Serotoninergic Neurons and 5-HT Receptors in the CNS


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The neurons of the raphe nuclei are the principal source of 5-HT release in the brain. 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. The serotonin nuclei may also be divided into two main groups, the rostral and caudal containing three and four nuclei respectively.

The rostral group consists of the caudal linear nuclei B8 , the dorsal raphe nuclei B6 and B7 and the median raphe nuclei B5, B8 and B9 , that project into multiple cortical and subcortical structures. The caudal group consists of the nucleus raphe magnus B3 , raphe obscurus nucleus B2 , raphe pallidus nucleus B1 , and lateral medullary reticular formation, that project into the brainstem. Serotonergic pathway are 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 suggest that serotonergic activity increases with motor activity, while firing rates of serotonergic neurons increase with intense visual stimuli. The descending projections form a pathway that inhibits pain called the "descending inhibitory pathway" that may be relevant to 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, emotion and hypo [42] or hyperserotonergic [43] states may be involved in depression and sickness behavior.

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.

5-HT synthesis and release

This halts their dopamine release, and thereby serotonin decreases appetite. Drugs that block 5-HT 2C 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, [44] especially in people with a low number of receptors. In macaques , alpha males have twice the level of serotonin released in the brain than subordinate males and females as measured by the levels of 5-Hydroxyindoleacetic acid 5-HIAA in the cerebro-spinal fluid.

Dominance status and cerebro-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. In humans, levels of 5-HT 1A receptor activation in the brain show negative correlation with aggression, [49] and a mutation in the gene that codes for the 5-HT 2A receptor may double the risk of suicide for those with that genotype.

Serotonin has been implicated in cognition, mood, anxiety and psychosis, but strong clarity has not been achieved. Serotonin regulated gastrointestinal function, 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. There are often serotonin abnormalities in gastrointestinal disorders like constipation and irritable bowel syndrome. If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.

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. 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.

In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass. In humans, increased blood serotonin levels have been shown to be significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at very low levels, in the bone cells.

It mediates its actions on bone cells using three different receptors.

Psychopharmacology Institute

There is very delicate balance between physiological role of gut serotonin and its pathology. Since serotonin signals resource availability it is not surprising that it affects organ development. Many human and animal studies have shown that nutrition in early life can influence, in adulthood, such things as body fatness, blood lipids, blood pressure, atherosclerosis, behavior, learning and longevity. Human serotonin can also act as a growth factor directly.

It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic growth factor , to aid healing. 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. Serotonin is stored in vesicle in the presynaptic neurone, when stimulated by nerve impulses, serotonin is released as a neurotransmitter into the synapse, it reversibly binds to the post synaptic receptor to induce a nerve impulse on the post synaptic neurone.

Serotonin can also bind to auto receptors on the presynaptic neurone to regulate the synthesis and release of serotonin. Normally serotonin is taken back into the presynaptic neurone to stop its action, it is then reused or broken down by monoamine oxidase. 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. Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases.


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  6. 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. Some 5-HT 3 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. Some serotonergic agonist drugs cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis , as well as cardiac valve fibrosis. These are the serotonergic vasoconstrictive antimigraine drugs ergotamine and methysergide , [88] the serotonergic appetite suppressant drugs fenfluramine , chlorphentermine , and aminorex , and certain anti-Parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT 2B 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 to be associated with cardiac fibrosis. Two independent studies published in the New England Journal of Medicine in January , implicated pergolide, along with cabergoline , in causing valvular heart disease. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease. Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino NH 2 and OH groups , are N -oxides , or miss the OH group.

    These compounds do reach the brain, although some portion of them are metabolized by monoamine oxidase enzymes mainly MAO-A in the liver. Examples are plants from the genus Anadenanthera that are used in the hallucinogenic yopo snuff. These compounds are widely present in the leaves of many plants, and may serve as deterrents for animal ingestion. Serotonin occurs in several mushrooms of the genus Panaeolus.

    5-HT receptor

    Serotonin is used by a variety of single-cell organisms for various purposes. SSRIs have been found to be toxic to algae. Outside the gut of a host, there is nothing that the entoamoebas provoke to release serotonin, hence the serotonin concentration is very low. Low serotonin signals to the entoamoebas they are outside a host and they become less virulent to conserve energy. When they enter a new host, they multiply in the gut, and become more virulent as the enterochromaffine cells get provoked by them and the serotonin concentration increases.

    In drying seeds , serotonin production is a way to get rid of the buildup of poisonous ammonia. The ammonia is collected and placed in the indole part of L - tryptophan , which is then decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by a cytochrome P monooxygenase , yielding serotonin. However, since serotonin is a major gastrointestinal tract modulator, it may be produced by plants in fruits 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 mushrooms , fruits and vegetables. Moderate levels from 0. Serotonin is one compound of the poison contained in stinging nettles Urtica dioica , where it causes pain on injection in the same manner as its presence in insect venoms see below. It is also naturally found in Paramuricea clavata , or the Red Sea Fan.

    Serotonin and Treatments for Depression, Animation.

    Serotonin and tryptophan have been found in chocolate with varying cocoa contents. The highest serotonin content 2. The intermediate in the synthesis from tryptophan to serotonin, 5-hydroxytryptophan, was not found. Serotonin functions as a neurotransmitter in the nervous systems of most animals. For example, in the roundworm Caenorhabditis elegans , which feeds on bacteria, serotonin is released as a signal in response to positive events, such as finding a new source of food or in male animals finding a female with which to mate.

    This mechanism increases the amount of time animals spend in the presence of food. If lobsters are injected with serotonin, they behave like dominant individuals whereas octopamine causes subordinate behavior. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals. The reason for this is social experience alters the proportion between serotonin receptors 5-HT receptors that have opposing effects on the fight-or-flight response.

    Serotonin is evolutionarily conserved and appears across the animal kingdom. It is seen in insect processes in roles similar to in the human central nervous system, such as memory, appetite, sleep, and behavior. Invertebrate drug response has been far less characterized than mammalian pharmacology and the potential for species selective insecticides has been discussed. Wasps and hornets have serotonin in their venom, [] which causes pain and inflammation. If flies are fed serotonin, they are more aggressive; flies depleted of serotonin still exhibit aggression, but they do so much less frequently.

    In the nematode C. 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. Genetically altered C. Serotonin is known to regulate aging, learning and memory. The first evidence comes from the study of longevity in C. The observation does not contradict with the notion that the serotonin level goes down in mammals and humans, which is typically seen in late but not early [ vague ] phase of aging.

    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 , and the coenzyme pyridoxal phosphate. The TPH-mediated reaction is the rate-limiting step in the pathway. 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. 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. 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. Consuming purified tryptophan increases brain serotonin whereas eating foods containing tryptophan does not. In , Italian Vittorio Erspamer showed an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline , but two years later, Erspamer was able to show it was a previously unknown amine , which he named "enteramine".

    Rapport , Arda Green, and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum , and since it was a serum agent affecting vascular tone, they named it serotonin. In , 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.

    From Wikipedia, the free encyclopedia. For other uses, see Serotonin disambiguation. IUPAC name. CAS Number. Interactive image. PubChem CID. Chemical formula.

    senjouin-kikishiro.com/images/qipozena/2784.php Solubility in water. Dipole moment. LD 50 median dose. Main article: 5-HT receptor. Main article: Serotonylation. Main article: Cardiac fibrosis. Main article: Serotonin syndrome. For details on tryptamine neurotransmitters in humans, see Trace amine. See also: Tryptophan. A new way to synthesize serotonin]". Il Farmaco; Edizione Scientifica in Italian. Ricerca Scientifica. Annales Medicinae Experimentalis et Biologiae Fenniae. Random House. Merriam-Webster Dictionary. Crimson Globe increases the urinary 6-sulfatoxymelatonin and total antioxidant capacity levels in young, middle-aged and elderly humans: Nutritional and functional characterization of their content".

    Journal of Food and Nutrition Research. The Medical Biochemistry Page. Indiana University School of Medicine. Retrieved 1 December Annual Review of Medicine. International Journal of Cardiology. PLOS One. Bibcode : PLoSO Progress in Neurobiology. Bibcode : Sci The American Journal of Clinical Nutrition. Cell Metabolism. Naunyn-Schmiedeberg's Archives of Pharmacology. Pharmacogenetics and Genomics. Behavioural Brain Research. Quantification of serotonin release in the brain has been difficult Paterson et al. Barnes NM, Sharp T. A review of central 5-HT receptors and their function.

    Bibliographic Information

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    Pharmacol Ther. Olivier B. Serotonin: a never-ending story. Eur J Pharmacol. Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab. Med Res Rev. Serotonin and molecular neuroimaging in humans using PET. Amino Acids ; 42 6 :

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