Serotonin

5-hydroxytryptamine (5-HT) or serotonin is a neurotransmitter that is synthesized from the transformation of the amino acid tryptophan. It is found in plants and animals intervening in many physiological processes. Its chemical formula is C₁₀H₁₂N₂O.

In humans, serotonin is synthesized in the intestines and in the brain, especially in the raphe nuclei of the brainstem. 90% of all serotonin in the human body is found in the gastrointestinal tract and in the blood platelets, the rest in the neurons of the nervous system.

It is a fundamental neuromodulator in the regulation of moods, physiological functions and behaviors of animals, including humans; in mammals it participates in the regulation of social behavior, eating behaviors, sleep, circadian rhythms, attention, anxiety, sexual behavior and the generation of rhythmic motor patterns such as chewing, locomotion or breathing.

In humans, disturbances in the serotonergic system are associated with behavioral and neurological disorders including eating disorders, depression, epilepsy, schizophrenia, and anxiety. Concentration is reduced by stress.

History

In 1935, the Italian researcher Vittorio Erspamer had shown that a hitherto unknown substance, which he called enteramine, produced by the enterochromaffin cells of the intestine, stimulated intestinal contraction. The name serotonin it reflects only the circumstances in which the compound was discovered. It was initially identified as a vasoconstrictor substance in blood plasma or serum, hence its name serotonin, an agent in serum that increases vascular tone.
In the late 1940s, serotonin was isolated and named by Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic. This agent was then chemically identified as 5-hydroxytryptamine (5-HT) by Rapport and a wide range of physiological properties have been associated with it ever since. 5-HT has been the name most adopted by the pharmaceutical industry.

Features

5-HT is a molecule that is included within the group of monoamines synthesized in this case, from the amino acid Tryptophan.
Approximately 90% of the total serotonin (5-HT) present in the human body is found in the gastrointestinal tract. Enterochromaffin cells and serotonergic neurons of the myenteric plexus synthesize, store, and secrete serotonin, which functions as a regulator of bowel secretion, motility, and sensation.
After being released from the intestine, serotonin can be found in blood platelets, which take it up from the serum and distribute it. Serotonin (5-HT) reuptake, via the transmembrane transport protein 5-HTT, represents the major mechanism of 5-HT clearance from blood plasma. Upon reaching a vessel lesion, the platelet releases serotonin that acts as a vasoconstrictor, thus functioning as a coagulation modulator.
A percentage of serotonin is synthesized in serotonergic neurons of the central nervous system. Serotonergic neurons reside primarily in the dorsal, median, and caudal raphe nuclei of the brainstem. These nuclei project to almost all parts of the brain. As a neurotransmitter, serotonin transmits signals between neurons, regulating the intensity of their discharge. During prenatal development it is a trophic factor in brain development, and it presents different expression patterns during embryonic and fetal development. It is produced within the brain, and does not cross the blood-brain barrier.

Serotonin is metabolized to 5-Hydroxyindoleacetic acid, mainly by the liver, and is excreted by the kidneys in its final phase.

Serotonin influences a variety of bodily and psychological functions; for example, it is related to bone metabolism, breast milk production, liver regeneration, and cell division.
Stimulates the vomiting center in the brain, causing nausea. There may be an increase in osteoporosis. With respect to sexuality, it has been shown that a percentage of people who take SSRI medications have reduced desire and sexual function, as a side effect of the drug.
However, the role of 5-HT in behavior remains poorly understood due to the lack of methods to target the brain and synthesis in adults.^{[citation needed]}

Neurotransmission of Serotonin

Fig.1 Parts of a neuron.

Neurons are interconnected to form neural networks or circuits, which transmit signals. The signals are the result of the interaction between these networks and not of the specific characteristics of each individual neuron.

The perikaryon or soma is the zone of protoplasm of the neuron that surrounds the nucleus and is the metabolic center of the neuron, where the fundamental activities are carried out. The single axon conducts the nerve impulse from the neuron to other cells, branching in its terminal portion and being the longest extension. Dendrites are short plasmatic extensions, which are found in large numbers throughout the neuron and have the function of receiving signals.

The nerve cell has two main functions, the propagation of the action potential (impulse or nerve signal) through the axon and its transmission to other neurons or effector cells to induce a response.

Criteria as a neurotransmitter

Serotonin meets the general criteria to be classified as a neurotransmitter. Serotonin is present, it is released, its action is identified, it activates its receptor, and it is inactivated after acting.
Presence of the neurotransmitter:

• The chemical agent must be located in the pre-synaptic elements and probably distributed throughout the brain.
• Neuron should contain precursors, selective enzymes or a specific transport mechanism for the neurotransmitter.
• In sinapsis there must be receptors for the neurotransmitter.

Release:

• The stimulation of the affers should produce neurotransmitter release in physiological quantities.

Action identity:

• The direct application of the neurotransmitter to the sinapsis should produce effects identical to those produced by electrical stimulation.

Neurotransmitter receptor activation

• The interaction of the neurotransmitter with its receptor must induce changes in the membrane that result in potential post-septic excitatory or inhibitory.
• Aferent stimulation or direct application of the substance should produce effects similar to those produced by the application of pharmacological agents.

Inactivation:

• Inactivation mechanisms (dissemination, metabolic enzymes, recaptation systems) must be in place to conclude the interaction of the neurotransmitter with the receptor.

Monoamine Neurotransmitters

Neurotransmitters are the chemicals that are responsible for the transmission of signals across synapses, from one neuron to the next. Serotonin is part of the monoamine neurotransmitter group along with norepinephrine, adrenaline, histamine, and dopamine.

Biochemical Events

• Neurotransmitter Synthesis: The neuronal body produces certain enzymes that are involved in synthesis. These enzymes act on certain precursor molecules captured by the neuron to form the serotonin neurotransmitter.
• Storage of neurotransmitter molecules in synaptic vesicles, in which the content (usually several thousand molecules) is quantum. Some neurotransmitting molecules are constantly released into completion, but in insufficient amount to produce a significant physiological response.
• Release of transmitters by exocytosis. To the presynaptic neuron comes a nervous impulse and opens the channels of Ca⁺². The Ca⁺² enter and the neurotransmitter is poured into the synaptic space.
• The neurotransmitter binds to the neuroreceptor. The substance is able to stimulate or inhibit quickly or slowly, can be released into the blood to act on several cells and away from the release site, can allow, facilitate or antagonize the effects of other neurotransmitters. You can also activate other substances inside the cell to produce biological effects. In addition, the same neuron may have different effects on post-synaptic structures, depending on the type of post-synaptic receptor present.
• Initiation of the actions of the second messenger. The post-synaptic neuron receiver sends intracellular responses that can trigger different responses. Inactivation of the transmitter, either by chemical degradation or by reabsorption in the membranes.
• The neurotransmitter has to disappear due to the presence of a specific enzyme that inactivates the neurotransmitter or through recaptation, a process through which the presynaptic cell retakes the neurotransmitter and keeps it inside (implies an energy saving).

Fig.4 Chemical Neurotransmission.

Alterations in the synthesis, storage, release, degradation of neurotransmitters, changes in the number or activity of receptors, can affect neurotransmission. Many neurological and psychiatric disorders are due to an increase or decrease in the activity of certain neurotransmitters and many drugs can modify it; some produce effects considered adverse, such as hallucinogens, and others can correct some pathological dysfunctions, such as antipsychotics. Like all neurotransmitters, the effects of 5-HT on human mood and mental state, and its role in consciousness, they are very difficult to determine.

• Among the main functions of serotonin is to regulate appetite through satiety, balance sexual desire, control body temperature, motor activity, and cognitive and perceptive functions.
• Serotonin intervenes in other known neurotransmitters such as dopamine and noradrenaline, which are related to anguish, anxiety, fear, aggressiveness, as well as food problems.
• Serotonin is also involved in bone density parameters. People who take antidepressants of the type inhibitors of serotonin reuptake can generate osteoporosis (reduce bone density).

Anatomical relationship

Neurons in the raphe nuclei are the main source of 5-HT release in the brain.

The raphe nuclei are bundles of neurons distributed in nine paired groups and located along the entire length of the brainstem, which is centered around the reticular formation.

Routes of Serotonin (5-HT).

Dahstrom and Fuxe described 9 groups of cells containing serotonin from B1 to B9:

• The largest group of serotonergic cells is group B7 contiguous to B6.
• The B6 and B7 group are the spinal core.
• B8 is the middle core of the raf. upper central core.
• The B9 side-tech of the bridge and the middle brain.
• B1 to B5 flow and contain a low number of serotonergic cells.

Serotonin released by the synaptic terminals of raphe neurons immediately activates autoreceptors in the terminals that released it. In this way, the subsequent excitability and the frequency of firing and release are decreased in a localized manner. The differential regulation of release in each cell compartment allows the same neuron to produce different types of effects depending on the firing frequency.

Fate of axons of neurons located in the rostral dorsal raphe nucleus:

• ♪
• Striated core
• Hipotálamo
• Núcleo accumbens
• Neoórtex
• Giro cingula
• Closing
• Hipocampo
• Amígdala

The axons of the neurons of the raphe nuclei end in, for example:

• Deep cerebelous cores
• Cerebel cortex
• Spinal cord

Thus, the activation of this serotonergic system has effects in several areas of the brain, which explains the therapeutic effects in its modulation.

Microanatomy

5-HT is thought to be released from serotonergic varicosities into the extra-neuronal space, in other words, from swellings (varicosities) and throughout along the axon, not only by terminal synaptic buttons (classical neurotransmission scheme). From this point it is free to diffuse over a relatively large region of space (> 20 µm) and activate 5-HT receptors located on dendrites, perikaryons, and the presynaptic endings of adjacent neurons.

Receivers

There is no single receptor for serotonin, but it has been seen that these comprise a large family of receptors with specific functions in the pre- and postsynaptic areas. Pharmacological and physiological studies have contributed to the definition of many receptor subtypes.

Postsynaptic serotonin receptors (R5-HT) have inhibitory or excitatory effects on cortical neurons. Serotonin receptors with inhibitory effects are (HTR-1A and HTR-5A), while serotonin receptors with excitatory effects are (HTR-2A, HTR-2C, HTR-4, HTR-6).

Fig.5 Serotonin receptors.

There are 7 types of serotonin receptors, which in turn have some differences between species: 5HT-1 to 5HT-7 receptors.

• The 5HT-1 receptor family are those that have an inhibiting effect of the activity. 5HT-1A acts in the somas of serotoninergic neurons or in the terminal areas of such neurons, usually in the lymbic system or the cerebral cortex. In them, the union of serotonin inhibits the very synthesis of the NT. The 5HT1B and 1D receptors in humans, by uniting serotonin inhibit the release of such neurotransmitter by the lack of cyclase adenylate in the post-inaptic receptors found in the synaptic cleft.
• 5HT-2 family receptors activate neurons, serotoninergics or heteroreceptors. They stimulate the production of second messengers such as IP3 or DAG. The 5HT-2A act at the cerebral cortex level and 5HT-2C in the coroid plexies, controlling the cerebrospinal fluid.
• 5HT-3 receptors are coupled to ionic channels of potassium, sodium or calcium, are called ionotropics. They are located in the brain trunk and are formed by 5 subunits (of the type 5HT-3A and -3B) and is very similar to the nicotynic receptor. It is found in serotonergic neurons, heterorreceptors, where it intervenes in the perception of pain through the release of the P substance, GABA neurons, dopamine and acetylcholinergicas where it is responsible for the release of dopamide and other neurotransmitters.
• Types 5HT-4, -6 and -7 are coupled, all of them, to the important G protein. When activating G proteins facilitate the activation of ciclase adenylate, increasing the internal levels of AMPc, increasing the ability to transmit a signal from the neuron. 5-HT4 is found in dopaminergic neurons of the hippocampus where it acts as heterorreceptor facilitating the release of dopamine, which entails an improvement in cognitive processes of memory.
• On the other hand 5HT-5 is very little known and its exact function still remains undiscovered.^{[chuckles]required]}
• 5HT-6 is closely related to the regulation of emotional behaviors. It is with this serotonin receptor that many psychotropics act with, having the LSD more affinity for this receptor than the serotonin itself. Many drugs against schizophrenia are related to inhibiting these receptors. It is found in the hippocampus, the cerebral cortex and the lymbic system.
• The 5HT-7 receptors are in the suprachemical core of hypothalamus. It performs its activity by activating the ciclase adenylate and the AMPc. It is responsible for regulating the electrophysiological and metabolic circadian cycles related to hunger or sleep.

Genetic factors

Genetic variations in the alleles that code for serotonin receptors are currently known to have a significant impact on the likelihood of certain physiological problems and disorders. For example, a mutation in the allele that codes for the HTR2A receptor leads to a doubling of the risk of suicide for those with that genotype.

However, the evidence of this finding has yet to be reproduced satisfactorily, as it is noted that doubts have been raised about the validity of this discovery. It is highly unlikely that a single gene is responsible for the increase in suicides. It is more likely that a number of genes combine with exogenous factors to affect behavior in this way.

This gene (HTR2A) encodes one of the receptors for serotonin. Mutations in this gene are associated with susceptibility to schizophrenia and obsessive-compulsive disorder, and are also associated with response to the antidepressant citalopram in patients with major depressive disorder.

Termination

Serotonergic action is terminated primarily by 5-HT uptake at the synapse. It is thought to be via a 5-HT-specific monoamine transporter, the 5-HT reuptake transporter, in the presynaptic neuron. Several agents can inhibit the reuptake of 5-HT including MDMA or ecstasy, amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants (TCAs), and Selective Serotonin Reuptake Inhibitors (SSRIs).

Summary

Serotonin synthesis.

In the body, serotonin is synthesized in the neuron, both in the nucleus and in the endings from the amino acid tryptophan that involves two enzymes: tryptophan hydroxylase (TPH) and an L-amino acid aromatic decarboxylase (DDC). Once the tryptophan is inside the appropriate neurons the enzyme tryptophan hydroxylase will generate 5-hydroxytryptophan, by adding a hydroxyl group to tryptophan, forming 5-hydroxytryptophan. Amino acid decarboxylase, the second enzyme present in this process, takes 5-hydroxytryptophan and removes the carboxyl group, resulting in serotonin. The TPH-mediated reaction is a rate-limiting step in the pathway. TPH has been seen in two naturally occurring forms: TPH1, found in various tissues, and TPH2, which is a brain-specific isoform. There is evidence of genetic polymorphisms in both types influencing susceptibility to anxiety and depression. There is also evidence of how ovarian hormones may affect TPH expression in various species, suggesting a possible mechanism for postpartum depression and premenstrual stress syndrome.

As already mentioned, serotonin synthesis takes place in serotonergic neurons where it is produced from tryptophan. This amino acid can pass through the blood-brain barrier and is obtained from the diet in sufficient quantities for the synthesis of serotonin and other compounds. Tryptophan is a neutral aromatic amino acid and competes for the membrane transporter with tyrosine.

Orally ingested serotonin 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 metabolites 5-hydroxytryptophan (5-HTP), with which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as dietary supplements and may be effective serotonergic agents. One product of cleavage is 5-hydroxyindolacetic acid (5 HIAA), which is excreted in the urine. Sometimes, Serotonin and 5 HIAA are produced in excessive amounts by certain tumors or cancers, and the levels of such substances can be measured in urine to verify the presence of such pathologies.

Functionality

Recent research suggests that serotonin plays an important role in liver regeneration and acts as a mitogen (inducing cell division) throughout the body.

The serotonergic function is fundamentally inhibitory.^{[citation needed]} It exerts an influence on sleep and is also related to moods, emotions and depressive states. It affects vascular function as well as the frequency of the heartbeat.

It regulates the secretion of hormones, such as growth hormones. Changes in the level of this substance are associated with mental imbalances such as schizophrenia or childhood autism.

It also plays an important role in obsessive-compulsive disorder, an anxiety disorder. Some hallucinogenic mushrooms, LSD and MDMA act strongly on serotonin receptors. Among the physiological functions of serotonin, the inhibition of gastric secretion, the stimulation of smooth muscle and the secretion of hormones by the pituitary gland stand out. Low serotonin levels in people with fibromyalgia partly explain the pain and sleep problems. These low levels have also been associated with aggressive states, depression and anxiety, and even migraines, because when serotonin levels drop, blood vessels dilate. It plays an important role in lymphocyte proliferation depending on the type of receptor stimulated (5-HT_1A vs. 5-HT₇).

Serotonin has a general modulatory and behavioral inhibitory effect, it influences almost all brain functions, directly inhibiting or by stimulating GABA (gamma-amino-butyric acid). In this way, it regulates thymia, which is the individual's outward behavior, sleep, sexual activity, appetite, circadian rhythms, neuroendocrine functions, body temperature, pain, motor activity, and cognitive functions:

• Sleep regulation: Serotonin is the mediator responsible for phases III and IV of slow sleep. The sleep-vigilia rhythm is regulated by the adrenergic-serotonergic balance, and the decrease in the REM latency, characteristic of the depressive states that is due to a serotonergic-colinergic imbalance.
• Regulation of sexual activity: Serotonin has an inhibitory effect on the hypothalamic release of gonadotrophine with the resulting decrease in normal sexual response. The pharmacological decrease in direct serotonin or aminergic competitiveness facilitates sexual conduct.
• Regulation of neuroendocrine functions: Serotonin is one of the main neurotransmitters of the hypothalamic suprachismatic nucleus on which the synchronization of endogenous circadian rhythms of the entire organism depends. It also influences the inhibitory or stimulating regulation of the peptidergic factors of the hypothalamus-hypophytic-peripheral axes.
• Thermo-nociceptive regulation: Serotonin produces a dual effect on thermos according to the stimulated receptor. 5TH1 produces hypothermia and 5HT2 hyperthermia. In the dream of slow waves, the minimum temperature peak coincides with the appearance of the peak of growth hormone secretion. Serotonin is an important nociceptive neuromodulator. Agonists produce analgesia in laboratory animals, the anthalgic effect of tricyclic antidepressants being well known.

Serotonin and sexual behavior

Human behavior depends on the amount of light the body receives each day. In this way, during the less sunny seasons (autumn and winter) an increase in depression and lack of sexual stimulation occurs. When spring and summer arrive, serotonin is conditioned to the light it receives from the body, which leads to a progressive increase in well-being and happiness with greater sexual stimulation, as a result of the concentrations of this neurotransmitter in the brain.

You could say that serotonin is the "pleasure hormone" as well as being the "mood hormone".
Let's see this through a clear example. For ejaculation or orgasm to occur, the hypothalamus releases oxytocin through the pituitary gland (a hormone that is secreted in the neurohypophysis and is also responsible for contractions during childbirth). After ejaculating, the amount of serotonin in the brain increases considerably, which causes a state of pleasure and tranquility.

After pleasure, a feedback mechanism occurs that reabsorbs serotonin. This mechanism stimulates the release of hormones such as somatotropin (growth hormone) and prolactin (it has an action on the mammary glands acting on their growth and milk formation) and inhibits the secretion of luteinizing hormones (LH), and follicle-stimulating hormones (FSH) that They are responsible for stimulating the synthesis of cyclic AMP, which in turn stimulates the biosynthesis of sex steroids. This feedback mechanism would not be possible if serotonin uptake by the pituitary gland did not occur.
Thus, it is known that the presence of serotonin produces pleasure, and the reabsorption of this neurohormone triggers a series of reactions that stimulate the secretion of hormones, which in turn produce minimal growth and control the maturation of the ovarian follicle, and the secretion of sex hormones and spermatogenesis among other things.

Serotonin and body weight

Serotonin plays a key role in regulating body weight. Since the 1980s, a direct relationship between serotonin levels and appetite control has been confirmed.

In 2010, a study was published confirming the specific receptors responsible for regulating body weight via serotonin. Serotonin 2C and serotonin 2B receptors influence appetite due to an increase or inhibition in the activity of melanocortin receptors.