selective for the other amino acids contained in protein sources. High plasma levels of other large neutral amino acids compete for transport and prevent the elevated plasma tryptophan from increasing serotonin synthesis.
In the Digestive Tract
The gut is surrounded by enterochromaffin cells, which release serotonin in response to food in the lumen. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin.
If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased.
This activates 5HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting. The enterochromaffin cells not only react to bad food but are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.
Gauge of Social Situation
How much food an animal gets not only depends on food availability but also depends on the animal’s ability to compete with others. This is especially true for social animals, where the stronger individuals might steal food from the weaker (this is not to say anti-social animals do not concern themselves with the needs of others and do not steal food from others). Thus, serotonin is not only involved in the perception of food availability but also involved in social rank.
If a lobster is injected with serotonin, it behaves as if it were alpha, while 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 effect of 5-HT1 receptors predominates in subordinate animals, while 5-HT2 receptors predominates in dominants.
With Macaque monkeys, it has been found that alpha males have twice the level of serotonin released in the brain, as measured by the levels of 5-Hydoxyindolacetic acid (5-HIAA) in the cerebro-spinal fluid, than that found in subordinate males and females. Dominance and high levels of cerebro-serotonon levels seem to go hand in hand.
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 rose to double that found in subdominant 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 activation in the brain show negative correlation with aggression, and a mutation in the gene that codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype. 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.
In the Brain
The neurons of the Raphe nuclei are the principal source of 5-HT release in the brain. There are 7 or 8 raphe nuclei (some scientists chose to group the nuclei raphes lineares into one nucleus), all of which located along the midline of the brainstem, and centered around the reticular formation. Axons from the neurons of the raphe nuclei form a neurotransmitter system reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord, while the axons of the higher nuclei spread out in the entire brain.
Dopamine / seratonin. Licensed under Public Domain
Serotonin is released into the space between neurons, and diffuses over a relatively wide gap (>20 µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.
The 5-HT receptors, the receptors for serotonin, are located on the cell membrane of nerve cells and other cell types in animals, and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors (also called seven-transmembrane, or heptahelical receptors) that activate an intracellular second messenger cascade.
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, dextromethorphan (an antitussive), tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). A 2006 study conducted by the University of Washington 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 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).
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 tone (this is the biological function from which serotonin originally got its name) depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.
In animals including humans, serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a neuron-specific isoform.
[caption id="attachment_17160” align="aligncenter” width="524”] “Serotonin biosynthesis” by NEUROtiker - Own work. Licensed under CC BY-SA 3.0[/caption]
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. 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-HTP), from which serotonin is synthesized, does cross the blood–brain barrier. These agents are available as dietary supplements, and may be effective serotonergic agents.
One product of serotonin breakdown is 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the urine. Serotonin and 5-HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors.
Drugs Targeting the 5-HT System
Several classes of drugs target the 5-HT system, including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs, as well as the psychedelic drugs and empathogens.
The psychedelic drugs ketamine, psilocin/psilocybin, DMT, mescaline, and LSD are agonists, primarily at 5HT2A/2C receptors. The empathogen-entactogen MDMA releases serotonin from synaptic vesicles of neurons.
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. The newer selective serotonin reuptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs. The side-effects that have become apparent recently include a decrease in bone mass in elderly and increased risk for osteoporosis.
However, it is not yet clear whether it is due to SSRI action on peripheral serotonin production and or action in the gut or in the brain.
There is investigation into whether SSRIs benefits to mood are somehow related to dopamine receptor sensitivity indirectly influenced by antidepressant mechanisms. In one study, patients with depression taking an SSRI were given a low dose D2 receptor antagonist(sulpiride), and reported negative effect on mood.
Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases. This has been connected to the observation that the benefit of SSRIs may decrease in selected patients after a long-term treatment. A switch in medication will usually resolve this issue (up to 70% of the time). The antidepressants mirtazapine and mianserin (5HT2 and 5HT3 receptors antagonists) have mood-elevating effects.
This provides evidence for the theory that serotonin is most likely used to regulate the extent or intensity of moods, rather than level directly correlating with mood. In fact, the 5-HTTLPR gene codes for the number of serotonin transporters in the brain, with more serotonin transporters causing decreased duration and magnitude of serotonergic signaling.
The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety. Therefore, increasing levels of extracellular serotonin may be associated with increased affect, for good or for worse.
Although phobias and depression might be attenuated by serotonin-altering drugs, this does not mean the individual’s situation has been improved, but only the individual’s perception of the environment. Sometimes, a lower serotonin level might be beneficial, for example in the ultimatum game, where players with normal serotonin levels are more prone to accept unfair offers than participants whose serotonin levels have been artificially lowered.
Extremely high levels of serotonin can cause a condition known as serotonin syndrome, with toxic and potentially fatal effects. In practice, such toxic levels are essentially impossible to reach through an overdose of a single antidepressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI.
The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at nontoxic levels.
Some 5-HT3 antagonists, such as ondansetron, granisetron, and tropisetron, are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in the treatment of postoperative nausea and vomiting.
Bryan L. Roth (Editor) The Serotonin Receptors: From Molecular Pharmacology to Human Therapeutics Humana Press; 2006 edition (June 1, 2006)
Christian P. Muller and Barry Jacobs Handbook of the Behavioral Neurobiology of Serotonin, Academic Press; 1 edition (December 16, 2009)
PsychoTropical Research Extensive reviews on serotonergic drugs and Serotonin Syndrome.
Serotonin bound to proteins in the Protein Data Bank
Robert Whitaker Broadway Books; Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America, 1 edition (August 2, 2011)
Caio Maximino Serotonin and Anxiety: Neuroanatomical, Pharmacological, and Functional Aspects, Springer; 2012 edition (June 7, 2012)