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Alteration of the serotonergic system via the intestine

Serotonin plays an important role in digestive regulation. We know that 95% of the body’s total serotonin is generated in the enterochromaffin (EC) cells of the intestinal epithelium. They secrete it both to the intestinal light and to the interstitial fluid in response to mechanical and chemical stimuli, such as increased intraluminal pressure, osmolarity changes, and changes in luminal acidity. These changes are controlled by a series of receptors, which can be stimulants such as b-adrenergic, muscarinic, nicotinic and 5-HT3, or inhibitors such as alpha2 adrenergic, gamma aminobutyrate, histaminergic H3, VIP receptors, somastostatin and 5-HT4.1

Enterocytes are responsible for the reuptake of serotonin through the expression of the serotonin transporter (SERT). The metabolization of serotonin occurs at the intracellular level, mainly by the activity of the enzyme monoamine oxidase (MAO) which produces an oxidative deamination, leading to the formation of an intermediate product, 5-hydroxy-indolacetaldehyde, which is subsequently oxidized by an aldehyde dehydrogenase to form 5-hydroxy-indolacetic acid (5-HIAA). When this system becomes saturated, the intermediate product is reduced in the liver, producing 5-hydroxytryptofol. In the digestive system, serotonin can also be catabolized by glucoronyl transferase and other intracellular enzymes, as can MAO and aldehyde dehydrogenase.1

The intestinal mucosal lamina itself is rich in mast cells. Murine mast cells are capable of synthesizing and releasing 5-HT, but under normal conditions mast cells in the intestinal mucosa of humans do not appear to synthesize 5-HT. On the other hand, there is evidence that human enteric mastocytes express TPH (tryptophan hydroxylase). It is possible for human mast cells to synthesize and release 5-HT under pathological conditions, contributing to conditions such as hypersensitivity.2

Not all serotonin-containing cells synthesize it. Such is the case with platelets, which accumulate 8% of the total by uptake from plasma via the serotonin transporter (SERT), a process in which intracellular calcium appears to play a regulatory role.1

Platelets that capture serotonin that has not been collected by epithelial cells at the intestinal level may promote hemostasis, influence bone development, and contribute to allergic inflammation of the airways.60 This accumulation of serotonin in platelets may increase their volume, as there is an increase in the mean volume of platelets in patients with panic disorder due to the storage of serotonin in them.3  Although we will discuss the behavior of platelets during the pathology described later.

There is evidence of alteration of the serotonergic intestinal system and gastrointestinal dysfunction in pathologies such as Irritable Bowel Syndrome and chronic inflammatory bowel disease4. It has also been observed that Irritable Bowel Syndrome (IBS) with predominance of diarrhea, leads to an increase in serotonin concentration, possibly due to alteration in the functionality of the serotonin transporter.5,1

On the other hand, numerous evidences indicate that serotonin plays a key role in the chronic intestinal inflammation of patients with Crohn’s disease, ulcerative colitis or with a history of diverticulitis. These processes have been associated with an increase in the number of enterochromafine cells6,7  and a decrease in the transcription of the serotonin transporter gene, causing both alterations an increase in the availability of 5-HT in the intestinal mucosa.1,7,8

In the intestine, the pathophysiological consequences of excessive 5-HT release are known, including diarrhea induced by cholera toxin9,10, nausea and vomiting. In fact, elevated serotonin concentration in Irritable Bowel Syndrome has also been associated with predominance of diarrhea. One of the causes of such an increase in serotonin concentration is altered transporter function.1,5

Therefore, circulating serotonin is often studied in gastrointestinal disorders as a reflection of the availability of 5-HT in the mucosa.2 Postprandial 5-HT levels are elevated in platelet-poor plasma samples obtained from patients with IBS-D (Irritable Bowel Syndrome with predominance of diarrhea)11,12 or post-infectious IBS,12 but 5-HT levels have been reported to be reduced12 or unchanged13 in IBS-C (with constipation). In contrast, levels of 5-HT in platelets are reduced in SII-D14, but are doubled compared to healthy controls in SII-C patients.13 Taken together, these results are consistent with a decrease in 5-HT uptake by the intestinal epithelium in both forms of SII, as more 5-HT appears to be ending up in circulation after food ingestion (especially carbohydrates). The ability to detect elevated post-prandial levels of 5-HT in platelet-poor plasma in IBS-D but not in IBS-C may reflect differences in SERT function in platelets in these disorders. The uptake of 5-HT by platelets appears to be altered in individuals with IBS-D.14,15,16 This may explain the elevated levels of post-prandial 5-HT in platelet-poor plasma samples from patients with IBS-D, since both platelets and enterocytes express TLR3.17,18 This receptor, when activated by viral infections such as EBV, causes a decrease in SERT activity thereby decreasing serotonin reuptake by both cells.15

In chronic constipation, SERT expression is not altered19, but the 5-HT content, the number of enterochromaffin cells (EC), and the release of 5-HT are increased.19,20

The intestinal epithelium, in addition to developing digestive and absorptive activity, constitutes an anatomical and immunological barrier between light and the internal intestinal compartment. This epithelium is in close contact with a great variety of commensal microorganisms and with the products of the digestion of the ingestion. Both pose a threat to the immune stability of the intestine.1

Three mechanisms are involved in the stability of the epithelium in its role as an intestinal barrier:1

  1.  The innate immune system, which is the first line of defense against resident intestinal microflora or luminal invading pathogens. TLR receptors are located in mononuclear, dendritic, and macrophage cells, as well as in different epithelial cells and are an important mechanism in the innate immunity of the intestinal epithelium.
  2. The transepithelial barrier in which the mucosal epithelium is the first line of physical defence against luminal aggressions. The integrity of this epithelial barrier is maintained by adhesion and intercellular bonding molecules that allow the epithelial polarity to be established.
  3. The adaptive intestinal immune system is activated when the balance between antigenic or pathogenic stimulation and innate intestinal immune activity is disturbed.

Alteration of any of these three systems, i.e., inappropriate regulation of the innate immune system, increased epithelial permeability, or defective regulation of the adaptive immune system, poses a risk for developing an inflammatory pathology in the intestinal mucosa.1

They demonstrated that the extracellular increase of factors released in inflammation inhibits the activity of the serotonin transporter. Because the transporter internalizes serotonin, the results indicated that these same inflammatory factors increase the extracellular availability of serotonin, which may attempt to palliate or contribute to the inflammatory situation.1

They concluded that activation of various toll receptors reduced the activity of the serotonin transporter. They observed that TLR3 was activated by double chain RNA of viral origin, TLR4 by lipopolysaccharide of gram-negative bacteria and TLR5 was activated by the flagellin protein of flagellin microorganisms present in the intestine such as Salmonella and Escherichia Coli.1EBV would activate TLR3 producing an increase in mucosal inflammation that would lead to an increase in the permeability of gram-negative bacteria that would also activate TLR4.

Therefore, reduced serotonin transporter activity and expression in the intestinal mucosa leads to increased availability of 5-HT at the local level.1,2

As in the case of EBV infection with HBMEC, infection of the epithelial cells of the intestinal mucosa by this virus leads to the rupture of the narrow junctions of the intestinal barrier, leading to the passage of bacteria and other substances. At the same time, EBV is able to infect plasma cells in the mucosa. Therefore, B cells with latent EBV infection release EBERs. The release of EBER1 from EBV-infected cells was shown to induce activation of TLR3 signalling, resulting in induction of type I IFN and pro-inflammatory cytokines. Circulating EBER1 can induce activation of dendritic cells and subsequent activation of T cells, leading to systemic production of proinflammatory cytokines. Since CD8+ T cells and NK cells express TLR3, they would be activated by these signals from EBER1.21 But EBV miRNAs would in turn inhibit CD8 lymphocyte response and CD4 lymphocyte activation, so there would only be an increase in pro-inflammatory cytokines without immune recognition of the infected cells.

CONSEQUENCES OF EXCESS EXTRACELLULAR SEROTONIN
We will first focus on the effect of serotonin on the gastrointestinal system, as this is where its accumulation occurs as a result of EBV infection. And later, as it would affect the extracellular excess of serotonin, due to intestinal pathology, to the rest of the organism.

At the peripheral level, 5-HT participates in physiological processes including: hemostasis, regulation of the cardiovascular system, control of motility, secretion and intestinal epithelial absorption.

SEROTONIN RECEPTOR ACTIVATION
This increase of serotonin in the gastrointestinal tract provokes relevant physiological responses by the presence of several receptor subtypes in various classes of myenteric neurons, smooth muscle cells and epithelial cells.1

The serotonin receptor subtypes 5-HT1, 5-HT2, 5-HT3, 5-HT4, and 5-HT7 are known to affect intestinal motor function. The 5-HT1A receptor is expressed in neurons of the myenteric plexus, submucosal and enterochromaffin cells. It produces a rapid decrease in the amplitude of the excitatory post-synaptic potentials. On the other hand, 5-HT1B, 5-HT1D and 5-HT2A have been shown to stimulate or inhibit smooth muscle contraction depending on the portion of the digestive tract and the reference species.

However, this type of receptor can fulfill other functions in humans such as mediating the contraction of longitudinal smooth muscle. Furthermore, 5-HT2 receptors appear to be involved in regulating intestinal absorption of nutrients.1 Serotonin is also known to be pro-inflammatory, acting through 5-HT2A receptors to increase extravasation of T-lymphocytes and eosinophils, and may also activate mast cells.15

5-HT3 and 5-HT4 receptors, when stimulated both centrally and peripherally, promote vomiting, gastric emptying, electrolyte secretion, serotonin secretion in enterochromaffin cells, contraction and/or relaxation of smooth muscles and modulate amino acid absorption at the intestinal level.1 The 5-HT3 receptor seems intimately involved in signaling the intestinal-brain system, particularly through the afferent (sensory) pathway of the vagus nerve. It is also involved in visceral hypersensitivity.22

With respect to the 5-HT7 receptor, its activation produces relaxation in the ileum and colon and it has also been postulated that its overstimulation may lead to exaggerated accommodation of the circular smooth muscle of the colon with increased volume, a common symptom in many intestinal functional disorders.1

Recent results have shown that both 5-HT1A and 5-HT7 are expressed in intestinal epithelial cells and modulate serotonin transporter activity.1

GASTROINTESTINAL TRACT
Serotonin secretion occurs both in the direction of the innermost portions of the wall of the intestinal tract (the lamina propia) and towards the intestinal light.1

If the secretion of serotonin is in the direction of the proper lamina, it can bind to receptors in the axons of the primary intrinsic submucosal afferent neurons that innervate the secretory epithelium and are in charge of initiating the secretory and peristaltic reflexes, and/or it can bind to its receptors in the primary afferent intrinsic myenteric neurons and participate in the regulation of the peristalsis through the initiation of migratory contractions. In addition, it has also been shown that serotonin regulates the activity of the interstitial cells of Cajal, with the corresponding regulation of the electrical activity of smooth muscle.1

On the other hand, extrinsic afferent neurons are activated directly by serotonin released from enterochromaffin cells and indirectly by intrinsic primary afferent neurons, carrying information from the intestinal tract to the central nervous system through the vagus nerve.1That is, parasympathetic innervation in the stomach, small intestine, and proximal colon is provided by the vagus nerve. A mixed nerve, which contains both sensory and motor fibers. It contains approximately 70-80% sensory fibers that transduce physiological events in the GI tract and transmit them to the CNS.22This information is related to sensitivity to luminal content. The presence of carbohydrates and hyperosmotic stimuli strongly induce the release of 5-HT.1

The release of EBER by plasma cells containing latent EBV at the level of the intestinal mucosa activates TLR3 causing a decrease in the activity of the serotonin transporter, which leads to an accumulation of this nerurotransmitter. As described above, the presence of carbohydrates in the lumen would further increase its secretion and consequently its accumulation together with a greater symptomatology.

Likewise, the vagus nerve means the inhibition of gastric emptying and duodenal motor responses, so it is related to nausea and vomiting. As well as with the conduction of signals that lead to perceptions of discomfort and pain in the gastrointestinal tract, process carried out by spinal afferent route.1

In the intestine, serotonin has been shown to regulate the proliferation of epithelial cells and inhibit the intestinal absorption of monosaccharides and amino acids.1

At the stomach level there are also 5-HT receptors where an increase in serotonin inhibits acid secretion. It decreases the release of gastrin by G cells and HCL (hydrochloric acid) as a consequence.23,24

In inflammatory bowel disorders, gastric hyposecretion with hypergastrinemia due to atrophic gastritis type A may also occur through autoimmune destruction of parietal cells by autoantibodies.25

In both cases there is gastric hyposecretion which is one of the causes of bacterial overgrowth in the small intestine (SIBO).26,27 And if we add changes in intestinal motility together with immunological alterations due to EBV infection, the probability of suffering from SIBO would increase even more.

Disturbance of the serotonergic system also occurs in patients with autism, as it has been observed that they have elevated serotonin levels due to alteration of the serotonin transporter (SERT).28

Autistic patients, as in the digestive pathologies described in this article, have altered the lining of the intestinal mucosa with a decrease in the activity of digestive enzymes of carbohydrates and large proteins such as gluten, gliadin and casein leading to a malabsorption of these, which can cause inflammation and is believed to act as neuropeptides.  Therefore, peptides derived from gluten and casein are not converted into amino acids. Increased intestinal permeability then allows these peptides to leak into the bloodstream, where they circulate and eventually cross the blood-brain barrier, which could lead to inflammation and impaired neurological functions. Neuropeptides have adverse effects on attention, brain maturation, social interactions, and learning in these patients.28,29

Lau et al. conducted a study aimed at evaluating gluten immune reactivity in pediatric patients diagnosed with autism relative to healthy controls of the same age. Children with autism had significantly higher levels of IgG antibodies to gliadin compared to healthy controls, but did not reach statistical significance. There was no difference in IgA response to gliadin in all groups. Levels of serological markers specific to celiac disease, i.e. antibodies against gliadin desamidada and TG2, did not differ between patients and controls. No association was observed between increased anti-gliadin antibody and the presence of HLA-DQ2 and/or -DQ8. In conclusion, a subset of children with autism showed an increased immune reactivity to gluten, whose mechanism appears to be distinct from that of celiac disease. The increased anti-gliadin antibody response and its association with gastrointestinal symptoms points to a potential mechanism involving alterations in immune and/or intestinal permeability in affected children.30

This increased intestinal permeability resulting from damage to the intestinal epithelial barrier in people with autism may be responsible for increased exposure of the immune system to partially digested gluten fragments, resulting in the detected increase in antibody response30 .

Another study showed that elevated casein and gliadin specific IgG titers were more frequent among patients with autism spectrum disorder (ASD) on a regular diet than with casein- and gluten-free diet controls. These findings confirm previous articles on increased reactivity to milk proteins (casein). An increase in specific gliadin IgG titers was found in autistic patients which could be explained in part by the significant increase in AGA-IgG (antigliadin IgG antibodies) and DPG-IgG (antibodies against the discouraged gliadin Ig G peptide). In addition, the fact that the AGA-IgA and DPG-IgA titers were similar in TEA and controls indicates that the immune response of the mucosal surface may not have been involved. It is therefore not considered celiac disease as these IgAs are not elevated but there is a reaction against these proteins due to elevated AGA-IgG titers due to increased intestinal permeability.31

Due to the damage produced in the intestinal mucosa, the absorptive capacity is reduced and/or the expression of lactase decreases, in addition to a possible significant increase in jejunal transit. This is hypolactasis secondary to EBV infection. When the lactase activity is decreased, the lactose arrives without hydrolyzing to the colon, where it is fermented by the intestinal flora with the consequent production of short chain fatty acids (SCFA) and gas, mainly hydrogen (H2), carbon dioxide (CO2) and methane (CH4). Thus, undigested lactose entering the large intestine can lead to osmotic diarrhoea and the products of its bacterial digestion to secretory diarrhoea and gas. But this type of intolerance, which also occurs in any disease of the small intestine such as celiac disease, Crohn… is reversible as long as the mucosa is repaired. (The same happens with fructose intolerance in the presence of enteropathies).32

Small Intestine
– HIV Enteropathy
– Crohn’s disease
– Regional enteritis
– Tropical sprue and celiac
– Whipple’s disease
– Severe gastroenteritis
Multisystemic
– Carcinoid syndrome
– Immune Deficiencies
– Cystic fibrosis
– Diabetic gastropathy
– Kwashiorkor
– Zollinger-Ellison syndrome
Iatrogenic
– Post-chemotherapy
– Radical enteritis

Figure: Causes of secondary hypolactasia.32

Bacterial fermentation in the colon of unabsorbed sugars such as fructose and/or sorbitol generates short-chain fatty acids AGCC (acetate, propionate, and butyrate), gases (hydrogen, carbon dioxide, and methane), and an osmotic charge in intestinal light. Like the decrease in lactase, due to inflammation caused by the infection (this would also be a secondary malabsorption). This type of malabsorption is not genetically coded está́ and is due to the presence of an intestinal disease that damages the intestinal mucosa temporarily, although it can also be permanent. It is common in gastroenteritis, bacterial overgrowth, inflammatory bowel disease, radiation enteritis, and celiac disease.32

Malabsorption of carbohydrates develops as a result of the premature breakdown of sugars by bacteria along with decreased disaccharidase activity, secondary to the interruption of the intestinal brush rim.26

The passage of undigested and properly absorbed food becomes a substrate for bacterial fermentation allowing the appearance of overgrowth along the small intestine. In fructose and lactose intolerance tests, the levels of methane and hydrogen in breath are measured after oral introduction of lactose or fructose solutions. The point is that many digestives think that the positive results of these tests are not because of these intolerances but because of the presence of SIBO, since the metabolism of carbohydrates in the small intestine, in the presence of colonic bacteria, leads to changes in the concentrations of hydrogen and methane from fermentation. But the fact that there is this overgrowth is already indicating that there is a problem in the digestion / absorption of carbohydrates. If these tests are positive, they will indicate malabsorptive problems (intolerances) and SIBO.

Due to inflammation, increased motility and malabsorption, patients are at risk for various deficiencies, especially of vitamins A, D, E, B12 and iron. (As it also happens in patients with CFS). They also suffer from weight loss and chronic diarrhoea.26

Fat malabsorption occurs as a result of bacterial deconjugation of bile salts. In addition, free bile acids are toxic to the intestinal mucosa, leading to mucosal inflammation and malabsorption. Deconjugated bile salts are reabsorbed into the jejunum instead of the ileum, leading to altered micellar formation, malabsorption of fats, and deficiencies of fat-soluble vitamins (A, D, E, and K). Fortunately, symptoms rarely develop; however, in severe cases, night blindness (vitamin A), osteomalacia and tetany due to hypocalcemia (vitamin D), prolonged prothrombin times (vitamin K), or neuropathy, retinopathy, and deficiencies in T-cell function may occur.26

A complication of bacterial overgrowth is cobalamin (vitamin B12) deficiency.  Patients with normal intestinal flora use intrinsic gastric factor to bind to vitamin B12 that allows its absorption in the ileum. An animal model of SIBO showed that there is a competitive uptake of vitamin B12 by bacteria (especially aerobic). Human subjects with atrophic gastritis and bacterial overgrowth absorb significantly less protein-bound B12 compared to controls, although this was reversed with antibiotic therapy. Folate levels may be normal, but are often elevated due to increased folic acid synthesis by bacteria in the small intestine.26

Other evidence suggesting poor digestion is the positivity of undigested food leftovers in stool.

CARDIOVASCULAR SYSTEM
As mentioned above, there is communication between the intestinal tract and the CNS via the vagus nerve. The activation of 5-HT3 receptors in these afferent vagal endings is associated with the Bezold-Jarisch reflex, causing hypotension and bradycardia. When these fibers are activated, an abnormal or paradoxical autonomic response is produced, resulting in vasodilatation (by reduction of sympathetic efference) and increased vagal tone, with subsequent reduction in cardiac filling and bradycardia, which may eventually lead to vasovagal syncope. This coincides with the fatigue and bradycardia that sometimes occurs in CFS patients.33 Due to bradycardia and hypotension, blurred vision may result from syncope (inadequate cerebral blood flow), especially in the erect position (orthostatic hypotension).

LOCOMOTOR SYSTEM
Platelets examine blood vessels, looking for endothelial damage and preventing loss of vascular integrity. However, there are circumstances in which vascular permeability increases, suggesting that platelets sometimes fail to perform their expected function. Inflammatory arthritis is associated with tissue edema attributed to increased permeability of the synovial microvasculature. Murine models have suggested that such a vascular leak facilitates the entry of autoantibodies and may therefore promote inflammation of the joints.34

Using an autoimmune arthritis model, the absence of platelets was shown to decrease permeability in inflamed joints. This effect was mediated by platelet serotonin accumulated through the serotonin transporter.34

Platelets become the main cause of vascular permeability in arthritis, through the release of serotonin, and may promote the development of the disease. The critical role of platelets in vascular leakage may not be unique to arthritis. In models of acid-induced lung inflammation or abdominal sepsis, platelet depletion prevents inflammation and vascular loss, indicating a potential role of platelets in vascular permeability during inflammation in the lung.34

Importantly, they identified serotonin as a platelet-derived mediator capable of initiating the formation of holes in the vasculature during inflammation, compatible with the extravasation of PMs (microparticles of platelets). However, holes formed in the joint vasculature during autoimmune arthritis can be detrimental to the joint. Like platelet MPs rich in IL-1, immune complexes, as the etiologic agent in RA (rheumatoid arthritis), are also submicronic in size, with diameters ranging from 0.1 m to approximately 1 m. The immune complexes, as the etiologic agent in RA (rheumatoid arthritis), are also submicronic in size, with diameters ranging from 0.1 m to approximately 1 m. The immune complexes, as the etiologic agent in RA (rheumatoid arthritis), are also submicronic in size, with diameters ranging from 0.1 m to approximately 1 m. It is therefore plausible that platelet-produced breccias contribute to joint invasion by both immunocomplexes and PMs, supporting a double contribution to joint inflammation.34

It also indicates that serotonin absorption by platelets is a prerequisite for permeability. Platelets obtain mainly 5-HT from the gut, therefore the excess serotonin generated by the decreased SERT activity of EBV infection in the intestinal mucosa should be collected and transported by the platelets. However, platelets do not collect all this excess since they also express TLR317,18 as enterocytes and when these receptors are activated by the infection, the reuptake of serotonin by these cells decreases15. This allows serotonin to accumulate in the intestinal mucosa.

Platelets contain different types of granules, primarily dense/delta granules, α granules and lysosomes. The activated platelets excrete the contents of these granules.35 Dense granules contain serotonin, so when the platelets are activated via TLR3 it would be released. This released neurotransmitter would increase vascular permeability and could favour inflammation in joints34  or other tissues where EBV-infected cells are present.

It would be logical to think that when the activity of the serotonin transporter (SERT) and its expression in the intestinal mucosa is decreased by viral infection, it would lead to an increase in the availability of 5-HT not only at a local level but also at a circulatory level. But in a study with mice modified not to express SERT, 5-HT was not found in blood. This indicates that these animals effectively prevent enteric 5-HT from reaching circulation through other means.36  The plasma absence of 5-HT in SERT mice – / – indicates that alternative transporters that are expressed in the intestine and liver must completely remove 5-HT from the portal blood (free 5-HT is absorbed in the portal vein and metabolized in the liver) and prevent it from reaching systemic circulation. But SERT – / – mouse stools contained more water than those of their SERT + / + litter partners, i.e. SERT -/- mice had aqueous diarrhea from the accumulation of serotonin at the intestinal level.34  Add that SERT – / – mouse platelets are not loaded with 5-HT as they circulate through the intestine.36  This occurs similarly in IBS-D patients and CFS patients. The decrease in SERT activity generated by EBV infection by activating TLR3 in platelets and enterocytes leads to a decrease in serotonin uptake and thus an increase in extracellular serotonin at the intestinal level. Under fasting conditions, both IBS-D11 and CFS patients have the same plasma levels of 5-HT as healthy patients. This occurs thanks to alternative transports that remove free serotonin from the portal blood.34  But in post-prandial conditions, further stimulation of serotonin release saturates the transport systems, thereby increasing plasma levels of free 5-HT, as has been seen to occur in patients with IBS-D, along with increased plasma levels of their 5-HIAA metabolite compared to healthy subjects.11 Hence, these patients’ symptoms increase after meals.

CENTRAL NERVOUS SYSTEM
Serotonergic and 5-HT compounds stimulate the secretion of PRL (prolactin) from the anterior pituitary gland. Being the 5-HT3 receptors involved in the regulation of both basal and stress-induced PRL response.37

The serotonergic neurons of the MRN (medial rafe nucleus) and DRN (dorsal rafe nucleus) project into the PVN (hypothalamic paraventricular nucleus) where they are in close contact with the CRH (corticotropin releasing hormone) neurons. These three nuclei are important for 5-HT-mediated responses but are not essential, as injury to 5-HT neurons in PVN or DRN reduced but did not inhibit ACTH response to stress.37

The serotonergic system stimulates the HPA axis (hypothalamic-pituitary-adrenal axis) at both the hypothalamic and pituitary gland levels with increased levels of CRH mRNA in the PVN, POMC mRNA (proopiomelanocortin) in the anterior pituitary lobe, CRH in the pituitary plasma, ACTH and corticosterone in the plasma. Serotonin stimulates the secretion of ACTH in vitro from the anterior pituitary gland. The effect of 5-HT is mediated primarily through 5-HT1A, 5-HT2A, and 5-HT2C receptors, but the 5-HT3 receptor does not appear to be involved in serotonergic regulation of the HPA axis.37

In another study, serotonin injections into rats showed decreased secretion of LH (luteinizing hormone).38 Serotonin was also observed to be involved in the regulation of postmenopausal LH to a greater extent and to a lesser extent in the secretion of FSH (follicle stimulating hormone.39

The neurohypophysial system (vasopressin and oxytocin)
5-HT releases AVP (vasopressin) into extracellular tissue in the PVN. Peripheral secretion of AVP mainly involves 5-HT2C, 5-HT4 and 5-HT7 receptors. The secretion of OT (oxytocin) is mainly mediated by 5-HT1A, 5-HT2C and 5-HT4 receptors and probably also 5-HT1B, 5-HT2A, 5-HT5A and 5-HT7 receptors.37

It can be concluded that 5-HT is involved in basal and stress regulation of PRL, ACTH, AVP and oxytocin by inducing their increase through 5-HT2A + 2C receptors mainly, but other receptors are also important, which differ between these hormones.

Temperature regulation
5-HT is an important neurotransmitter for thermoregulation through heat loss and heat production. The subtypes of 5-HT receptors involved in this regulation were discussed, especially 5-HT3 and 5-HT7, rather than 5-HT1A. In terms of the anatomical regions of the brain involved in this regulation, VTA (ventral tegmental area) or DMH (dorsomedial nucleus of the hypothalamus) are the main candidate areas instead of PO / AH.40

Selective 5HT1A receptor agonists produce a considerable hypothermic response. Activation of the 5-HT1A receptor was also shown to have effects on both heat loss and heat production. Not only 5-HT1A caused this, but also 5-HT3 and 5-HT7.40

Sleep regulation
Patients with autism have been observed to have elevated levels of serotonin along with intestinal problems and insomnia. Serotonin being a precursor of melatonin would alter the secretion of melatonin.

In animal models it has been suggested that the level of serotonin in the brain controls sleep-wake behavior. In an animal study it was shown that mice without 5-HT exhibit greater amounts of REM sleep than their wild type counterparts. Mice without serotonin receptors also showed a significant increase in wakefulness and a reduction in slow-wave sleep.28

It was later observed that the variation in the SLC6A4 gene encoding the 5-HT transporter (SERT), especially the HTTLPR locus, has been associated with high blood serotonin levels and susceptibility to autism spectrum disorder. Thus, due to the alteration of the serotonin transporter, serotonin is unable to enter cells and perform its function, leading subsequently to a compensatory elevation of 5-HT production. High levels of serotonin may function as an endogenous reaction to try to overcome the pathogenesis of autism.28,41,42

The consequences would be the same in CFS where a low activity of the serotonin transporter, through the activation of TLR (would decrease the uptake of 5-HT), would lead to a compensatory elevation. This, by influencing sleep-wake regulation, would lead to insomnia.

Cognitive Consequences 
This disorder we are describing would behave like patients with carcinoid syndrome as these types of tumors secrete this hormone.

Patients with CS (carcinoid syndrome) exhibit greater cognitive difficulties than healthy controls in multiple domains, including measures of visual scanning speed, verbal and visual memory measures, visual perception, and letter fluency. However, they showed no deficits in other measures of processing speed, semantic fluency, or their ability to use comments and alter responses. This study confirmed that patients with CS suffer from cognitive impairment43

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