Serotonin, or 5-hydroxytryptamine (5-HT), is a ubiquitous monoamine neurotransmitter that signals perceived resource availability. It is present in numerous different organisms, from fungi to man. In humans it is found in the gastrointestinal tract regulating bowel movement, in platelets contributing to hemostasis and in the central nervous system, regulating mood, cognition, appetite and sleep. Serotonin also plays a role in bone metabolism and organ development. Serotonergic neurons are found in the raphe nuclei in the brainstem, from where serotonergic fiber pathways innervate almost every part of the central nervous system (CNS). Inside the CNS it is produced by serotonergic neurons from the essential amino acid tryptophan. After its release, 5-HT’s signaling action is terminated by reuptake or enzymatic breakdown. A wide variety of drugs target various parts of the serotonin system, from antidepressants, anxiolytics and antipsychotics to recreational drugs like psychedelics.
Serotonin production and release
Serotonin is produced from the essential amino acid tryptophan (TRY), found in most protein-containing foods. Meat, fish, dairy products, soybeans and other legumes, eggs, nuts and seeds, oats, spirulina and dark chocolate are all examples of tryptophan rich foods. After being absorbed by the digestive system, tryptophan is transported by the bloodstream to the brain, where it crosses the blood-brain barrier (BBB) and enters the extracellular space by the use of the large neutral amino acid transporter (LAT). A specialized tryptophan transporter (TT) on serotonergic neurons moves tryptophan across the cell membrane (CM) into the cell. Inside, serotonin (5-HT) is produced from tryptophan by a two-step enzymatic process involving the enzymes tryptophan hydroxylase (TRY-OH) and aromatic amino acid decarboxylase (AAADC), with 5-hydoxytryptophan (5-HTP) as an intermediate product. Conversion by tryptophan hydroxylase is the rate-limiting step and requires tetrahydrobiopterin as a cofactor. Serotonin is then packed into synaptic vesicles by the vesicular monoamine transporter (VMAT2), where the neurotransmitter is stored until a neuronal impulse signals release into the synaptic cleft, where it can bind to various serotonin receptors (5-HT-R).
Serotonin termination of action and metabolism
The signalling action of serotonin in the synaptic cleft is terminated by active transport into the presynaptic neuron or surrounding astrocytic glial cells (astroglia). The transport is facilitated by the serotonin transporter (SERT), also known as the serotonin reuptake pump, and the less specific plasma membrane monoamine transporter (PMAT). Once back inside the neuron, serotonin can be repacked into synaptic vesicles by vesicular monoamine transporter (VMAT2) and reused during later neurotransmission. Alternatively, serotonin is broken down by the enzyme monoamine oxidase (MAO) into the inactive metabolite 5-hydroxyindole acetaldehyde (5-HIAL). Two subtypes of monoamine oxidase exists; MAO-A with high affinity for serotonin and MAO-B with low affinity for serotonin. MAO-B is present inside serotonergic neurons, but degrades serotonin only at high concentrations. Astroglia envelopes synapses in the CNS and contain both MAO-A and MAO-B to metabolize excess monoamine neurotransmitters. 5-hydroxyindole acetaldehyde (5-HIAL) is later metabolized by the enzyme aldehyde dehydrogenase (ALDH) into 5-hydroxyindoleacetic acid (5-HIAA) which is excreted in urine.
Serotonin acts on 13 different serotonin receptors in the human body. All can be postsynaptic heteroreceptor found on other neurons and cells, while a few can also be presynaptic autoreceptors (5-HT1A, 5-HT1B/D and possibly 5-HT5A and 5-HT7) that provide negative regulatory feedback to the serotonergic neuron itself. All serotonin receptors are G protein-coupled receptors, except for the 5-HT3 receptor, which is a ligand-gated cation channel. The 5-HT1 and 5-HT5 family of serotonin receptors are inhibitory, while the rest are excitatory.
5-HT1A receptors can be presynaptic autoreceptors or postsynaptic heteroreceptors. 5-HT1A autoreceptors are found on the soma (cell body) and dendrites of serotonergic neurons in the raphe nucleus. Activation of these somatodendritic autoreceptors slows down the neuronal impulse flow and thus reduces further serotonin release from the axon terminal, providing negative feedback. Postsynaptic 5-HT1A reptors are widespread in the CNS. Postsynaptic 5-HT1A receptor activation inhibits norepinephrine, glutamate and acetylcholine release, indirectly increases dopamine release in the striatum and the medial prefrontal cortex and increase secretion of certain hormones like cortisol, oxytocin and beta endorphin. Desensitization of presynaptic 5-HT1A autoreceptors and activation of postsynaptic 5-HT1A heteroreceptors is a major mediator of antidepressant and anxiolytic effect in antidepressants. The net effects of 5-HT1A activation also leads to increased prosocial behavior and decreased impulsiveness and aggression, but probably also inhibit certain aspects of memory formation and learning.
5-HT1B/D receptors can be presynaptic autoreceptors or postsynaptic heteroreceptors. 5-HT1B/D autoreceptors are found on the axons of serotonergic neurons and activation of these terminal autoreceptors inhibits further serotonin release, providing negative feedback. Postsynaptic 5-HT1B/D heteroreceptors inhibits a range of neurotransmitters. Blocking the 5-HT1B/D receptor could thus theoretically give an antidepressant effect. Several antimigraine drugs work through 5HT1B/D receptor activation, which results in constriction of cranial blood vessels and inhibition of pro-inflammatory neuropeptides.
5-HT1E/F receptors have so far proven difficult to study due to a lack of selective drugs and antibodies.
5-HT2A receptor activation indirectly inhibit dopamine release in the striatum, increase dopamine release in the prefrontal cortex and stimulates prolactin release from pituitary lactotrophs. The psychedelic effects of drugs like LSD, mescaline and psilocin mediated by activation of the 5-HT2A receptor. The 5-HT2A blocking properties found in many second-generation antipsychotics reduces the incidence of side effects like extrapyramidal symptoms and hyperprolactinemia.
5-HT2B receptors mediate many of the cardiovascular functions of serotonin. Experimental drugs activating this receptor have turned out to be cardiotoxic.
5-HT2C receptors regulate mood and feeding. 5-HT2C receptor activation inhibits dopamine and norepinephrine release in several areas of the brain. Drugs with 5-HT2C receptor blocking properties thus stimulates dopamine and norepinephrine release and has pro-cognitive and antidepressant action, but are associated with hyperphagia and weight gain as well.
5-HT3 receptors regulate inhibitory GABA interneurons in various brain areas that release serotonin, norepinephrine, dopamine, histamine and achetylcholine. Drugs with 5-HT3 receptor blocking properties consequently indirectly increase the release of these neurotransmitters and probably have antidepressant and pro-cognitive effecst. Such drugs also mitigates nausea from chemotherapy by blocking 5-HT3 receptors in the brain’s chemoreceptor trigger zone. Activation of 5-HT3 receptors on enterochromaffin cells stimulates bowel motility.
5-HT4 receptors are widely distributed in the CNS and in peripheral tissues, but their distinct function has not been characterized properly yet.
5-HT5A receptors are not well known, but have been implicated in regulation of circadian rhythm and can possibly also be autoreceptors. Humans also carry the gene for a 5-HT5B receptor, but stop codons in the gene inhibits its transcription.
5-HT6 receptors are found on inhibitory GABAergic spiny neurons. Activation of these receptors produce an overall inhibition of brain activity. Drugs with 5-HT6 receptor blocking properties increases norepinephrine and dopamine release in the prefrontal cortex and glutamate and acetylcholine release in various areas. Such drugs have possible pro-cognitive effects and appetite suppressing effects.
5-HT7 receptors regulate serotonin release and are thought to be involved in mood, learning, thermoregulation and circadian rhythm, and can possibly also be autoreceptors. Drugs with 5-HT7 blocking properties are investigated for possible antidepressant, anxiolytic and pro-cognitive effects.
90% of the body’s total serotonin is produces by enterochomaffin cells in the GI tract, which release serotonin into the gut lumen to activate peristaltic and secretory reflexes in response to stimuli there. Serotonin absorbed into the blood stream is taken up by platelets which later releases serotonin to produce vasoconstriction and promote wound healing if the platelets bind to a clot. Serotonergic neurons in the CNS are found in the raphe nuclei, a set of 8 nuclei located along the midline of the brainstem. The raphe nuclei makes up part of the reticular formation, a set of interconnected nuclei in the brainstem, which phylogenetically is one of the oldest portions of the brain. Axons from serotonergic neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord, while axons from serotonergic neurons in the higher nuclei spread out in the entire brain.
Several different classes of medical (and recreational) drugs affect the brain’s serotonin receptors:
Even though the basic monoamine hypothesis of depression is somewhat outdated, all antidepressants in clinical use modulate the monoamine system. Of the monoamines, serotonin seems to be the most important as a majority of antidepressants have a direct effect on the serotonin system. For antidepressants affecting the serotonergic system, inhibition of serotonin reuptake (SERT inhibition) is the most common mechanism to exert antidepressant effect. Other options include inhibition of enzymatic serotonin breakdown (MAO-A inhibition) or direct modulation of serotonin receptors thought to be involved in mood regulation (activating the 5HT1A receptor or blocking the 5HT1B/D, 5HT2C, 5HT3 or 5HT7 receptor).
Most antidepressants which affect the serotonergic system also have anxiolytic properties and many antidepressants are therefore approved for various anxiety disorders. Increased anxiety might be an initial, but passingy side effect of these drugs. The anxiolytic drug buspirone exerts its effect through activation of the 5HT1A receptor.
All antipsychotics block the D2 dopamine receptor or are partial agonists for the D2-receptor, but atypical or second-generation antipsychotics often also bind to specific serotonin receptors. Antipsychotic drugs that activates the 5HT1A receptor or blocks the 5HT2A receptor show less extrapyramidal side effects. Blocking the 5HT2A receptor also have the added benefit of reducing the incidence of hyperprolactinemia. Modulation of serotonin receptors thought to be involved in mood regulation is the likely reason for the antidepressant properties found in some antipsychotics.
Triptans are a class of antimigraine drugs that work by activating the 5HT1B/D receptors, which results in constriction of cranial blood vessels and inhibition of pro-inflammatory neuropeptides.
Certain drugs that block the 5HT3 receptor in the brain’s chemoreceptor zone and in the gastrointestinal tract are used to treat nausea and vomiting. These drugs have proven particularly useful for patients receiving chemotherapy.
A psychedelic is a hallucinogenic drug that alter cognition and perception in radically different ways from ordinary consciousness. Classical serotonergic psychedelics include LSD, psilocybin, mescaline and DMT and work by activating the 5HT2A receptor. Empathogens-enactogens produce experiences of emotional communion, oneness and openness. MDMA is the best known of these and function as a monoamine releasing agent and reuptake inhibitor, but mainly affect the serotonin system due to its high affinity for the serotonin transporter. Distribution and possession of these substances are illegal in many countries due to the various adverse effects associated with them.
Some other useful facts about serotonin:
Contrary to the turkey-tryptophan myth, eating turkey or other tryptophan rich food will not increase your brain serotonin (unless you’re severely malnourished) as tryptophan will have to compete with other amino acids for passage on the large neutral amino acid transporter to get across the blood brain barrier. Eating purified tryptophan might do the trick, but evidence for any clinical effect of this is currently insufficient. Tryptophan deficiency is rare as long as there is no concurrent, severe undernutrition, but can occur as a result of fructose malabsorption. Excess fructose in the gastrointestinal tract can reduce tryptophan uptake, which among other things can lead to symptoms of depression. The treatment for this would be to eliminate fructose from the diet. Tryptophan metabolism is quite interesting and might hold the link between stress, inflammation and depression. Dark chocolate contains some actual serotonin in addition to tryptophan. Serotonin is also found is seeds, fruits, nuts and a number of vegetables. Serotonin production is a way for plants to avoid buildup of ammonia and might also serve a function to speed the passage of seeds through the digestive tracts of hungry animals. The blood-brain barrier stops ingested serotonin from reaching the brain though.
Encoded by the SLC6A4 gene, the serotonin transporter removes serotonin from the synaptic cleft and back into the serotonergic neuron. 5HTTLPR is a polymorphic region in the promotor part of the gene with two common variants called “short” and “long”. Research on these variants and their influence on neuropsychiatric disorders and personality traits have yielded mixed results, but being homozygous for the short variant seem to predict poor response from antidepressants that work through SERT inhibition, which includes many of the most commonly used antidepressants. Pharmacogenetic analysis of 5HTTLPR (and cytochrome P450) polymorphism is an easy, but underutilized, way to help provide more individualized therapy.
The hormone melatonin, which is produced in the pineal gland and regulates circadian rhythms, is synthesized from the neurotransmitter serotonin.
Author: Sverre Gunnarsson Larne. Last updated: December 27nd 2015.