Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Serotonin: Difference between pages

{{short description|Monoamine neurotransmitter}}

{{Other uses}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Use dmy dates|date=March 2016}}

{{Infobox drug

| drug_name =

| type =

| IUPAC_name = 3-(2-Aminoethyl)-1''H''-indol-5-ol

| synonyms = 5-HT, 5-Hydroxytryptamine, Enteramine, Thrombocytin, 3-(β-Aminoethyl)-5-hydroxyl solution , Thrombotonin

| image = Serotonin-2D-skeletal.svg

| alt = Skeletal formula of serotonin

| caption =

| MedlinePlus =

| source_tissues = [[raphe nuclei]], [[enterochromaffin cell]]s

| target_tissues = system-wide

| receptors = [[5-HT1 receptor|5-HT₁]], [[5-HT2 receptor|5-HT₂]], [[5-HT3 receptor|5-HT₃]], [[5-HT4 receptor|5-HT₄]], [[5-HT5 receptor|5-HT₅]], [[5-HT6 receptor|5-HT₆]], [[5-HT7 receptor|5-HT₇]]

| agonists = Indirectly: [[SSRI]]s, [[MAOI]]s

| antagonists =

| precursor = [[5-HTP]]

| biosynthesis = [[Aromatic L-amino acid decarboxylase|Aromatic <small>L</small>-amino acid decarboxylase]]

| licence_EU =

| licence_US =

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category =

| legal_status =

| metabolism = [[Monoamine oxidase|MAO]]

| CAS_number = 50-67-9

| PubChem = 5202

| ChemSpiderID = 5013

| KEGG = C00780

| IUPHAR_ligand = 5

| DrugBank =

| PDB_ligand = SRO

}}

| Watchedfields = changed

| verifiedrevid = 477173047

| ImageFile2 =

| ImageName2 =

| IUPACName = 5-Hydroxytryptamine

| PIN = 3-(2-Aminoethyl)-1''H''-indol-5-ol

| OtherNames = 5-Hydroxytryptamine, 5-HT, Enteramine; Thrombocytin, 3-(β-Aminoethyl)-5-hydroxyindole, 3-(2-Aminoethyl)indol-5-ol, Thrombotonin

|Section1={{Chembox Identifiers

| CASNo_Ref = {{cascite|correct|CAS}}

| CASNo = 50-67-9

| SMILES = C1=CC2=C(C=C1O)C(=CN2)CCN

|Section2={{Chembox Properties

| Formula = C₁₀H₁₂N₂O

| pKa =10.16 in water at 23.5&nbsp;°C<ref name="pK">{{cite journal | vauthors = Mazák K, Dóczy V, Kökösi J, Noszál B | title = Proton speciation and microspeciation of serotonin and 5-hydroxytryptophan | journal = Chemistry & Biodiversity | volume = 6 | issue = 4 | pages = 578–590 | date = April 2009 | pmid = 19353542 | doi = 10.1002/cbdv.200800087 | s2cid = 20543931 }}</ref>

| MeltingPtC = 167.7

| MeltingPt_notes = 121–122 °C (ligroin)<ref name="MP">{{cite journal | vauthors = Pietra S | title = [Indolic derivatives. II. A new way to synthesize serotonin] | language = it | journal = Il Farmaco; Edizione Scientifica | volume = 13 | issue = 1 | pages = 75–79 | date = 1958 | pmid = 13524273 }}</ref>

| BoilingPt = 416 ± 30 °C

| BoilingPt_notes = (at 760 Torr)<ref name="CAPLUS">Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994–2011 ACD/Labs)</ref>

|Section3={{Chembox Structure

|Section7={{Chembox Hazards

| ExternalSDS = [http://www.chemcas.com/msds/cas/msds70/50-67-9.asp External MSDS]

| HPhrases =

| PPhrases =

| GHS_ref =

| LD50 = 750 mg/kg (subcutaneous, rat),<ref name="rat2">{{cite journal | vauthors = Erspamer V | author-link=Vittorio Erspamer | title = Ricerche preliminari sulle indolalchilamine e sulle fenilalchilamine degli estratti di pelle di Anfibio |journal= Ricerca Scientifica|year= 1952|volume= 22|pages= 694–702}}</ref> 4500 mg/kg (intraperitoneal, rat),<ref name="rat">{{cite journal | vauthors = Tammisto T | title = Increased toxicity of 5-hydroxytryptamine by ethanol in rats and mice | journal = Annales Medicinae Experimentalis et Biologiae Fenniae | volume = 46 | issue = 3 | pages = 382–384 | date = 1967 | pmid = 5734241 }}</ref> 60 mg/kg (oral, rat)

'''Serotonin''' ({{IPAc-en|ˌ|s|ɛr|ə|ˈ|t|oʊ|n|ᵻ|n|,_|ˌ|s|ɪər|ə|-}}){{refn|{{cite book | vauthors = Jones D |author-link= Daniel Jones (phonetician) |title= English Pronouncing Dictionary | veditors = Roach P, Hartmann J, Setter J |place= Cambridge |publisher= Cambridge University Press |orig-date= 1917 |year= 2003 |isbn= 978-3-12-539683-8 }}}}{{refn|{{Dictionary.com| Serotonin}}}}{{refn|{{MerriamWebsterDictionary| Serotonin}}}} or '''5-hydroxytryptamine''' ('''5-HT''') is a [[monoamine neurotransmitter]]. Its biological function is complex, touching on diverse functions including [[Mood (psychology)|mood]], [[cognition]], [[Reward system|reward]], [[learning]], [[memory]], and numerous physiological processes such as [[vomiting]] and [[vasoconstriction]].<ref name="pmid18043762">{{cite journal | vauthors = Young SN | title = How to increase serotonin in the human brain without drugs | journal = Journal of Psychiatry & Neuroscience | volume = 32 | issue = 6 | pages = 394–399 | date = November 2007 | pmid = 18043762 | pmc = 2077351 }}</ref>

Serotonin is produced in the [[central nervous system]] (CNS), specifically in the [[brainstem]]'s [[raphe nuclei]], the skin's [[Merkel cells]], [[pulmonary neuroendocrine cell]]s and the tongue's [[taste bud|taste receptor cells]]. Approximately 90% of the serotonin the [[human body]] produces is in the [[gastrointestinal tract]]'s [[enterochromaffin cell]]s, where it regulates intestinal movements.<ref name="Caltech 2015">{{cite web | title=Microbes Help Produce Serotonin in Gut | website=California Institute of Technology | date=2015-04-09 | url=https://www.caltech.edu/about/news/microbes-help-produce-serotonin-gut-46495 | access-date=2022-06-03}}</ref><ref name="urlthemedicalbiochemistrypage.org">{{cite web |url = http://themedicalbiochemistrypage.org/nerves.html#5ht |title = Serotonin | vauthors = King MW |work = The Medical Biochemistry Page |publisher = Indiana University School of Medicine |access-date = 1 December 2009}}</ref><ref name="pmid19630576">{{cite journal | vauthors = Berger M, Gray JA, Roth BL | title = The expanded biology of serotonin | journal = Annual Review of Medicine | volume = 60 | pages = 355–366 | year = 2009 | pmid = 19630576 | pmc = 5864293 | doi = 10.1146/annurev.med.60.042307.110802 | author3-link = Bryan Roth }}</ref> Additionally, it is stored in blood [[platelet]]s and is released during agitation and vasoconstriction, where it then acts as an [[agonist]] to other platelets.<ref name="pmid14727927">{{cite journal | vauthors = Schlienger RG, Meier CR | title = Effect of selective serotonin reuptake inhibitors on platelet activation: can they prevent acute myocardial infarction? | journal = American Journal of Cardiovascular Drugs | volume = 3 | issue = 3 | pages = 149–162 | date = 2003 | pmid = 14727927 | doi = 10.2165/00129784-200303030-00001 | s2cid = 23986530 }}</ref> About 8% is found in platelets and 1–2% in the CNS.<ref name=thesis>{{cite thesis |vauthors=Kling A |title=5-HT2A: a serotonin receptor with a possible role in joint diseases | publisher = Umeå Universitet | year = 2013| url = https://www.diva-portal.org/smash/get/diva2:586490/FULLTEXT02.pdf | isbn = 978-91-7459-549-9}}</ref>

The serotonin is secreted [[lumen (anatomy)|luminally]] and [[basolateral]]ly, which leads to increased serotonin uptake by circulating platelets and activation after stimulation, which gives increased stimulation of [[myenteric]] neurons and [[gastrointestinal motility]].<ref>{{cite journal | vauthors = Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY | title = Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis | journal = Cell | volume = 161 | issue = 2 | pages = 264–276 | date = April 2015 | pmid = 25860609 | pmc = 4393509 | doi = 10.1016/j.cell.2015.02.047 }}</ref> The remainder is synthesized in serotonergic [[neuron]]s of the CNS, where it has various functions, including the regulation of mood, [[appetite]], and [[sleep]].<ref>{{cite journal | vauthors = Sangare A, Dubourget R, Geoffroy H, Gallopin T, Rancillac A | title = Serotonin differentially modulates excitatory and inhibitory synaptic inputs to putative sleep-promoting neurons of the ventrolateral preoptic nucleus | journal = Neuropharmacology | volume = 109 | pages = 29–40 | date = October 2016 | pmid = 27238836 | doi = 10.1016/j.neuropharm.2016.05.015 | url = https://www.hal.inserm.fr/inserm-02121065v2/file/Serotonin%20differentially%20modulates%20excitatory.pdf }}</ref>{{Unreliable medical source|sure=y|reason=primary|date=August 2024}}<ref>{{cite journal | vauthors = Rancillac A | title = Serotonin and sleep-promoting neurons | journal = Oncotarget | volume = 7 | issue = 48 | pages = 78222–78223 | date = November 2016 | pmid = 27861160 | pmc = 5346632 | doi = 10.18632/oncotarget.13419 }}</ref>{{Unreliable medical source|sure=y|reason=primary|date=August 2024}}

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 can serve as a [[vasoconstrictor]] or a vasodilator while regulating [[hemostasis]] and blood clotting. In high concentrations, serotonin acts as a vasoconstrictor by contracting [[endothelial]] [[smooth muscle]] directly or by potentiating the effects of other vasoconstrictors (e.g. angiotensin&nbsp;II and norepinephrine). The vasoconstrictive property is mostly seen in pathologic states affecting the endothelium{{snd}}such as [[atherosclerosis]] or chronic [[hypertension]]. In normal physiologic states, vasodilation occurs through the serotonin mediated release of nitric oxide from endothelial cells, and the inhibition of release of norepinephrine from [[Adrenergic nerve fibre|adrenergic nerves]].<ref>{{cite journal | vauthors = Vanhoutte PM | title = Serotonin and the vascular wall | journal = International Journal of Cardiology | volume = 14 | issue = 2 | pages = 189–203 | date = February 1987 | pmid = 3818135 | doi = 10.1016/0167-5273(87)90008-8 }}</ref> Serotonin is also a [[growth factor]] for some types of cells, which may give it a role in wound healing. There are various [[5-HT receptor|serotonin receptors]].

Biochemically, the [[indoleamine]] molecule derives from the amino acid [[tryptophan]]. Serotonin is metabolized mainly to [[5-hydroxyindoleacetic acid]] (5-HIAA), chiefly by the [[liver]].

Several classes of [[antidepressant]]s, such as [[selective serotonin reuptake inhibitor]]s (SSRIs) and [[serotonin–norepinephrine reuptake inhibitor]]s (SNRIs), interfere with the normal [[reuptake|reabsorption]] of serotonin after it is done with the transmission of the signal, therefore augmenting the neurotransmitter levels in the [[synapse]]s.

Besides mammals, serotonin is found in all [[bilateral animals]] including worms and insects,<ref name="Huser_2012">{{cite journal | vauthors = Huser A, Rohwedder A, Apostolopoulou AA, Widmann A, Pfitzenmaier JE, Maiolo EM, Selcho M, Pauls D, von Essen A, Gupta T, Sprecher SG, Birman S, Riemensperger T, Stocker RF, Thum AS | title = The serotonergic central nervous system of the Drosophila larva: anatomy and behavioral function | journal = PLOS ONE | volume = 7 | issue = 10 | pages = e47518 | year = 2012 | pmid = 23082175 | pmc = 3474743 | doi = 10.1371/journal.pone.0047518 | veditors = Zars T | doi-access = free | bibcode = 2012PLoSO...747518H }}</ref> as well as in [[fungi]] and in [[plant]]s.<ref name="Ramakrishna_2011">{{cite journal | vauthors = Ramakrishna A, Giridhar P, Ravishankar GA | title = Phytoserotonin: a review | journal = Plant Signaling & Behavior | volume = 6 | issue = 6 | pages = 800–809 | date = June 2011 | pmid = 21617371 | pmc = 3218476 | doi = 10.4161/psb.6.6.15242 | bibcode = 2011PlSiB...6..800A }}</ref> Serotonin's presence in insect venoms and plant spines serves to cause pain, which is a side-effect of serotonin injection.<ref name="Chen_2010" /><ref name="Erspamer-1966">{{cite book | vauthors = Erspamer V | author-link=Vittorio Erspamer | title=5-Hydroxytryptamine and Related Indolealkylamines | chapter=Occurrence of indolealkylamines in nature | publisher=[[Springer Berlin Heidelberg]] | publication-place=[[Berlin]], [[Heidelberg]] | year=1966 | isbn=978-3-642-85469-9 | doi=10.1007/978-3-642-85467-5_4 | pages=132–181}}</ref> Serotonin is produced by pathogenic amoebae, causing [[diarrhea]] in the human gut.<ref name="pmid6308760"/> Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.<ref name=feld/>{{failed verification|no mention of this hypothesis in source.|date=May 2023}}

==Molecular structure==

Biochemically, the [[indoleamine]] molecule derives from the amino acid [[tryptophan]], via the (rate-limiting) [[Tryptophan hydroxylase|hydroxylation]] of the 5&nbsp;position on the ring (forming the intermediate [[5-hydroxytryptophan]]), and then [[Aromatic L-amino acid decarboxylase|decarboxylation]] to produce serotonin.<ref>{{cite journal | vauthors = González-Flores D, Velardo B, Garrido M, et al. | year = 2011 | title = Ingestion of Japanese plums (Prunus salicina Lindl. cv. 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 | url = https://www.researchgate.net/publication/259983119 | journal = Journal of Food and Nutrition Research | volume = 50 | issue = 4| pages = 229–236 }}</ref> Preferable conformations are defined via ethylamine chain, resulting in six different conformations.<ref>{{Cite journal | vauthors = Rychkov DA, Hunter S, Kovalskii VY, Lomzov AA, Pulham CR, Boldyreva EV |date=July 2016 |title=Towards an understanding of crystallization from solution. DFT studies of multi-component serotonin crystals |journal=Computational and Theoretical Chemistry |language=en |volume=1088 |pages=52–61 |doi=10.1016/j.comptc.2016.04.027}}</ref>

==Crystal structure==

Serotonin crystallizes in P2₁2₁2₁ chiral space group forming different hydrogen-bonding interactions between serotonin molecules via N-H...O and O-H...N intermolecular bonds.<ref>{{cite journal | vauthors = Naeem M, Chadeayne AR, Golen JA, Manke DR | title = Crystal structure of serotonin | journal = Acta Crystallographica Section E | volume = 78 | issue = Pt 4 | pages = 365–368 | date = April 2022 | pmid = 35492269 | pmc = 8983975 | doi = 10.1107/S2056989022002559 | bibcode = 2022AcCrE..78..365N }}</ref> Serotonin also forms several salts, including pharmaceutical formulation of serotonin adipate.<ref>{{cite journal | vauthors = Rychkov D, Boldyreva EV, Tumanov NA | title = A new structure of a serotonin salt: comparison and conformational analysis of all known serotonin complexes | journal = Acta Crystallographica Section C | volume = 69 | issue = Pt 9 | pages = 1055–1061 | date = September 2013 | pmid = 24005521 | doi = 10.1107/S0108270113019823 | bibcode = 2013AcCrC..69.1055R }}</ref>

==Biological role==

Serotonin is involved in numerous physiological processes,<ref>{{cite journal | vauthors = Mohammad-Zadeh LF, Moses L, Gwaltney-Brant SM | title = Serotonin: a review | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 31 | issue = 3 | pages = 187–199 | date = June 2008 | pmid = 18471139 | doi = 10.1111/j.1365-2885.2008.00944.x | doi-access = free }}</ref> including [[sleep]],<ref name="Vaseghi_2022">{{cite journal | vauthors = Vaseghi S, Arjmandi-Rad S, Eskandari M, Ebrahimnejad M, Kholghi G, Zarrindast MR | title = Modulating role of serotonergic signaling in sleep and memory | journal = Pharmacological Reports | volume = 74 | issue = 1 | pages = 1–26 | date = February 2022 | pmid = 34743316 | doi = 10.1007/s43440-021-00339-8 }}</ref> [[thermoregulation]], [[learning]] and [[memory]], [[pain]], (social) behavior,<ref name="pmid2902685" /> [[sexual activity]], feeding, motor activity, neural development,<ref name="Sinclair-Wilson Lawrence Ferezou Cartonnet">{{cite journal | vauthors = Sinclair-Wilson A, Lawrence A, Ferezou I, Cartonnet H, Mailhes C, Garel S, Lokmane L | title = Plasticity of thalamocortical axons is regulated by serotonin levels modulated by preterm birth | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 120 | issue = 33 | pages = e2301644120 | date = August 2023 | pmid = 37549297 | pmc = 10438379 | doi = 10.1073/pnas.2301644120 | bibcode = 2023PNAS..12001644S }}</ref> and [[Chronobiology|biological rhythms]].<ref name="Zifa_1992">{{cite journal | vauthors = Zifa E, Fillion G | title = 5-Hydroxytryptamine receptors | journal = Pharmacological Reviews | volume = 44 | issue = 3 | pages = 401–458 | date = September 1992 | pmid = 1359584 | url = https://pubmed.ncbi.nlm.nih.gov/1359584 }}</ref> In less complex animals, such as some [[invertebrates]], serotonin regulates feeding and other processes.<ref name="pmid18522834"/> In plants serotonin synthesis seems to be associated with stress signals.<ref name = "Ramakrishna_2011" /><ref name="Akula-Ravishankar-2011">{{cite journal | vauthors = Ramakrishna A, Ravishankar GA | title = Influence of abiotic stress signals on secondary metabolites in plants | journal = Plant Signaling & Behavior | volume = 6 | issue = 11 | pages = 1720–1731 | date = November 2011 | pmid = 22041989 | pmc = 3329344 | doi = 10.4161/psb.6.11.17613 | publisher = [[Informa]] | doi-access = free | bibcode = 2011PlSiB...6.1720A }}</ref> Despite its longstanding prominence in pharmaceutical advertising, the claim that low serotonin levels cause depression is not supported by scientific evidence.<ref name="WhitakerCosgrove2015">{{cite book | vauthors = Whitaker R, Cosgrove L |title=Psychiatry Under the Influence: Institutional Corruption, Social Injury, and Prescriptions for Reform |year=2015 |publisher=Springer |isbn=978-1-137-51602-2 |pages=55–56 |url=https://books.google.com/books?id=fxPACQAAQBAJ&pg=PA55}}</ref><ref>{{cite journal | vauthors = Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA | title = The serotonin theory of depression: a systematic umbrella review of the evidence | journal = Molecular Psychiatry | volume = 28 | issue = 8 | pages = 3243–3256 | date = August 2023 | pmid = 35854107 | pmc = 10618090 | doi = 10.1038/s41380-022-01661-0 | publisher = Nature Publishing Group | s2cid = 250646781 | doi-access = free }}</ref><ref>{{Citation | vauthors = Ghaemi N | year=2022 | title=Has the Serotonin Hypothesis Been Debunked? | url=https://www.psychologytoday.com/us/blog/mood-swings/202210/has-the-serotonin-hypothesis-been-debunked | access-date=2 May 2023}}</ref>

===Cellular effects===

Serotonin primarily acts through its receptors and its effects depend on which cells and tissues express these receptors.<ref name="Zifa_1992" />

Metabolism involves first [[oxidation]] by [[monoamine oxidase]] to [[5-Hydroxyindoleacetaldehyde|5-hydroxyindoleacetaldehyde]] (5-HIAL).<ref name="BortolatoChenShih2010">{{cite book | vauthors = Bortolato M, Chen K, Shih JC | title=Handbook of Behavioral Neuroscience | chapter=The Degradation of Serotonin: Role of MAO | publisher=Elsevier | volume=21 | date=2010 | isbn=978-0-12-374634-4 | doi=10.1016/s1569-7339(10)70079-5 | pages=203–218}}</ref><ref name="MatthesMosienkoBashammakh2010">{{cite journal | vauthors = Matthes S, Mosienko V, Bashammakh S, Alenina N, Bader M | title = Tryptophan hydroxylase as novel target for the treatment of depressive disorders | journal = Pharmacology | volume = 85 | issue = 2 | pages = 95–109 | date = 2010 | pmid = 20130443 | doi = 10.1159/000279322 | url = }}</ref> The rate-limiting step is hydride transfer from serotonin to the flavin cofactor.<ref>{{cite journal | vauthors = Prah A, Purg M, Stare J, Vianello R, Mavri J | title = How Monoamine Oxidase A Decomposes Serotonin: An Empirical Valence Bond Simulation of the Reactive Step | journal = The Journal of Physical Chemistry B | volume = 124 | issue = 38 | pages = 8259–8265 | date = September 2020 | pmid = 32845149 | pmc = 7520887 | doi = 10.1021/acs.jpcb.0c06502 }}</ref> There follows oxidation by [[aldehyde dehydrogenase]] (ALDH) to [[5-hydroxyindoleacetic acid]] ({{nowrap|5-HIAA}}), the [[indole]] acetic-acid derivative. The latter is then excreted by the kidneys.

====Receptors====

{{Main|Serotonin receptor}}

The 5-HT receptors, the [[receptor (biochemistry)|receptors]] for serotonin, are located on the cell membrane of [[Neuron|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 [[Psychedelics|psychedelic drugs]]. Except for the [[5-HT3|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.<ref name="pmid18571247">{{cite journal | vauthors = Hannon J, Hoyer D | title = Molecular biology of 5-HT receptors | journal = Behavioural Brain Research | volume = 195 | issue = 1 | pages = 198–213 | date = December 2008 | pmid = 18571247 | doi = 10.1016/j.bbr.2008.03.020 | s2cid = 46043982 }}</ref>

====Termination====

Serotonergic action is terminated primarily via [[reuptake|uptake]] of 5-HT from the synapse. This is accomplished through the specific [[monoamine transporter]] for 5-HT, [[Serotonin transporter|SERT]], on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including [[cocaine]], [[dextromethorphan]] (an [[antitussive]]), [[tricyclic antidepressants]] and [[selective serotonin reuptake inhibitor]]s (SSRIs). A 2006 study found that a significant portion of 5-HT's synaptic clearance is due to the selective activity of the [[plasma membrane monoamine transporter]] (PMAT) which actively transports the molecule across the membrane and back into the presynaptic cell.<ref name="pmid 1828907">{{cite journal | vauthors = Zhou M, Engel K, Wang J | title = Evidence for significant contribution of a newly identified monoamine transporter (PMAT) to serotonin uptake in the human brain | journal = Biochemical Pharmacology | volume = 73 | issue = 1 | pages = 147–154 | date = January 2007 | pmid = 17046718 | pmc = 1828907 | doi = 10.1016/j.bcp.2006.09.008 }}</ref>

In contrast to the high affinity of SERT, the PMAT has been identified as a low-affinity transporter, with an apparent ''K''_m of 114 micromoles/l for serotonin, which is 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."<ref name="pmid 1828907" /> The study also suggests that the administration of SSRIs such as [[fluoxetine]] and [[sertraline]] may be associated with an inhibitory effect on PMAT activity when used at higher than normal dosages ([[IC50|IC₅₀]] test values used in trials were 3–4 fold higher than typical prescriptive dosage).

====Serotonylation====

{{Main|Serotonylation}}

Serotonin can also signal through a nonreceptor mechanism called serotonylation, in which serotonin modifies proteins.<ref name="pmid19859528"/> This process underlies serotonin's effects upon platelet-forming cells ([[thrombocyte]]s) in which it links to the modification of signaling enzymes called [[GTPase]]s that then trigger the release of vesicle contents by [[exocytosis]].<ref name="pmid14697203">{{cite journal | vauthors = Walther DJ, Peter JU, Winter S, Höltje M, Paulmann N, Grohmann M, Vowinckel J, Alamo-Bethencourt V, Wilhelm CS, Ahnert-Hilger G, Bader M | title = Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release | journal = Cell | volume = 115 | issue = 7 | pages = 851–862 | date = December 2003 | pmid = 14697203 | doi = 10.1016/S0092-8674(03)01014-6 | s2cid = 16847296 | doi-access = free }}</ref> A similar process underlies the pancreatic release of insulin.<ref name="pmid19859528"/>

The effects of serotonin upon vascular smooth [[muscle tone]]{{snd}}the biological function after which serotonin was originally named{{snd}}depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.<ref name="pmid19479059">{{cite journal | vauthors = Watts SW, Priestley JR, Thompson JM | title = Serotonylation of vascular proteins important to contraction | journal = PLOS ONE | volume = 4 | issue = 5 | pages = e5682 | date = May 2009 | pmid = 19479059 | pmc = 2682564 | doi = 10.1371/journal.pone.0005682 | doi-access = free | bibcode = 2009PLoSO...4.5682W }}</ref>

{| class = wikitable

|+ <big>Binding profile of serotonin</big>

! Receptor !! K_i (nM)<ref>{{cite web | title = PDSP K_i Database | work = Psychoactive Drug Screening Program (PDSP) | vauthors = Roth BL, Driscol J | url = http://pdsp.med.unc.edu/pdsp.php | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 17 December 2013 | date = 12 January 2011 | url-status = dead | archive-url = https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php | archive-date = 8 November 2013 | df = dmy-all }}</ref> !! Receptor function<ref group = Note>References for the functions of these receptors are available on the wikipedia pages for the specific receptor in question</ref>

|-

| colspan ="3" align="center" | 5-HT₁ receptor family signals via [[Gi alpha subunit|G_i/o]] inhibition of [[adenylyl cyclase]].

|-

| [[5-HT1A receptor|5-HT_1A]] || 3.17 || Memory{{Vague|date=March 2014}} (agonists ↓); learning{{Vague|date=March 2014}} (agonists ↓); anxiety (agonists ↓); depression (agonists ↓); positive, negative, and cognitive symptoms of schizophrenia (partial agonists ↓); analgesia (agonists ↑); [[aggression]] (agonists ↓); dopamine release in the prefrontal cortex (agonists ↑); serotonin release and synthesis (agonists ↓)

|-

| [[5-HT1B receptor|5-HT_1B]] || 4.32 || Vasoconstriction (agonists ↑); aggression (agonists ↓); bone mass (↓). Serotonin autoreceptor.

|-

| [[5-HT1D receptor|5-HT_1D]] || 5.03 || Vasoconstriction (agonists ↑)

|-

| [[5-HT1E receptor|5-HT_1E]] || 7.53 ||

|-

| [[5-HT1F receptor|5-HT_1F]] || 10 ||

|-

| colspan ="3" align="center" | 5-HT₂ receptor family signals via [[Gq alpha subunit|G_q]] activation of [[phospholipase C]].

|-

| [[5-HT2A receptor|5-HT_2A]] || 11.55 || Psychedelia (agonists ↑); depression (agonists & antagonists ↓); anxiety (antagonists ↓); positive and negative symptoms of schizophrenia (antagonists ↓); norepinephrine release from the [[locus coeruleus]] (antagonists ↑); glutamate release in the [[prefrontal cortex]] (agonists ↑); dopamine in the prefrontal cortex (agonists ↑);<ref>{{cite journal | vauthors = Bortolozzi A, Díaz-Mataix L, Scorza MC, Celada P, Artigas F | title = The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity | journal = Journal of Neurochemistry | volume = 95 | issue = 6 | pages = 1597–1607 | date = December 2005 | pmid = 16277612 | doi = 10.1111/j.1471-4159.2005.03485.x | hdl-access = free | s2cid = 18350703 | hdl = 10261/33026 }}</ref> urinary bladder contractions (agonists ↑)<ref name="MoroEdwards2016">{{cite journal | vauthors = Moro C, Edwards L, Chess-Williams R | title = 5-HT_2A receptor enhancement of contractile activity of the porcine urothelium and lamina propria | journal = International Journal of Urology | volume = 23 | issue = 11 | pages = 946–951 | date = November 2016 | pmid = 27531585 | doi = 10.1111/iju.13172 | doi-access = free }}</ref>

|-

| [[5-HT2B receptor|5-HT_2B]] || 8.71 || Cardiovascular functioning (agonists increase risk of pulmonary hypertension), empathy (via [[von Economo neurons]]<ref>{{cite web|url=http://neuronbank.org/wiki/index.php/Von_Economo_neuron|title=Von Economo neuron – NeuronBank|website=neuronbank.org}}{{MEDRS|date=October 2017}}</ref>)

|-

| [[5-HT2C receptor|5-HT_2C]] || 5.02 || Dopamine release into the mesocorticolimbic pathway (agonists ↓); acetylcholine release in the prefrontal cortex (agonists ↑); dopaminergic and noradrenergic activity in the [[frontal cortex]] (antagonists ↑);<ref>{{cite journal | vauthors = Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D | title = The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 306 | issue = 3 | pages = 954–964 | date = September 2003 | pmid = 12750432 | doi = 10.1124/jpet.103.051797 | s2cid = 18753440 }}</ref> appetite (agonists ↓); antipsychotic effects (agonists ↑); antidepressant effects (agonists & antagonists ↑)

|-

| colspan =3 align = center | Other 5-HT receptors

|-

| [[5-HT3 receptor|5-HT₃]] || 593 || Emesis (agonists ↑); anxiolysis (antagonists ↑).

|-

| [[5-HT4 receptor|5-HT₄]] || 125.89 || Movement of food across the GI tract (agonists ↑); memory & learning (agonists ↑); antidepressant effects (agonists ↑). Signalling via [[Gs alpha subunit|G_αs]] activation of adenylyl cyclase.

|-

| [[5-HT5A receptor|5-HT_5A]] || 251.2 || Memory consolidation.<ref>{{cite journal | vauthors = Gonzalez R, Chávez-Pascacio K, Meneses A | title = Role of 5-HT5A receptors in the consolidation of memory | journal = Behavioural Brain Research | volume = 252 | pages = 246–251 | date = September 2013 | pmid = 23735322 | doi = 10.1016/j.bbr.2013.05.051 | s2cid = 140204585 }}</ref> Signals via [[Gi alpha subunit|G_i/o]] inhibition of [[adenylyl cyclase]].

|-

| [[5-HT6 receptor|5-HT₆]] || 98.41 || Cognition (antagonists ↑); antidepressant effects (agonists & antagonists ↑); [[anxiogenic]] effects (antagonists ↑<ref>{{cite journal | vauthors = Nautiyal KM, Hen R | title = Serotonin receptors in depression: from A to B | journal = F1000Research | volume = 6 | pages = 123 | year = 2017 | pmid = 28232871 | pmc = 5302148 | doi = 10.12688/f1000research.9736.1 | doi-access = free }}</ref>). [[Gs alpha subunit|G_s]] signalling via activating [[adenylyl cyclase]].

|-

| [[5-HT7 receptor|5-HT₇]] || 8.11 || Cognition (antagonists ↑); antidepressant effects (antagonists ↑). Acts by [[Gs alpha subunit|G_s]] signalling via activating [[adenylyl cyclase]].

|}

===Nervous system===

[[File:Pubmed equitativa hormonal.png|thumb|right|alt= In this drawing of the brain, the serotonergic system is red and the mesolimbic dopamine pathway is blue. There is one collection of serotonergic neurons in the upper brainstem that sends [[axon]]s upwards to the whole cerebrum, and one collection next to the cerebellum that sends axons downward to the spinal cord. Slightly forward the upper serotonergic neurons is the [[ventral tegmental area]] (VTA), which contains dopaminergic neurons. These neurons' axons then connect to the [[nucleus accumbens]], [[hippocampus]], and the [[frontal cortex]]. Over the VTA is another collection of dopaminergic cells, the [[substansia nigra]], which send axons to the [[striatum]]. |Serotonin system, contrasted with the [[Mesolimbic pathway|dopamine system]]]]

The neurons of the [[raphe nuclei]] are the principal source of 5-HT release in the brain.<ref>{{cite book | vauthors = Frazer A, Hensler JG | veditors = Siegel GJ, Agranoff, Bernard W, Fisher SK, Albers RW, Uhler MD |title = Basic Neurochemistry | url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm|edition = Sixth|year = 1999|publisher = Lippincott Williams & Wilkins|isbn = 978-0-397-51820-3|chapter = Understanding the neuroanatomical organization of serotonergic cells in the brain provides insight into the functions of this neurotransmitter|chapter-url = https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=raphe+AND+serotonin+release+AND+bnchm%5Bbook%5D+AND+160428%5Buid%5D&rid=bnchm.section.946#949|quote = In 1964, Dahlstrom and Fuxe (discussed in [2]), using the [[Falck-Hillarp technique]] of histofluorescence, observed that the majority of serotonergic soma are found in cell body groups, which previously had been designated as the Raphe nuclei.|editor-link1 = George J. Siegel}}</ref> There are nine raphe nuclei, designated B1–B9, which contain the majority of serotonin-containing neurons (some scientists chose to group the ''nuclei raphes lineares'' into one nucleus), all of which are located along the midline of the [[brainstem]], and centered on the [[reticular formation]].<ref>{{cite book| vauthors = Binder MD, Hirokawa N |title=encyclopedia of neuroscience|date=2009|publisher=Springer|location=Berlin|isbn=978-3-540-23735-8|page=705}}</ref><ref>The raphe nuclei group of [[neurons]] are located along the [[reticular formation|brain stem]] from the labels '[[mesencephalon|Mid Brain]]' to '[[medulla oblongata|Oblongata]]', centered on the [[pons]]. ([[:Image:Gray715.png|See relevant image]].)</ref> 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.

====Ultrastructure and function====

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.<ref>{{cite book | veditors = Müller CP, Jacobs BL |title=Handbook of the behavioral neurobiology of serotonin |date=2009 |publisher= Academic |location=London |isbn=978-0-12-374634-4|pages=51–59|edition=1st}}</ref>

The serotonergic pathway is 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 suggests that serotonergic activity increases with motor activity while firing rates of serotonergic neurons increase with intense visual stimuli. Animal models suggest that kainate signaling negatively regulates serotonin actions in the retina, with possible implications for the control of the visual system.<ref>{{cite journal | vauthors = Passos AD, Herculano AM, Oliveira KR, de Lima SM, Rocha FA, Freitas HR, da Silva Sampaio L, Figueiredo DP, da Costa Calaza K, de Melo Reis RA, do Nascimento JL | title = Regulation of the Serotonergic System by Kainate in the Avian Retina | journal = Cellular and Molecular Neurobiology | volume = 39 | issue = 7 | pages = 1039–1049 | date = October 2019 | pmid = 31197744 | doi = 10.1007/s10571-019-00701-8 | s2cid = 189763144 }}</ref> The descending projections form a pathway that inhibits pain called the "descending inhibitory pathway" that may be relevant to a disorder such as fibromyalgia, migraine, and other pain disorders, and the efficacy of antidepressants in them.<ref>{{cite book | chapter = Serotonin in Pain and Pain Control | vauthors = Sommer C | veditors = Müller CP, Jacobs BL |title=Handbook of the behavioral neurobiology of serotonin|date=2009|publisher=Academic|location=London|isbn=978-0-12-374634-4|pages=457–460|edition=1st}}</ref>

Serotonergic projections from the caudal nuclei are involved in regulating mood and emotion, and hypo-<ref>{{cite book | chapter = Serotonin in Mode and Emotions | vauthors = Hensler JG | veditors = Müller CP, Jacobs BL | title=Handbook of the behavioral neurobiology of serotonin|date=2009|publisher=Academic|location=London|isbn=978-0-12-374634-4|pages=367–399|edition=1st}}</ref> or hyper-serotonergic<ref>{{cite journal | vauthors = Andrews PW, Bharwani A, Lee KR, Fox M, Thomson JA | title = Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response | journal = Neuroscience and Biobehavioral Reviews | volume = 51 | pages = 164–188 | date = April 2015 | pmid = 25625874 | doi = 10.1016/j.neubiorev.2015.01.018 | s2cid = 23980182 }}</ref> states may be involved in depression and sickness behavior.

====Microanatomy====

Serotonin is released into the synapse, or space between neurons, and diffuses over a relatively wide gap (>20&nbsp;nm) to activate [[5-HT receptor]]s located on the [[dendrite]]s, cell bodies, and [[presynaptic terminal]]s of adjacent neurons.

When humans smell food, dopamine is released to [[incentive salience|increase the appetite]]. But, unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates [[5-HT2C receptor]]s on dopamine-producing cells. 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,<ref name="pmid19178394">{{cite journal | vauthors = Stahl SM, Mignon L, Meyer JM | title = Which comes first: atypical antipsychotic treatment or cardiometabolic risk? | journal = Acta Psychiatrica Scandinavica | volume = 119 | issue = 3 | pages = 171–179 | date = March 2009 | pmid = 19178394 | doi = 10.1111/j.1600-0447.2008.01334.x | s2cid = 24035040 | doi-access = free }}</ref> especially in people with a low number of receptors.<ref name="pmid15741483">{{cite journal | vauthors = Buckland PR, Hoogendoorn B, Guy CA, Smith SK, Coleman SL, O'Donovan MC | title = Low gene expression conferred by association of an allele of the 5-HT2C receptor gene with antipsychotic-induced weight gain | journal = The American Journal of Psychiatry | volume = 162 | issue = 3 | pages = 613–615 | date = March 2005 | pmid = 15741483 | doi = 10.1176/appi.ajp.162.3.613 }}</ref> The expression of 5-HT_2C receptors in the [[hippocampus]] follows a [[circadian rhythm|diurnal rhythm]],<ref name="pmid9151722">{{cite journal | vauthors = Holmes MC, French KL, Seckl JR | title = Dysregulation of diurnal rhythms of serotonin 5-HT2C and corticosteroid receptor gene expression in the hippocampus with food restriction and glucocorticoids | journal = The Journal of Neuroscience | volume = 17 | issue = 11 | pages = 4056–4065 | date = June 1997 | pmid = 9151722 | pmc = 6573558 | doi = 10.1523/JNEUROSCI.17-11-04056.1997 }}</ref> just as the serotonin release in the [[ventromedial nucleus]], which is characterised by a peak at morning when the motivation to eat is strongest.<ref name="pmid2197074">{{cite journal | vauthors = Leibowitz SF | title = The role of serotonin in eating disorders | journal = Drugs | volume = 39 | issue = Suppl 3 | pages = 33–48 | year = 1990 | pmid = 2197074 | doi = 10.2165/00003495-199000393-00005 | s2cid = 8612545 }}</ref>

In [[macaque]]s, alpha males have twice the level of serotonin in the brain as subordinate males and females (measured by the concentration of [[5-Hydroxyindoleacetic acid|5-HIAA]] in the [[cerebrospinal fluid]] (CSF)). Dominance status and CSF 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.<ref>McGuire, Michael (2013) "Believing, the neuroscience of fantasies, fears, and confictions" (Prometius Books)</ref>

In humans, levels of 5-HT_1A receptor inhibition in the brain show negative correlation with aggression,<ref>{{cite journal | vauthors = Caspi N, Modai I, Barak P, Waisbourd A, Zbarsky H, Hirschmann S, Ritsner M | title = Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study | journal = International Clinical Psychopharmacology | volume = 16 | issue = 2 | pages = 111–115 | date = March 2001 | pmid = 11236069 | doi = 10.1097/00004850-200103000-00006 | s2cid = 24822810 }}</ref> and a mutation in the gene that codes for the [[5-HT2A receptor|5-HT_2A]] receptor may double the risk of suicide for those with that genotype.<ref name="Basky_2000">{{cite journal | vauthors = Ito Z, Aizawa I, Takeuchi M, Tabe M, Nakamura T | title = [Proceedings: Study of gastrointestinal motility using an extraluminal force transducer. 6. Observation of gastric and duodenal motility using synthetic motilin] | journal = Nihon Heikatsukin Gakkai Zasshi | volume = 11 | issue = 4 | pages = 244–246 | date = December 1975 | pmid = 1232434 }}</ref> Serotonin in the brain is not usually degraded after use, but is collected by serotonergic neurons by [[serotonin transporter]]s on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the [[5-HTTLPR|description of where, when and how many]] serotonin transporters the neurons should deploy.<ref name="pmid8929413">{{cite journal | vauthors = Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL | title = Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region | journal = Science | volume = 274 | issue = 5292 | pages = 1527–1531 | date = November 1996 | pmid = 8929413 | doi = 10.1126/science.274.5292.1527 | s2cid = 35503987 | bibcode = 1996Sci...274.1527L }}</ref>

===Outside the nervous system===

====Digestive tract (emetic)====

Serotonin regulates gastrointestinal (GI) function. The gut is surrounded by [[enterochromaffin cell]]s, which release serotonin in response to food in the [[Lumen (anatomy)|lumen]]. This makes the gut contract around the food. Platelets in the [[Hepatic portal system|veins draining the gut]] collect excess serotonin. There are often serotonin abnormalities in gastrointestinal disorders such as constipation and irritable bowel syndrome.<ref name="ReferenceA">{{cite journal | vauthors = Beattie DT, Smith JA | title = Serotonin pharmacology in the gastrointestinal tract: a review | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 377 | issue = 3 | pages = 181–203 | date = May 2008 | pmid = 18398601 | doi = 10.1007/s00210-008-0276-9 | s2cid = 32820765 }}</ref>

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 [[5-HT3 receptor]]s in the [[chemoreceptor trigger zone]] that stimulate [[vomiting]].<ref>{{cite book | vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |page=187 |isbn=978-0-443-07145-4}}</ref> Thus, drugs and toxins stimulate serotonin release from enterochromaffin cells in the gut wall can induce emesis. The enterochromaffin cells not only react to bad food but are also very sensitive to [[Radiation therapy|irradiation]] and [[chemotherapy|cancer chemotherapy]]. Drugs that [[5-HT antagonist|block 5HT3]] are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.<ref>{{cite journal | vauthors = de Wit R, Aapro M, Blower PR | title = Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients? | journal = Cancer Chemotherapy and Pharmacology | volume = 56 | issue = 3 | pages = 231–238 | date = September 2005 | pmid = 15838653 | doi = 10.1007/s00280-005-1033-0 | s2cid = 27576150 }}</ref>

====Lungs====

The [[lung]],<ref name="Lauweryns_1973">{{cite journal | vauthors = Lauweryns JM, Cokelaere J, Theunynck P | title = Serotonin producing neuroepithelial bodies in rabbit respiratory mucosa | journal = Science | volume = 180 | issue = 4084 | pages = 410–413 | date = April 1973 | pmid = 4121716 | doi = 10.1126/science.180.4084.410 | s2cid = 2809307 | bibcode = 1973Sci...180..410L }}</ref> including that of reptiles,<ref name="Pastor Ballesta Perez-Tomas Marin 1987 pp. 713–715">{{cite journal | vauthors = Pastor LM, Ballesta J, Perez-Tomas R, Marin JA, Hernandez F, Madrid JF | title = Immunocytochemical localization of serotonin in the reptilian lung | journal = Cell and Tissue Research | volume = 248 | issue = 3 | pages = 713–715 | date = June 1987 | pmid = 3301000 | doi = 10.1007/bf00216504 | publisher = Springer Science and Business Media LLC | s2cid = 9871728 }}</ref> contains specialized [[epithelial cells]] that occur as solitary cells or as clusters called neuroepithelial bodies or bronchial Kulchitsky cells or alternatively ''K cells''.<ref name="Sonstegard_1982">{{cite journal | vauthors = Sonstegard KS, Mailman RB, Cheek JM, Tomlin TE, DiAugustine RP | title = Morphological and cytochemical characterization of neuroepithelial bodies in fetal rabbit lung. I. Studies of isolated neuroepithelial bodies | journal = Experimental Lung Research | volume = 3 | issue = 3–4 | pages = 349–377 | date = November 1982 | pmid = 6132813 | doi = 10.3109/01902148209069663 }}</ref> These are enterochromaffin cells that like those in the gut release serotonin.<ref name="Sonstegard_1982" /> Their function is probably [[Hypoxic pulmonary vasoconstriction|vasoconstriction during hypoxia]].<ref name="Lauweryns_1973" />

====Skin====

Serotonin is also produced by [[Merkel cell]]s which are part of the [[somatosensory]] system.<ref>{{cite journal | vauthors = Chang W, Kanda H, Ikeda R, Ling J, DeBerry JJ, Gu JG | title = Merkel disc is a serotonergic synapse in the epidermis for transmitting tactile signals in mammals | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 37 | pages = E5491–E5500 | date = September 2016 | pmid = 27573850 | pmc = 5027443 | doi = 10.1073/pnas.1610176113 | bibcode = 2016PNAS..113E5491C | doi-access = free }}</ref>

====Bone metabolism====

In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass.<ref name="pmid20200960">{{cite journal | vauthors = Frost M, Andersen TE, Yadav V, Brixen K, Karsenty G, Kassem M | title = Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin | journal = Journal of Bone and Mineral Research | volume = 25 | issue = 3 | pages = 673–675 | date = March 2010 | pmid = 20200960 | doi = 10.1002/jbmr.44 | s2cid = 24280062 | doi-access = free }}</ref><ref name="pmid19197289">{{cite journal | vauthors = Rosen CJ | title = Breaking into bone biology: serotonin's secrets | journal = Nature Medicine | volume = 15 | issue = 2 | pages = 145–146 | date = February 2009 | pmid = 19197289 | doi = 10.1038/nm0209-145 | s2cid = 5489589 }}</ref><ref name="pmid19594297">{{cite journal | vauthors = Mödder UI, Achenbach SJ, Amin S, Riggs BL, Melton LJ, Khosla S | title = Relation of serum serotonin levels to bone density and structural parameters in women | journal = Journal of Bone and Mineral Research | volume = 25 | issue = 2 | pages = 415–422 | date = February 2010 | pmid = 19594297 | pmc = 3153390 | doi = 10.1359/jbmr.090721 }}</ref><ref name="pmid21351148">{{cite journal | vauthors = Frost M, Andersen T, Gossiel F, Hansen S, Bollerslev J, van Hul W, Eastell R, Kassem M, Brixen K | title = Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5 | journal = Journal of Bone and Mineral Research | volume = 26 | issue = 8 | pages = 1721–1728 | date = August 2011 | pmid = 21351148 | doi = 10.1002/jbmr.376 | doi-access = free }}</ref> Mice that lack brain serotonin have [[osteopenia]], while mice that lack gut serotonin have high bone density. In humans, increased blood serotonin levels have been shown to be a 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. Through [[5-HT1B receptor|5-HT_1B receptors]], it negatively regulates bone mass, while it does so positively through [[5-HT2B receptor|5-HT_2B receptors]] and [[5-HT2C receptor|5-HT_2C receptors]]. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events.<ref name="pmid22945629">{{cite journal | vauthors = Kode A, Mosialou I, Silva BC, Rached MT, Zhou B, Wang J, Townes TM, Hen R, DePinho RA, Guo XE, Kousteni S | title = FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin | journal = The Journal of Clinical Investigation | volume = 122 | issue = 10 | pages = 3490–3503 | date = October 2012 | pmid = 22945629 | pmc = 3461930 | doi = 10.1172/JCI64906 }}</ref> Following the 2008 findings that gut serotonin regulates bone mass, the mechanistic investigations into what regulates serotonin synthesis from the gut in the regulation of bone mass have started. [[PIEZO1|Piezo1]] has been shown to sense RNA in the gut and relay this information through serotonin synthesis to the bone by acting as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse ''Piezo1'' profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of ''Piezo1'' increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders. Studies in 2008, 2010 and 2019 have opened the potential for serotonin research to treat bone mass disorders.<ref name="pmid20139991">{{cite journal | vauthors = Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P | title = Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis | journal = Nature Medicine | volume = 16 | issue = 3 | pages = 308–312 | date = March 2010 | pmid = 20139991 | pmc = 2836724 | doi = 10.1038/nm.2098 }}</ref><ref name="pmid32640190">{{cite journal | vauthors = Sugisawa E, Takayama Y, Takemura N, Kondo T, Hatakeyama S, Kumagai Y, Sunagawa M, Tominaga M, Maruyama K | title = RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis | journal = Cell | volume = 182 | issue = 3 | pages = 609–624.e21 | date = August 2020 | pmid = 32640190 | doi = 10.1016/j.cell.2020.06.022 | doi-access = free }}</ref>

====Organ development====

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.<ref>{{cite journal | vauthors = Ozanne SE, Hales CN | title = Lifespan: catch-up growth and obesity in male mice | journal = Nature | volume = 427 | issue = 6973 | pages = 411–412 | date = January 2004 | pmid = 14749819 | doi = 10.1038/427411b | s2cid = 40256021 | bibcode = 2004Natur.427..411O }}</ref><ref>{{cite journal | vauthors = Lewis DS, Bertrand HA, McMahan CA, McGill HC, Carey KD, Masoro EJ | title = Preweaning food intake influences the adiposity of young adult baboons | journal = The Journal of Clinical Investigation | volume = 78 | issue = 4 | pages = 899–905 | date = October 1986 | pmid = 3760191 | pmc = 423712 | doi = 10.1172/JCI112678 }}</ref><ref name="Hahn1984">{{cite journal | vauthors = Hahn P | title = Effect of litter size on plasma cholesterol and insulin and some liver and adipose tissue enzymes in adult rodents | journal = The Journal of Nutrition | volume = 114 | issue = 7 | pages = 1231–1234 | date = July 1984 | pmid = 6376732 | doi = 10.1093/jn/114.7.1231 }}</ref> Rodent experiment shows that neonatal exposure to SSRIs makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes,<ref name="pmid18385313">{{cite journal | vauthors = Popa D, Léna C, Alexandre C, Adrien J | title = Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: evidence from sleep, stress, and behavior | journal = The Journal of Neuroscience | volume = 28 | issue = 14 | pages = 3546–3554 | date = April 2008 | pmid = 18385313 | pmc = 6671102 | doi = 10.1523/JNEUROSCI.4006-07.2008 }}</ref><ref name="pmid16012532">{{cite journal | vauthors = Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RC, Paul IA | title = Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry | journal = Neuropsychopharmacology | volume = 31 | issue = 1 | pages = 47–57 | date = January 2006 | pmid = 16012532 | pmc = 3118509 | doi = 10.1038/sj.npp.1300823 }}</ref> which are reversed by treatment with antidepressants.<ref name="pmid16483567">{{cite journal | vauthors = Maciag D, Williams L, Coppinger D, Paul IA | title = Neonatal citalopram exposure produces lasting changes in behavior which are reversed by adult imipramine treatment | journal = European Journal of Pharmacology | volume = 532 | issue = 3 | pages = 265–269 | date = February 2006 | pmid = 16483567 | pmc = 2921633 | doi = 10.1016/j.ejphar.2005.12.081 }}</ref> By treating normal and [[Knockout mouse|knockout mice]] lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.<ref>{{cite journal | vauthors = Holden C | title = Neuroscience. Prozac treatment of newborn mice raises anxiety | journal = Science | volume = 306 | issue = 5697 | pages = 792 | date = October 2004 | pmid = 15514122 | doi = 10.1126/science.306.5697.792 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA | title = Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice | journal = Science | volume = 306 | issue = 5697 | pages = 879–881 | date = October 2004 | pmid = 15514160 | doi = 10.1126/science.1101678 | doi-access = free | bibcode = 2004Sci...306..879A }}</ref>

Human serotonin can also act as a [[growth factor]] directly. Liver damage increases cellular expression of [[5-HT2A receptor|5-HT_2A]] and [[5-HT2B receptor|5-HT_2B receptor]]s, mediating liver compensatory regrowth (see {{section link|Liver|Regeneration and transplantation}})<ref name="pmid16601191">{{cite journal | vauthors = Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA | title = Platelet-derived serotonin mediates liver regeneration | journal = Science | volume = 312 | issue = 5770 | pages = 104–107 | date = April 2006 | pmid = 16601191 | doi = 10.1126/science.1123842 | s2cid = 43189753 | bibcode = 2006Sci...312..104L }}</ref> Serotonin present in the blood then stimulates cellular growth to repair liver damage.<ref name="pmid19246633">{{cite journal | vauthors = Matondo RB, Punt C, Homberg J, Toussaint MJ, Kisjes R, Korporaal SJ, Akkerman JW, Cuppen E, de Bruin A | title = Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 296 | issue = 4 | pages = G963–G968 | date = April 2009 | pmid = 19246633 | doi = 10.1152/ajpgi.90709.2008 | url = http://www.suaire.suanet.ac.tz:8080/xmlui/handle/123456789/2619 | access-date = 5 December 2019 | url-status = dead | archive-url = https://web.archive.org/web/20191228005416/http://www.suaire.suanet.ac.tz:8080/xmlui/handle/123456789/2619 | archive-date = 28 December 2019 }}</ref>

5-HT_2B receptors also activate [[osteocyte]]s, which build up bone<ref name="pmid17846081">{{cite journal | vauthors = Collet C, Schiltz C, Geoffroy V, Maroteaux L, Launay JM, de Vernejoul MC | title = The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation | journal = FASEB Journal | volume = 22 | issue = 2 | pages = 418–427 | date = February 2008 | pmid = 17846081 | pmc = 5409955 | doi = 10.1096/fj.07-9209com | doi-access = free }}</ref> However, serotonin also inhibits [[osteoblast]]s, through 5-HT_1B receptors.<ref name="pmid19041748">{{cite journal | vauthors = Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G | title = Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum | journal = Cell | volume = 135 | issue = 5 | pages = 825–837 | date = November 2008 | pmid = 19041748 | pmc = 2614332 | doi = 10.1016/j.cell.2008.09.059 }}

* {{cite press release |date=December 1, 2008 |title=It Takes Guts To Build Bone, Scientists Discover |website=ScienceDaily |url=https://www.sciencedaily.com/releases/2008/11/081126122209.htm}}</ref>

====Cardiovascular growth factor====

{{Main|Cardiac fibrosis}}

Serotonin, in addition, evokes [[endothelium|endothelial]] [[nitric oxide synthase]] activation and stimulates, through a [[5-HT1B receptor]]-mediated mechanism, the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.{{clarify|incomprehensible to lay readers|date=December 2018}}<ref name="pmid10710124">{{cite journal | vauthors = McDuffie JE, Motley ED, Limbird LE, Maleque MA | title = 5-hydroxytryptamine stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures | journal = Journal of Cardiovascular Pharmacology | volume = 35 | issue = 3 | pages = 398–402 | date = March 2000 | pmid = 10710124 | doi = 10.1097/00005344-200003000-00008 | doi-access = free }}</ref> In blood, serotonin is collected from plasma by platelets, which store it. 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.<ref>{{cite journal | vauthors = Noguchi M, Furukawa KT, Morimoto M | title = Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease | journal = Disease Models & Mechanisms | volume = 13 | issue = 12 | pages = dmm046920 | date = December 2020 | pmid = 33355253 | pmc = 7774893 | doi = 10.1242/dmm.046920 }}</ref>

==Pharmacology==

Several classes of [[drugs]] target the serotonin system, including some [[antidepressant]]s, [[anxiolytic]]s, [[antipsychotic]]s, [[analgesic]]s, [[antimigraine drug]]s, [[antiemetic]]s, [[appetite suppressant]]s, and [[anticonvulsant]]s, as well as [[psychedelic drug|psychedelic]]s and [[entactogen]]s.

===Mechanism of action===

At rest, serotonin is stored within the vesicles of presynaptic neurons. When stimulated by nerve impulses, serotonin is released as a neurotransmitter into the synapse, reversibly binding to the postsynaptic receptor to induce a nerve impulse on the postsynaptic neuron. Serotonin can also bind to auto-receptors on the presynaptic neuron to regulate the synthesis and release of serotonin. Normally serotonin is taken back into the presynaptic neuron to stop its action, then reused or broken down by monoamine oxidase.<ref>{{cite journal | vauthors = Fuller RW | title = Pharmacology of central serotonin neurons | journal = Annual Review of Pharmacology and Toxicology | volume = 20 | pages = 111–127 | date = 1980 | pmid = 6992697 | doi = 10.1146/annurev.pa.20.040180.000551 }}</ref>

===Antidepressants===

{{Main|Selective serotonin reuptake inhibitor|Monoamine oxidase inhibitor}}

Drugs that alter serotonin levels are used in treating [[Major depressive disorder|depression]], [[generalized anxiety disorder]], and [[social anxiety disorder|social phobia]]. [[Monoamine oxidase inhibitor]]s (MAOIs) prevent the breakdown of [[monoamine neurotransmitter]]s (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 and non-selective|selective]] serotonin reuptake inhibitors ([[SSRI]]s) have fewer side-effects and fewer interactions with other drugs.<ref>{{Cite book | vauthors = Goodman LS, Brunton LL, Chabner B, Knollmann BC | title = Goodman and Gilman's pharmacological basis of therapeutics | year = 2001 | publisher = McGraw-Hill | location = New York | isbn = 978-0-07-162442-8 | pages = 459–461 }}</ref>

Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases.<ref name="pmid10575045">{{cite journal | vauthors = Benmansour S, Cecchi M, Morilak DA, Gerhardt GA, Javors MA, Gould GG, Frazer A | title = Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level | journal = The Journal of Neuroscience | volume = 19 | issue = 23 | pages = 10494–10501 | date = December 1999 | pmid = 10575045 | pmc = 6782424 | doi = 10.1523/JNEUROSCI.19-23-10494.1999 }}</ref> 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.<ref>{{cite journal | vauthors = Beitchman JH, Baldassarra L, Mik H, De Luca V, King N, Bender D, Ehtesham S, Kennedy JL | title = Serotonin transporter polymorphisms and persistent, pervasive childhood aggression | journal = The American Journal of Psychiatry | volume = 163 | issue = 6 | pages = 1103–1105 | date = June 2006 | pmid = 16741214 | doi = 10.1176/appi.ajp.163.6.1103 }}</ref> The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety.<ref>{{cite journal | vauthors = Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR | title = 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression | journal = Nature Neuroscience | volume = 8 | issue = 6 | pages = 828–834 | date = June 2005 | pmid = 15880108 | doi = 10.1038/nn1463 | s2cid = 1864631 }}</ref><ref>{{cite journal | vauthors = Schinka JA, Busch RM, Robichaux-Keene N | title = A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety | journal = Molecular Psychiatry | volume = 9 | issue = 2 | pages = 197–202 | date = February 2004 | pmid = 14966478 | doi = 10.1038/sj.mp.4001405 | doi-access = free }}</ref>

Besides their use in treating depression and anxiety, certain serotonergic antidepressants are also approved and used to treat [[fibromyalgia]], [[neuropathic pain]], and [[chronic fatigue syndrome]].<ref name="O'MalleyJacksonSantoro1999">{{cite journal | vauthors = O'Malley PG, Jackson JL, Santoro J, Tomkins G, Balden E, Kroenke K | title = Antidepressant therapy for unexplained symptoms and symptom syndromes | journal = J Fam Pract | volume = 48 | issue = 12 | pages = 980–990 | date = December 1999 | pmid = 10628579 | doi = | url = }}</ref><ref name="WelschÜçeylerKlose2018">{{cite journal | vauthors = Welsch P, Üçeyler N, Klose P, Walitt B, Häuser W | title = Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia | journal = Cochrane Database Syst Rev | volume = 2 | issue = 2 | pages = CD010292 | date = February 2018 | pmid = 29489029 | pmc = 5846183 | doi = 10.1002/14651858.CD010292.pub2 | url = }}</ref>

===Anxiolytics===

[[Azapirone]] [[anxiolytic]]s like [[buspirone]] and [[tandospirone]] act as serotonin [[5-HT1A receptor|5-HT_1A receptor]] [[agonist]]s.<ref name="TaylorMoon1991">{{cite journal | vauthors = Taylor DP, Moon SL | title = Buspirone and related compounds as alternative anxiolytics | journal = Neuropeptides | volume = 19 | issue = Suppl | pages = 15–19 | date = July 1991 | pmid = 1679210 | doi = 10.1016/0143-4179(91)90078-w | url = }}</ref><ref name="KishiMeltzerMatsuda2014">{{cite journal | vauthors = Kishi T, Meltzer HY, Matsuda Y, Iwata N | title = Azapirone 5-HT1A receptor partial agonist treatment for major depressive disorder: systematic review and meta-analysis | journal = Psychol Med | volume = 44 | issue = 11 | pages = 2255–2269 | date = August 2014 | pmid = 24262766 | doi = 10.1017/S0033291713002857 | url = }}</ref>

===Antipsychotics===

Many [[antipsychotic]]s bind to and modulate [[serotonin receptor]]s, including the serotonin [[5-HT1A receptor|5-HT_1A]], [[5-HT2A receptor|5-HT_2A]], [[5-HT2B receptor|5-HT_2B]], [[5-HT2C receptor|5-HT_2C]], [[5-HT6 receptor|5-HT₆]], and [[5-HT7 receptor|5-HT₇ receptor]]s, among others.<ref name="Meltzer1999">{{cite journal | vauthors = Meltzer HY | title = The role of serotonin in antipsychotic drug action | journal = Neuropsychopharmacology | volume = 21 | issue = 2 Suppl | pages = 106S–115S | date = August 1999 | pmid = 10432496 | doi = 10.1016/S0893-133X(99)00046-9 | url = }}</ref><ref name="Meltzer2012">{{cite journal | vauthors = Meltzer HY | title = Serotonergic mechanisms as targets for existing and novel antipsychotics | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 212| issue = 212 | pages = 87–124 | date = 2012 | pmid = 23129329 | doi = 10.1007/978-3-642-25761-2_4 | isbn = 978-3-642-25760-5 | url = }}</ref> Activation of serotonin 5-HT_1A receptors and blockade of serotonin 5-HT_2A receptors may contribute to the therapeutic antipsychotic effects of these agents, whereas antagonism of serotonin 5-HT_2C receptors has been especially implicated in [[side effect]]s of antipsychotics.<ref name="Meltzer1999" /><ref name="Meltzer2012" />

===Antimigraine agents===

[[Antimigraine agent]]s such as the [[triptan]]s like [[sumatriptan]] act as [[agonist]]s of the serotonin [[5-HT1B receptor|5-HT_1B]], [[5-HT1D receptor|5-HT_1D]], and/or [[5-HT1F receptor|5-HT_1F receptor]]s.<ref name="Tfelt-HansenDeVriesSaxena2000">{{cite journal | vauthors = Tfelt-Hansen P, De Vries P, Saxena PR | title = Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy | journal = Drugs | volume = 60 | issue = 6 | pages = 1259–1287 | date = December 2000 | pmid = 11152011 | doi = 10.2165/00003495-200060060-00003 | url = }}</ref><ref name="RamírezRosasLabruijereVillalón2013" /> Earlier antimigraine agents were the [[ergoline]] [[chemical derivative|derivative]]s and [[ergot]]-related drugs such as [[ergotamine]], [[dihydroergotamine]], and [[methysergide]], which act as [[binding selectivity|non-selective]] [[serotonin receptor agonist]]s.<ref name="RamírezRosasLabruijereVillalón2013">{{cite journal | vauthors = Ramírez Rosas MB, Labruijere S, Villalón CM, Maassen Vandenbrink A | title = Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs | journal = Expert Opin Pharmacother | volume = 14 | issue = 12 | pages = 1599–1610 | date = August 2013 | pmid = 23815106 | doi = 10.1517/14656566.2013.806487 | url = }}</ref><ref name="SaxenaDenBoer1991">{{cite journal | vauthors = Saxena PR, Den Boer MO | title = Pharmacology of antimigraine drugs | journal = J Neurol | volume = 238 | issue = Suppl 1 | pages = S28–S35 | date = 1991 | pmid = 1646288 | doi = 10.1007/BF01642903 | url = }}</ref><ref name="WhealyBecker2024">{{cite book | vauthors = Whealy M, Becker WJ | chapter = The 5-HT1B and 5-HT1D agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans | title = Handbook of Clinical Neurology | volume = 199 | issue = | pages = 17–42 | date = 2024 | pmid = 38307644 | doi = 10.1016/B978-0-12-823357-3.00008-2 | isbn = 978-0-12-823357-3 | url = }}</ref>

===Antiemetics===

Some serotonin [[5-HT3 antagonist|5-HT₃ receptor antagonist]]s, such as [[ondansetron]], [[granisetron]], and [[tropisetron]], are important [[antiemetic]] agents.<ref name="HoGan2006">{{cite journal | vauthors = Ho KY, Gan TJ | title = Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting | journal = Curr Opin Anaesthesiol | volume = 19 | issue = 6 | pages = 606–611 | date = December 2006 | pmid = 17093363 | doi = 10.1097/01.aco.0000247340.61815.38 | url = }}</ref><ref name="SeynaeveVerweijdeMulder1991">{{cite journal | vauthors = Seynaeve C, Verweij J, de Mulder PH | title = 5-HT3 receptor antagonists, a new approach in emesis: a review of ondansetron, granisetron and tropisetron | journal = Anticancer Drugs | volume = 2 | issue = 4 | pages = 343–355 | date = August 1991 | pmid = 1665723 | doi = 10.1097/00001813-199108000-00003 | url = }}</ref> They are particularly important in treating the [[nausea]] and [[vomiting]] that [[Chemotherapy-induced nausea and vomiting|occur during anticancer chemotherapy]] using [[cytotoxic drugs]].<ref name="SeynaeveVerweijdeMulder1991" /> Another application is in the treatment of [[postoperative nausea and vomiting]].<ref name="HoGan2006" />

===Appetite suppressants===

Some [[serotonin releasing agent]]s, [[serotonin reuptake inhibitor]]s, and/or serotonin [[5-HT2C receptor|5-HT_2C receptor]] [[agonist]]s, such as [[fenfluramine]], [[dexfenfluramine]], [[chlorphentermine]], [[sibutramine]], and [[lorcaserin]], have been approved and used as [[appetite suppressant]]s for purposes of [[weight loss]] in the treatment of [[overweightness]] or [[obesity]].<ref name="HalfordHarroldBoyland2007">{{cite journal | vauthors = Halford JC, Harrold JA, Boyland EJ, Lawton CL, Blundell JE | title = Serotonergic drugs : effects on appetite expression and use for the treatment of obesity | journal = Drugs | volume = 67 | issue = 1 | pages = 27–55 | date = 2007 | pmid = 17209663 | doi = 10.2165/00003495-200767010-00004 | url = }}</ref><ref name="HurrenBerlie2011">{{cite journal | vauthors = Hurren KM, Berlie HD | title = Lorcaserin: an investigational serotonin 2C agonist for weight loss | journal = Am J Health Syst Pharm | volume = 68 | issue = 21 | pages = 2029–2037 | date = November 2011 | pmid = 22011982 | doi = 10.2146/ajhp100638 | url = }}</ref><ref name="HalfordBoylandLawton2011">{{cite journal | vauthors = Halford JC, Boyland EJ, Lawton CL, Blundell JE, Harrold JA | title = Serotonergic anti-obesity agents: past experience and future prospects | journal = Drugs | volume = 71 | issue = 17 | pages = 2247–2255 | date = December 2011 | pmid = 22085383 | doi = 10.2165/11596680-000000000-00000 | url = }}</ref><ref name="HalfordHarrold2012">{{cite journal | vauthors = Halford JC, Harrold JA | title = 5-HT(2C) receptor agonists and the control of appetite | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 209| issue = 209 | pages = 349–356 | date = 2012 | pmid = 22249823 | doi = 10.1007/978-3-642-24716-3_16 | isbn = 978-3-642-24715-6 | url = }}</ref><ref name="PrzegalińskiWitekWydra2023">{{cite journal | vauthors = Przegaliński E, Witek K, Wydra K, Kotlińska JH, Filip M | title = 5-HT2C Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators | journal = Nutrients | volume = 15 | issue = 6 | date = March 2023 | page = 1449 | pmid = 36986191 | pmc = 10058696 | doi = 10.3390/nu15061449 | doi-access = free | url = }}</ref> Several of the preceding agents have been [[withdrawn drug|withdrawn from the market]] due to [[toxicity]], such as [[cardiac fibrosis]] or [[pulmonary hypertension]].<ref name="PrzegalińskiWitekWydra2023" />

===Anticonvulsants===

Although it was previously [[withdrawn drug|withdrawn from the market]] as an appetite suppressant, fenfluramine was reintroduced as an [[anticonvulsant]] for treatment of [[seizure]]s in certain rare forms of [[epilepsy]] like [[Dravet syndrome]] and [[Lennox–Gastaut syndrome]].<ref name="DiniDiCaraFerrara2023">{{cite journal | vauthors = Dini G, Di Cara G, Ferrara P, Striano P, Verrotti A | title = Reintroducing Fenfluramine as a Treatment for Seizures: Current Knowledge, Recommendations and Gaps in Understanding | journal = Neuropsychiatr Dis Treat | volume = 19 | issue = | pages = 2013–2025 | date = 2023 | pmid = 37790801 | pmc = 10543412 | doi = 10.2147/NDT.S417676 | doi-access = free | url = }}</ref> Selective serotonin 5-HT_2C receptor agonists, like lorcaserin, [[bexicaserin]], and [[BMB-101]], are also being developed for this use.<ref name="DiniDiCaraFerrara2023" /><ref name="BialerPerucca2022">{{cite journal | vauthors = Bialer M, Perucca E | title = Lorcaserin for Dravet Syndrome: A Potential Advance Over Fenfluramine? | journal = CNS Drugs | volume = 36 | issue = 2 | pages = 113–122 | date = February 2022 | pmid = 35094259 | doi = 10.1007/s40263-022-00896-3 | url = }}</ref><ref name="Dell'isolaVerrottiSciaccaluga2024">{{cite journal | vauthors = Dell'isola GB, Verrotti A, Sciaccaluga M, Roberti R, Parnetti L, Russo E, Costa C | title = Evaluating bexicaserin for the treatment of developmental epileptic encephalopathies | journal = Expert Opin Pharmacother | volume = 25 | issue = 9 | pages = 1121–1130 | date = June 2024 | pmid = 38916481 | doi = 10.1080/14656566.2024.2373350 | url = }}</ref><ref name="AdisInsight-BMB-101">{{cite web | title=BMB 101 | website=AdisInsight | date=23 October 2024 | url=https://adisinsight.springer.com/drugs/800065004 | access-date=30 October 2024}}</ref>

===Psychedelics===

[[Serotonergic psychedelic]]s, including drugs like [[psilocybin]] (found in [[psilocybin mushroom]]s), [[dimethyltryptamine]] (DMT) (found in [[ayahuasca]]), [[lysergic acid diethylamide]] (LSD), and [[mescaline]] (found in [[peyote|peyote cactus]]), are [[binding selectivity|non-selective]] [[agonist]]s of the [[serotonin receptor]]s and mediate their [[hallucinogen]]ic effects specifically by activation of the serotonin [[5-HT2A receptor|5-HT_2A receptor]].<ref name="SlocumDiBertoRoth2022">{{cite journal | vauthors = Slocum ST, DiBerto JF, Roth BL | title = Molecular insights into psychedelic drug action | journal = J Neurochem | volume = 162 | issue = 1 | pages = 24–38 | date = July 2022 | pmid = 34797943 | doi = 10.1111/jnc.15540 | url = }}</ref><ref name="DuanCaoWang2024">{{cite journal | vauthors = Duan W, Cao D, Wang S, Cheng J | title = Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants | journal = Chem Rev | volume = 124 | issue = 1 | pages = 124–163 | date = January 2024 | pmid = 38033123 | doi = 10.1021/acs.chemrev.3c00375 | url = }}</ref><ref name="Nichols2018">{{cite journal | vauthors = Nichols DE | title = Chemistry and Structure-Activity Relationships of Psychedelics | journal = Curr Top Behav Neurosci | series = Current Topics in Behavioral Neurosciences | volume = 36 | issue = | pages = 1–43 | date = 2018 | pmid = 28401524 | doi = 10.1007/7854_2017_475 | isbn = 978-3-662-55878-2 | url = }}</ref> This is evidenced by the fact that serotonin 5-HT_2A receptor antagonists and so-called "[[trip killer]]s" like [[ketanserin]] block the hallucinogenic effects of serotonergic psychedelics in humans, among many other findings.<ref name="SlocumDiBertoRoth2022" /><ref name="DuanCaoWang2024" /><ref name="HalmanKongSarris2024">{{Cite journal |vauthors=Halman A, Kong G, Sarris J, Perkins D |date=January 2024 |title=Drug-drug interactions involving classic psychedelics: A systematic review |journal=J Psychopharmacol |volume=38 |issue=1 |pages=3–18 |doi=10.1177/02698811231211219 |pmc=10851641 |pmid=37982394}}</ref> Some serotonergic psychedelics, like [[psilocin]] and DMT, are [[substituted tryptamine]]s and are very similar in [[chemical structure]] to serotonin.<ref name="Nichols2018" />

Serotonin itself, despite acting as a serotonin 5-HT_2A receptor agonist, is thought to be non-hallucinogenic.<ref name="VargasDunlapDong2023" /> The hallucinogenic effects of serotonergic psychedelics appear to be mediated specifically by activation of serotonin 5-HT_2A receptors expressed in a population of [[cortex|cortical]] [[neuron]]s in the [[medial prefrontal cortex]] (mPFC).<ref name="Sapienza2023">{{cite journal | vauthors = Sapienza J | title=The Key Role of Intracellular 5-HT2A Receptors: A Turning Point in Psychedelic Research? | journal=Psychoactives | volume=2 | issue=4 | date=13 October 2023 | issn=2813-1851 | doi=10.3390/psychoactives2040018 | doi-access=free | pages=287–293}}</ref><ref name="VargasDunlapDong2023">{{cite journal | vauthors = Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE | title = Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors | journal = Science | volume = 379 | issue = 6633 | pages = 700–706 | date = February 2023 | pmid = 36795823 | pmc = 10108900 | doi = 10.1126/science.adf0435 | bibcode = 2023Sci...379..700V | url = | quote = In addition to promoting psychedelic-induced structural neuroplasticity, the intracellular population of 5-HT2ARs might also contribute to the hallucinogenic effects of psychedelics. When we administered a serotonin-releasing agent to wild type mice, we did not observe a HTR. However, the same drug was able to induce a HTR in mice expressing SERT on cortical neurons of the mPFC—a brain region known to be essential for the HTR (49). Thus, activation of intracellular cortical 5-HT2ARs may play a role in the subjective effects of psychedelics. This hypothesis is further supported by previous work demonstrating that a high dose of the serotonin precursor 5-hydroxytryptophan (5-HTP) induces a HTR in WT mice, which can be blocked by an N-methyltransferase inhibitor that prevents the metabolism of 5-HTP to N-methyltryptamines (50). Inhibition of N-methyltransferase failed to block the HTR induced by 5-MeO-DMT (50). Taken together, this work emphasizes that accessing intracellular 5-HT2ARs is important for 5-HT2AR agonists to produce a HTR.}}</ref> These serotonin 5-HT_2A receptors, unlike most serotonin and related receptors, are expressed [[intracellular]]ly.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> In addition, the neurons containing them lack [[gene expression|expression]] of the [[serotonin transporter]] (SERT), which normally [[active transport|transport]]s serotonin from the [[extracellular]] space to the intracellular space within neurons.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Serotonin itself is too [[hydrophilic]] to enter serotonergic neurons without the SERT, and hence these serotonin 5-HT_2A receptors are inaccessible to serotonin.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Conversely, serotonergic psychedelics are more [[lipophilic]] than serotonin and readily enter these neurons.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> In addition to explaining why serotonin does not show psychedelic effects, these findings may explain why drugs that increase serotonin levels, like [[selective serotonin reuptake inhibitor]]s (SSRIs) and various other types of serotonergic agents, do not produce psychedelic effects.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Artificial expression of the SERT in these medial prefrontal cortex neurons resulted in the [[serotonin releasing agent]] [[para-chloroamphetamine|''para''-chloroamphetamine]] (PCA), which does not normally show psychedelic-like effects, being able to produce psychedelic-like effects in animals.<ref name="VargasDunlapDong2023" />

Although serotonin itself is non-hallucinogenic, administration of very high doses of a [[serotonin precursor]], like [[tryptophan]] or [[5-hydroxytryptophan]] (5-HTP), or [[intracerebroventricular injection]] of high doses of serotonin directly into the brain, can produce psychedelic-like effects in animals.<ref name="SchmidBohn2018">{{cite book | vauthors = Schmid CL, Bohn LM | title=5-HT2A Receptors in the Central Nervous System | chapter=βArrestins: Ligand-Directed Regulators of 5-HT2A Receptor Trafficking and Signaling Events | publisher=Springer International Publishing | publication-place=Cham | date=2018 | isbn=978-3-319-70472-2 | doi=10.1007/978-3-319-70474-6_2 | pages=31–55}}</ref><ref name="KozlenkovGonzález-Maeso2013">{{cite book | vauthors = Kozlenkov A, González-Maeso J | title=The Neuroscience of Hallucinations | chapter=Animal Models and Hallucinogenic Drugs | publisher=Springer New York | publication-place=New York, NY | date=2013 | isbn=978-1-4614-4120-5 | doi=10.1007/978-1-4614-4121-2_14 | pages=253–277}}</ref><ref name="SchmidBohn2010">{{cite journal | vauthors = Schmid CL, Bohn LM | title = Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a β-arrestin2/Src/Akt signaling complex in vivo | journal = J Neurosci | volume = 30 | issue = 40 | pages = 13513–24 | date = October 2010 | pmid = 20926677 | pmc = 3001293 | doi = 10.1523/JNEUROSCI.1665-10.2010 | url = }}</ref> These psychedelic-like effects can be abolished by [[indolethylamine N-methyltransferase|indolethylamine ''N''-methyltransferase]] (INMT) [[enzyme inhibitor|inhibitor]]s, which block conversion of serotonin and other endogenous tryptamines into ''N''-[[methyl group|methylated]] tryptamines, including [[N-Methylserotonin|''N''-methylserotonin]] (NMS; norbufotenin), [[bufotenin]] (5-hydroxy-''N'',''N''-dimethyltryptamine; 5-HO-DMT), [[N-methyltryptamine|''N''-methyltryptamine]] (NMT), and [[dimethyltryptamine|''N'',''N''-dimethyltryptamine]] (DMT).<ref name="KozlenkovGonzález-Maeso2013" /><ref name="HalberstadtGeyer2018">{{cite journal | vauthors = Halberstadt AL, Geyer MA | title = Effect of Hallucinogens on Unconditioned Behavior | journal = Curr Top Behav Neurosci | series = Current Topics in Behavioral Neurosciences | volume = 36 | issue = | pages = 159–199 | date = 2018 | pmid = 28224459 | pmc = 5787039 | doi = 10.1007/7854_2016_466 | isbn = 978-3-662-55878-2 | url = }}</ref><ref name="SchmidBohn2010" /> These ''N''-methyltryptamines are much more lipophilic than serotonin and, in contrast, are able to [[passive diffusion|diffuse]] into serotonergic neurons and activate intracellular serotonin 5-HT_2A receptors.<ref name="KozlenkovGonzález-Maeso2013" /><ref name="SchmidBohn2010" /><ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" />

DMT is a [[natural product|naturally occurring]] [[endogenous]] compound in the body.<ref name="JiménezBouso2022">{{cite journal | vauthors = Jiménez JH, Bouso JC | title = Significance of mammalian N, N-dimethyltryptamine (DMT): A 60-year-old debate | journal = J Psychopharmacol | volume = 36 | issue = 8 | pages = 905–919 | date = August 2022 | pmid = 35695604 | doi = 10.1177/02698811221104054 | url = }}</ref><ref name="Barker2018">{{cite journal | vauthors = Barker SA | title = N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function | journal = Front Neurosci | volume = 12 | issue = | pages = 536 | date = 2018 | pmid = 30127713 | pmc = 6088236 | doi = 10.3389/fnins.2018.00536 | doi-access = free | url = }}</ref><ref name="CameronOlson2018">{{cite journal | vauthors = Cameron LP, Olson DE | title = Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT) | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2344–2357 | date = October 2018 | pmid = 30036036 | doi = 10.1021/acschemneuro.8b00101 | url = }}</ref> In relation to the fact that serotonin itself is unable to activate intracellular serotonin 5-HT_2A receptors, it is possible that DMT might be the endogenous [[ligand (biochemistry)|ligand]] of these receptors rather than serotonin.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" />

====Methyltryptamines and hallucinogens====

{{For|details on tryptamine neurotransmitters in humans|Trace amine}}

Several plants contain serotonin together with a family of related [[tryptamine]]s that are [[methylation|methylated]] at the [[amine|amino]] (NH₂) and [[hydroxyl|(OH) groups]], are [[amine oxide|''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 [[hallucinogen]]ic [[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]]''.<ref>{{cite journal | vauthors = Tyler VE | title = Occurrence of serotonin in a hallucinogenic mushroom | journal = Science | volume = 128 | issue = 3326 | pages = 718 | date = September 1958 | pmid = 13580242 | doi = 10.1126/science.128.3326.718 | bibcode = 1958Sci...128..718T }}</ref>

===Entactogens===

{{See also|Entactogen#Mechanism of action}}

The [[entactogen]] [[MDMA]] is a [[serotonin releasing agent]] and, while it also possesses other actions such as concomitant [[norepinephrine releasing agent|release of norepinephrine]] and [[dopamine releasing agent|dopamine]] and weak direct [[receptor agonist|agonism]] of the serotonin [[5-HT2 receptor|5-HT₂ receptor]]s, its serotonin release plays a key role in its unique entactogenic effects.<ref name="DunlapAndrewsOlson2018">{{cite journal | vauthors = Dunlap LE, Andrews AM, Olson DE | title = Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2408–2427 | date = October 2018 | pmid = 30001118 | pmc = 6197894 | doi = 10.1021/acschemneuro.8b00155 | url = }}</ref> Entactogens like MDMA should be distinguished from other drugs such as [[stimulant]]s like [[amphetamine]] and psychedelics like [[LSD]], although MDMA itself also has some characteristics of both of these types of agents.<ref name="DunlapAndrewsOlson2018" /><ref name="Nichols2022">{{cite journal | vauthors = Nichols DE | title = Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated | journal = Front Psychiatry | volume = 13 | issue = | pages = 863088 | date = 2022 | pmid = 35401275 | pmc = 8990025 | doi = 10.3389/fpsyt.2022.863088 | doi-access = free | url = }}</ref> Coadministration of [[selective serotonin reuptake inhibitor]]s (SSRIs), which block the [[serotonin transporter]] (SERT) and prevent MDMA from inducing serotonin release, markedly reduce the subjective effects of MDMA, demonstrating the key role of serotonin in the effects of the drug.<ref name="SarparastThomasMalcolm2022">{{cite journal | vauthors = Sarparast A, Thomas K, Malcolm B, Stauffer CS | title = Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review | journal = Psychopharmacology (Berl) | volume = 239 | issue = 6 | pages = 1945–1976 | date = June 2022 | pmid = 35253070 | pmc = 9177763 | doi = 10.1007/s00213-022-06083-y | url = }}</ref> Serotonin releasing agents like MDMA achieve much greater increases in serotonin levels than SSRIs and have far more robust of subjective effects.<ref name="RothmanBaumann2006">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Curr Top Med Chem | volume = 6 | issue = 17 | pages = 1845–1859 | date = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 | url = }}</ref><ref name="ScorzaSilveiraNichols1999">{{cite journal |vauthors=Scorza C, Silveira R, Nichols DE, Reyes-Parada M | title = Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action | journal = Neuropharmacology | volume = 38 | issue = 7 | pages = 1055–1061 |date=July 1999 | pmid = 10428424 | doi = 10.1016/S0028-3908(99)00023-4| s2cid = 13714807 }}</ref><ref name="Marona-LewickaNichols1997">{{cite journal | vauthors = Marona-Lewicka D, Nichols DE | title = The Effect of Selective Serotonin Releasing Agents in the Chronic Mild Stress Model of Depression in Rats | journal = Stress | volume = 2 | issue = 2 | pages = 91–100 | date = December 1997 | pmid = 9787258 | doi = 10.3109/10253899709014740 | url = }}</ref><ref name="Marona-LewickaNichols1998">{{cite journal | vauthors = Marona-Lewicka D, Nichols DE | title = Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents | journal = Psychopharmacology (Berl) | volume = 138 | issue = 1 | pages = 67–75 | date = July 1998 | pmid = 9694528 | doi = 10.1007/s002130050646 | url = }}</ref> Besides MDMA, many other entactogens also exist and are known.<ref name="SimmlerLiechti2018">{{cite journal | vauthors = Simmler LD, Liechti ME | title = Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 252 | issue = | pages = 143–164 | date = 2018 | pmid = 29633178 | doi = 10.1007/164_2018_113 | isbn = 978-3-030-10560-0 | url = }}</ref><ref name="Oeri2021">{{cite journal | vauthors = Oeri HE | title = Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy | journal = J Psychopharmacol | volume = 35 | issue = 5 | pages = 512–536 | date = May 2021 | pmid = 32909493 | pmc = 8155739 | doi = 10.1177/0269881120920420 | url = }}</ref><ref name="Nichols2022" />

===Serotonin syndrome===

{{Main|Serotonin syndrome}}

Extremely high levels of serotonin or activation of certain serotonin receptors 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 a [[MAOI]], which may occur in therapeutic doses.<ref name="New 285–293">{{cite journal | vauthors = New AM, Nelson S, Leung JG | title = Psychiatric Emergencies in the Intensive Care Unit | journal = AACN Advanced Critical Care | volume = 26 | issue = 4 | pages = 285–293; quiz 294–295 | date = 2015-10-01 | pmid = 26484986 | doi = 10.4037/NCI.0000000000000104 | veditors = Alexander E, Susla GM }}</ref><ref>{{cite journal | vauthors = Isbister GK, Bowe SJ, Dawson A, Whyte IM | title = Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose | journal = Journal of Toxicology. Clinical Toxicology | volume = 42 | issue = 3 | pages = 277–285 | year = 2004 | pmid = 15362595 | doi = 10.1081/CLT-120037428 | s2cid = 43121327 }}</ref> However, serotonin syndrome can occur with overdose of certain serotonin receptor agonists, like the [[25-NB|NBOMe]] series of serotonergic psychedelics.<ref name="ScottonHillWilliams2019">{{cite journal | vauthors = Scotton WJ, Hill LJ, Williams AC, Barnes NM | title = Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions | journal = Int J Tryptophan Res | volume = 12 | issue = | pages = 1178646919873925 | date = 2019 | pmid = 31523132 | pmc = 6734608 | doi = 10.1177/1178646919873925 | url = }}</ref><ref name="OrdakZmysłowskaBielski2021">{{cite journal | vauthors = Ordak M, Zmysłowska A, Bielski M, Rybak D, Tomaszewska M, Wyszomierska K, Kmiec A, Garlicka N, Zalewska M, Zalewski M, Nasierowski T, Muszynska E, Bujalska-Zadrozny M | title = Pharmacotherapy of Patients Taking New Psychoactive Substances: A Systematic Review and Analysis of Case Reports | journal = Front Psychiatry | volume = 12 | issue = | pages = 669921 | date = 2021 | pmid = 33967865 | pmc = 8102790 | doi = 10.3389/fpsyt.2021.669921 | doi-access = free | url = }}</ref><ref name="JacbosAkersVohra2020">{{cite journal | vauthors = Jacobs ET, Akers KG, Vohra V, King AM | title=Cyproheptadine for Serotonin Toxicity: an Updated Systematic Review and Grading of Evidence | journal=Current Emergency and Hospital Medicine Reports | publisher=Springer Science and Business Media LLC | volume=8 | issue=4 | date=10 October 2020 | issn=2167-4884 | doi=10.1007/s40138-020-00222-5 | pages=151–159}}</ref>

The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at nontoxic levels.<ref name="pmid12925718">{{cite journal | vauthors = Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM | title = The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity | journal = QJM | volume = 96 | issue = 9 | pages = 635–642 | date = September 2003 | pmid = 12925718 | doi = 10.1093/qjmed/hcg109 | doi-access = free }}</ref> It is estimated that 14% of patients experiencing serotonin syndrome overdose on SSRIs; meanwhile the fatality rate is between 2% and 12%.<ref name="New 285–293"/><ref name="pmid18625822">{{cite journal | vauthors = Frank C | title = Recognition and treatment of serotonin syndrome | journal = Canadian Family Physician | volume = 54 | issue = 7 | pages = 988–992 | date = July 2008 | pmid = 18625822 | pmc = 2464814 | doi = }}</ref><ref name="pmid15784664">{{cite journal | vauthors = Boyer EW, Shannon M | title = The serotonin syndrome | journal = The New England Journal of Medicine | volume = 352 | issue = 11 | pages = 1112–1120 | date = March 2005 | pmid = 15784664 | doi = 10.1056/NEJMra041867 }}</ref>

===Cardiac fibrosis and other fibroses===

Some serotonergic agonist drugs cause fibrosis anywhere in the body, particularly the syndrome of [[retroperitoneal fibrosis]], as well as [[cardiac fibrosis|cardiac valve fibrosis]].<ref name="Baskin">{{cite book | vauthors = Baskin SI|title = Principles of cardiac toxicology|publisher = CRC Press|location = Boca Raton|year = 1991|isbn = 978-0-8493-8809-5|url = https://books.google.com/books?id=AW7M6jBixj4C&pg=PA626|access-date = 3 February 2010}}</ref>

In the past, three groups of serotonergic drugs have been epidemiologically linked with these syndromes. These are the serotonergic vasoconstrictive antimigraine drugs ([[ergotamine]] and [[methysergide]]),<ref name=Baskin/> 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]].<ref name="urluserpage.fu-berlin.de">{{cite web|url = http://userpage.fu-berlin.de/~hpertz/Presentation001.pdf|title = Pergolide and Cabergoline But not Lisuride Exhibit Agonist Efficacy at Serotonin 5-HT_2B Receptors| vauthors = Jähnichen S, Horowski R, Pertz H |access-date = 3 February 2010}}</ref>

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 2003 to be associated with cardiac fibrosis.<ref name="ADRAC_2004">{{cite journal |year=2004 |title=Cardiac valvulopathy with pergolide |journal=Aust Adv Drug React Bull |volume=23 |issue=4 | author = Adverse Drug Reactions Advisory Committee, Australia |url=http://www.tga.gov.au/adr/aadrb/aadr0408.htm | url-status = dead | archive-url = https://web.archive.org/web/20120627200919/http://www.tga.gov.au/adr/aadrb/aadr0408.htm |archive-date=27 June 2012 }}</ref>

Two independent studies published in ''[[The New England Journal of Medicine]]'' in January 2007 implicated pergolide, along with [[cabergoline]], in causing [[valvular heart disease]].<ref name="pmid17202453">{{cite journal | vauthors = Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E | title = Dopamine agonists and the risk of cardiac-valve regurgitation | journal = The New England Journal of Medicine | volume = 356 | issue = 1 | pages = 29–38 | date = January 2007 | pmid = 17202453 | doi = 10.1056/NEJMoa062222 | doi-access = free }}</ref><ref name="pmid17202454">{{cite journal | vauthors = Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G | title = Valvular heart disease and the use of dopamine agonists for Parkinson's disease | journal = The New England Journal of Medicine | volume = 356 | issue = 1 | pages = 39–46 | date = January 2007 | pmid = 17202454 | doi = 10.1056/NEJMoa054830 | doi-access = free }}</ref> As a result of this, the [[Food and Drug Administration|FDA]] removed pergolide from the United States market in March 2007.<ref>{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152695.htm |title=Food and Drug Administration Public Health Advisory |website=[[Food and Drug Administration]] |date=29 March 2007 |access-date=7 February 2010}}</ref> (Since cabergoline is not approved in the United States for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).<ref name="FDAwithdraw">{{cite web|url = https://www.fda.gov/medwatch/safety/2007/safety07.htm#Pergolide|title = MedWatch – 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents|publisher = United States [[Food and Drug Administration]]|date = 29 March 2007|access-date = 30 March 2007}}</ref>

==Comparative biology and evolution==

===Unicellular organisms===

Serotonin is used by a variety of single-cell organisms for various purposes. [[SSRIs]] have been found to be toxic to algae.<ref name="pmid16753215">{{cite journal | vauthors = Johnson DJ, Sanderson H, Brain RA, Wilson CJ, Solomon KR | title = Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae | journal = Ecotoxicology and Environmental Safety | volume = 67 | issue = 1 | pages = 128–139 | date = May 2007 | pmid = 16753215 | doi = 10.1016/j.ecoenv.2006.03.016 | bibcode = 2007EcoES..67..128J }}</ref> The gastrointestinal parasite ''[[Entamoeba histolytica]]'' secretes serotonin, causing a sustained secretory diarrhea in some people.<ref name="pmid6308760">{{cite journal | vauthors = McGowan K, Kane A, Asarkof N, Wicks J, Guerina V, Kellum J, Baron S, Gintzler AR, Donowitz M | title = Entamoeba histolytica causes intestinal secretion: role of serotonin | journal = Science | volume = 221 | issue = 4612 | pages = 762–764 | date = August 1983 | pmid = 6308760 | doi = 10.1126/science.6308760 | bibcode = 1983Sci...221..762M }}</ref><ref name="pmid2861068">{{cite book | vauthors = McGowan K, Guerina V, Wicks J, Donowitz M | chapter = Secretory Hormones of ''Entamoeba histolytica'' | title = Ciba Foundation Symposium | volume = 112 | pages = 139–154 | year = 1985 | pmid = 2861068 | doi = 10.1002/9780470720936.ch8 | series = Novartis Foundation Symposia | isbn = 978-0-470-72093-6 }}</ref> Patients infected with ''E. histolytica'' have been found to have highly elevated serum serotonin levels, which returned to normal following resolution of the infection.<ref name = "Banu_2005">{{cite journal | vauthors = Banu N, Zaidi KR, Mehdi G, Mansoor T | title = Neurohumoral alterations and their role in amoebiasis | journal = Indian Journal of Clinical Biochemistry | volume = 20 | issue = 2 | pages = 142–145 | date = July 2005 | pmid = 23105547 | pmc = 3453840 | doi = 10.1007/BF02867414 }}</ref> ''E. histolytica'' also responds to the presence of serotonin by becoming more virulent.<ref name="pmid2561282">{{cite journal | vauthors = Acharya DP, Sen MR, Sen PC | title = Effect of exogenous 5-hydroxytryptamine on pathogenicity of Entamoeba histolytica in experimental animals | journal = Indian Journal of Experimental Biology | volume = 27 | issue = 8 | pages = 718–720 | date = August 1989 | pmid = 2561282 }}</ref> This means serotonin secretion not only serves to increase the spread of [[entamoeba]]s by giving the host diarrhea but also serves to coordinate their behaviour according to their population density, a phenomenon known as [[quorum sensing]]. Outside the gut of a host, there is nothing that the entamoebas provoke to release serotonin, hence the serotonin concentration is very low. Low serotonin signals to the entamoebas 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.

{{anchor|Plants|Mushrooms}}

===Edible plants and mushrooms===

In drying [[seed]]s, 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 <small>L</small>-[[tryptophan]], which is then [[decarboxylation|decarboxylated]] by [[Aromatic L-amino acid decarboxylase|tryptophan decarboxylase]] to give tryptamine, which is then [[hydroxylation|hydroxylated]] by a [[cytochrome P450 monooxygenase]], yielding serotonin.<ref name="Schröder et al.">{{cite book | vauthors = Schröder P, Abele C, Gohr P, Stuhlfauth-Roisch U, Grosse W | chapter = Latest on Enzymology of Serotonin Biosynthesis in Walnut Seeds | volume = 467 | pages = 637–644 | year = 1999 | pmid = 10721112 | doi = 10.1007/978-1-4615-4709-9_81 | isbn = 978-0-306-46204-7 | series = Advances in Experimental Medicine and Biology | title = Tryptophan, Serotonin, and Melatonin }}</ref>

However, since serotonin is a major gastrointestinal tract modulator, it may be produced in the fruits of plants 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 [[Edible mushroom|mushrooms]], [[fruit]]s, and [[vegetable]]s. The highest values of 25–400&nbsp;mg/kg have been found in nuts of the [[walnut]] (''Juglans'') and [[hickory]] (''Carya'') genera. Serotonin concentrations of 3–30&nbsp;mg/kg have been found in [[Plantain (cooking)|plantains]], [[pineapple]]s, [[banana]], [[kiwifruit]], [[plum]]s, and [[tomato]]es. Moderate levels from 0.1–3&nbsp;mg/kg have been found in a wide range of tested vegetables.<ref name=feld>{{cite journal | vauthors = Feldman JM, Lee EM | title = Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid | journal = The American Journal of Clinical Nutrition | volume = 42 | issue = 4 | pages = 639–643 | date = October 1985 | pmid = 2413754 | doi = 10.1093/ajcn/42.4.639 | doi-access = free }}</ref><ref name="Ramakrishna_2011" />

Serotonin is one compound of the poison contained in [[stinging nettle]]s (''Urtica dioica''), where it causes pain on injection in the same manner as its presence in insect venoms.<ref name="Erspamer-1966" /> It is also naturally found in ''[[Paramuricea clavata]]'', or the Red Sea Fan.<ref>{{cite journal | vauthors = Pénez N, Culioli G, Pérez T, Briand JF, Thomas OP, Blache Y | title = Antifouling properties of simple indole and purine alkaloids from the Mediterranean gorgonian Paramuricea clavata | journal = Journal of Natural Products | volume = 74 | issue = 10 | pages = 2304–2308 | date = October 2011 | pmid = 21939218 | doi = 10.1021/np200537v }}</ref>

Serotonin and tryptophan have been found in chocolate with varying cocoa contents. The highest serotonin content (2.93&nbsp;μg/g) was found in chocolate with 85% cocoa, and the highest tryptophan content (13.27–13.34&nbsp;μg/g) was found in 70–85% cocoa. The intermediate in the synthesis from tryptophan to serotonin, 5-hydroxytryptophan, was not found.<ref>{{cite journal | vauthors = Guillén-Casla V, Rosales-Conrado N, León-González ME, Pérez-Arribas LV, Polo-Díez LM | title = Determination of serotonin and its precursors in chocolate samples by capillary liquid chromatography with mass spectrometry detection | journal = Journal of Chromatography A | volume = 1232 | pages = 158–165 | date = April 2012 | pmid = 22186492 | doi = 10.1016/j.chroma.2011.11.037 }}</ref>

Root development in ''[[Arabidopsis thaliana]]'' is stimulated and modulated by serotonin – in various ways at various concentrations.<ref name="Pelagio-Flores-et-al-2011">{{cite journal | vauthors = Pelagio-Flores R, Ortíz-Castro R, Méndez-Bravo A, Macías-Rodríguez L, López-Bucio J | title = Serotonin, a tryptophan-derived signal conserved in plants and animals, regulates root system architecture probably acting as a natural auxin inhibitor in Arabidopsis thaliana | journal = Plant & Cell Physiology | volume = 52 | issue = 3 | pages = 490–508 | date = March 2011 | pmid = 21252298 | doi = 10.1093/pcp/pcr006 | publisher = [[Oxford University Press]] (OUP) | doi-access = free }}</ref>

Serotonin serves as a plant defense chemical against fungi. When infected with [[Fusarium crown rot of wheat|Fusarium crown rot]] (''Fusarium pseudograminearum''), [[wheat]] (''Triticum aestivum'') greatly increases its production of tryptophan to synthesize new serotonin.<ref name="Powell-et-al-2016">{{cite journal | vauthors = Powell JJ, Carere J, Fitzgerald TL, Stiller J, Covarelli L, Xu Q, Gubler F, Colgrave ML, Gardiner DM, Manners JM, Henry RJ, Kazan K | title = The Fusarium crown rot pathogen Fusarium pseudograminearum triggers a suite of transcriptional and metabolic changes in bread wheat (Triticum aestivum L.) | journal = Annals of Botany | volume = 119 | issue = 5 | pages = 853–867 | date = March 2017 | pmid = 27941094 | pmc = 5604588 | doi = 10.1093/aob/mcw207 | publisher = [[Oxford University Press]] (OUP) | s2cid = 3823345 | doi-access = free }}</ref> The function of this is poorly understood<ref name="Powell-et-al-2016" /> but wheat also produces serotonin when infected by ''[[Stagonospora nodorum]]'' – in that case to retard spore production.<ref name="Du-Fall-Solomon-2013">{{cite journal | vauthors = Du Fall LA, Solomon PS | title = The necrotrophic effector SnToxA induces the synthesis of a novel phytoalexin in wheat | journal = The New Phytologist | volume = 200 | issue = 1 | pages = 185–200 | date = October 2013 | pmid = 23782173 | doi = 10.1111/nph.12356 | publisher = [[Wiley-Blackwell|Wiley]] | doi-access = free | bibcode = 2013NewPh.200..185D }}</ref> The model [[cereal]] ''[[Brachypodium distachyon]]'' – used as a research substitute for wheat and other production cereals – also produces serotonin, [[coumaroyl]]-serotonin, and [[feruloyl]]-serotonin in response to ''[[Fusarium graminearum|F. graminearum]]''. This produces a slight [[antimicrobial]] effect. ''B.&nbsp;distachyon'' produces more serotonin (and conjugates) in response to [[deoxynivalenol]] (DON)-producing ''F. graminearum'' than non-DON-producing.<ref name="Pasquet-et-al-2014">{{cite journal | vauthors = Pasquet JC, Chaouch S, Macadré C, Balzergue S, Huguet S, Martin-Magniette ML, Bellvert F, Deguercy X, Thareau V, Heintz D, Saindrenan P, Dufresne M | title = Differential gene expression and metabolomic analyses of Brachypodium distachyon infected by deoxynivalenol producing and non-producing strains of Fusarium graminearum | journal = BMC Genomics | volume = 15 | issue = 1 | pages = 629 | date = July 2014 | pmid = 25063396 | pmc = 4124148 | doi = 10.1186/1471-2164-15-629 | publisher = [[BioMed Central]] | doi-access = free }}</ref> ''[[Solanum lycopersicum]]'' produces many [[amino acid|AA]] conjugates – including several of serotonin – in its leaves, stems, and roots in response to ''[[Ralstonia solanacearum]]'' infection.<ref name="Zeiss-et-al-2021">{{cite journal | vauthors = Zeiss DR, Piater LA, Dubery IA | title = Hydroxycinnamate Amides: Intriguing Conjugates of Plant Protective Metabolites | journal = Trends in Plant Science | volume = 26 | issue = 2 | pages = 184–195 | date = February 2021 | pmid = 33036915 | doi = 10.1016/j.tplants.2020.09.011 | publisher = [[Cell Press]] | bibcode = 2021TPS....26..184Z | s2cid = 222256660 }}</ref>

===Invertebrates===

Serotonin functions as a neurotransmitter in the nervous systems of most animals.

====Nematodes====

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.<ref>{{cite journal | vauthors = Jonz MG, EkateriniMercier A, JoffrePotter JW | year = 2001 | title = Effects Of 5-HT (Serotonin) On Reproductive Behaviour In Heterodera Schachtii (Nematoda) | journal = Canadian Journal of Zoology | volume = 79 | issue = 9| page = 1727 | doi = 10.1139/z01-135 | bibcode = 2001CaJZ...79.1727J }}</ref> 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.<ref name="pmid10896158">{{cite journal | vauthors = Sawin ER, Ranganathan R, Horvitz HR | title = C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway | journal = Neuron | volume = 26 | issue = 3 | pages = 619–631 | date = June 2000 | pmid = 10896158 | doi = 10.1016/S0896-6273(00)81199-X | s2cid = 9247380 | doi-access = free }}</ref> The released serotonin activates the muscles used for feeding, while [[octopamine]] suppresses them.<ref name="pmid12477893">{{cite journal | vauthors = Niacaris T, Avery L | title = Serotonin regulates repolarization of the C. elegans pharyngeal muscle | journal = The Journal of Experimental Biology | volume = 206 | issue = Pt 2 | pages = 223–231 | date = January 2003 | pmid = 12477893 | pmc = 4441752 | doi = 10.1242/jeb.00101 }}</ref><ref name="Rosso-et-al-2009">{{cite journal | vauthors = Rosso MN, Jones JT, Abad P | title = RNAi and functional genomics in plant parasitic nematodes | journal = Annual Review of Phytopathology | volume = 47 | issue = 1 | pages = 207–232 | year = 2009 | pmid = 19400649 | doi = 10.1146/annurev.phyto.112408.132605 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] | quote-page = 218 | quote = Octopamine and serotonin regulates the activity of the M3 neurons that direct contraction of the pharynx during ''C. elegans'' feeding... Soaking ''Meloidogyne'' J2 in dsRNA in the presence of ... resorcinol plus serotonin resulted in uptake of solutions and silencing of genes expressed in the intestine and esophageal glands. }}</ref> Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability.

====Decapods====

If [[lobster]]s are injected with serotonin, they behave like dominant individuals whereas octopamine causes [[Dominance hierarchy|subordinate behavior]].<ref name="pmid2902685">{{cite journal | vauthors = Kravitz EA | title = Hormonal control of behavior: amines and the biasing of behavioral output in lobsters | journal = Science | volume = 241 | issue = 4874 | pages = 1775–1781 | date = September 1988 | pmid = 2902685 | doi = 10.1126/science.2902685 | bibcode = 1988Sci...241.1775K }}</ref> A [[crayfish]] that is frightened may [[Caridoid escape reaction|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 reason for this is social experience alters the proportion between [[serotonin receptor]]s (5-HT receptors) that have opposing effects on the [[fight-or-flight response]].{{Clarify|date=January 2012}} The effect of [[5-HT1 receptor|5-HT₁ receptors]] predominates in subordinate animals, while [[5-HT2 receptor|5-HT₂ receptors]] predominates in dominants.<ref name="pmid8553075">{{cite journal | vauthors = Yeh SR, Fricke RA, Edwards DH | title = The effect of social experience on serotonergic modulation of the escape circuit of crayfish | journal = Science | volume = 271 | issue = 5247 | pages = 366–369 | date = January 1996 | pmid = 8553075 | doi = 10.1126/science.271.5247.366 | s2cid = 1575533 | citeseerx = 10.1.1.470.6528 | bibcode = 1996Sci...271..366Y }}</ref>

{{anchor|Invertebrate venom|Invertebrate venoms|In venom}}

====In venoms====

Serotonin is a common component of invertebrate venoms, salivary glands, nervous tissues, and various other tissues, across molluscs, insects, crustaceans, scorpions, various kinds of worms, and jellyfish.<ref name="Erspamer-1966" /> Adult ''[[Rhodnius prolixus]]'' – [[hematophagous]] on vertebrates – secrete [[lipocalin]]s into the wound during feeding. In 2003 these lipocalins were demonstrated to sequester serotonin to prevent vasoconstriction (and possibly coagulation) in the host.<ref name="Fry-et-al-2009">{{cite journal | vauthors = Fry BG, Roelants K, Champagne DE, Scheib H, Tyndall JD, King GF, Nevalainen TJ, Norman JA, Lewis RJ, Norton RS, Renjifo C, de la Vega RC | title = The toxicogenomic multiverse: convergent recruitment of proteins into animal venoms | journal = Annual Review of Genomics and Human Genetics | volume = 10 | issue = 1 | pages = 483–511 | year = 2009 | pmid = 19640225 | doi = 10.1146/annurev.genom.9.081307.164356 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] | doi-access = free }}</ref>

====Insects====

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.<ref>{{cite journal |doi=10.14800/nt.314 |title=Serotonin, serotonin receptors and their actions in insects |journal=Neurotransmitter |year=2015 |volume=2 |pages=1–14 |doi-access=free }}</ref><ref name="Huser_2012" /> Some circuits in [[mushroom bodies]] are serotonergic.<ref name="Schoofs-et-al-2017">{{cite journal | vauthors = Schoofs L, De Loof A, Van Hiel MB | title = Neuropeptides as Regulators of Behavior in Insects | journal = Annual Review of Entomology | volume = 62 | issue = 1 | pages = 35–52 | date = January 2017 | pmid = 27813667 | doi = 10.1146/annurev-ento-031616-035500 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] | doi-access = free }}</ref> (See specific ''Drosophila'' example below, [[#Dipterans|§Dipterans]].)

=====Acrididae=====

Locust swarming is initiated ''but not maintained'' by serotonin,<ref name="Wang-Kang-2014">{{cite journal | vauthors = Wang X, Kang L | title = Molecular mechanisms of phase change in locusts | journal = Annual Review of Entomology | volume = 59 | issue = 1 | pages = 225–244 | date = 2014-01-07 | pmid = 24160426 | doi = 10.1146/annurev-ento-011613-162019 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] | quote = <br />p.{{spaces}}231,<br />The change in the number of several potential neurotransmitters ... such as serotonin... may play an important role in remodeling the CNS during phase change (26, 56, 80).<br />p.{{spaces}}233,<br />In the locust ''S. gregaria'', the amount of serotonin in the thoracic ganglia was positively correlated with the extent of gregarious behavior induced by different periods of crowding. A series of pharmacological and behavioral experiments demonstrated that serotonin plays a key role in inducing initial behavioral gregarization (2, 80). However, serotonin is not responsible for maintaining gregarious behavior because its amount in long-term gregarious locusts is less than half that in long-term solitarious locusts (80). In ''L. migratoria'', the injection of serotonin can also slightly initiate gregarious behavior, but serotonin when accompanying crowding treatment induced more solitarious-like behavior than did serotonin injection alone (48). Significant differences in serotonin levels were not found in brain tissues between the two phases of ''L. migratoria''. A recent report by Tanaka & Nishide (97) measured attraction/avoidance behavior in ''S. gregaria'' after single and multiple injections of serotonin at different concentrations. Serotonin had only a short-term effect on the level of some locomotor activities and was not involved in the control of gregarious behavior (97). In addition, it is not clear how the neurotransmitter influences this unique behavior, because a binary logistic regression model used in these studies for the behavioral assay focused mostly on only one behavioral parameter representing an overall phase state. Obviously, behavioral phase change might involve alternative regulatory mechanisms in different locust species. Therefore, these studies demonstrate that CNS regulatory mechanisms governing initiation and maintenance of phase change are species specific and involve the interactions between these neurotransmitters.<br />Given the key roles of aminergic signaling, what are the downstream pathways involved in the establishment of long-term memory? Ott et al. (63) investigated the role of [] protein kinase[] in the phase change in ''S. gregaria'': ... cAMP-dependent protein kinase A (PKA). Through use of pharmacological and RNAi intervention, these authors have demonstrated that PKA... has a critical role in modulating the propensity of locusts to acquire and express gregarious behavior. ... Unfortunately, although a correlation between serotonin and PKA was hypothesized, direct evidence was not provided. | doi-access = free }}</ref> with release being triggered by tactile contact between individuals.<ref name="Zhang-et-al-2019">{{cite journal | vauthors = Zhang L, Lecoq M, Latchininsky A, Hunter D | title = Locust and Grasshopper Management | journal = Annual Review of Entomology | volume = 64 | issue = 1 | pages = 15–34 | date = January 2019 | pmid = 30256665 | doi = 10.1146/annurev-ento-011118-112500 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] | quote-page = 20 | s2cid = 52843907 | doi-access = free | quote = ...gregarization is evoked by... tactile stimulation... Tactile stimuli trigger the increase of biogenic amines, particularly serotonin, in the locust nervous system (1, 116); these amines play critical roles in the neurophysiology of locust behavioral phase change. }}</ref> This transforms social preference from aversion to a gregarious state that enables coherent groups.<ref name="Anstey">{{cite journal | vauthors = Anstey ML, Rogers SM, Ott SR, Burrows M, Simpson SJ | title = Serotonin mediates behavioral gregarization underlying swarm formation in desert locusts | journal = Science | volume = 323 | issue = 5914 | pages = 627–630 | date = January 2009 | pmid = 19179529 | doi = 10.1126/science.1165939 | s2cid = 5448884 | bibcode = 2009Sci...323..627A }}

* {{cite news | vauthors = Morgan J |date=29 January 2009 |title=Locust swarms 'high' on serotonin |work=BBC News |url=http://news.bbc.co.uk/2/hi/science/nature/7858996.stm}}</ref><ref name="Zhang-et-al-2019" /><ref name="Wang-Kang-2014" /> Learning in flies and honeybees is affected by the presence of serotonin.<ref>{{cite journal | vauthors = Sitaraman D, LaFerriere H, Birman S, Zars T | title = Serotonin is critical for rewarded olfactory short-term memory in Drosophila | journal = Journal of Neurogenetics | volume = 26 | issue = 2 | pages = 238–244 | date = June 2012 | pmid = 22436011 | doi = 10.3109/01677063.2012.666298 | s2cid = 23639918 }}</ref><ref>{{cite journal | vauthors = Bicker G, Menzel R | title = Chemical codes for the control of behaviour in arthropods | journal = Nature | volume = 337 | issue = 6202 | pages = 33–39 | date = January 1989 | pmid = 2562906 | doi = 10.1038/337033a0 | s2cid = 223750 | bibcode = 1989Natur.337...33B }}</ref>

{{anchor|Insecticide|Insecticides}}

=====Role in insecticides=====

Insect 5-HT receptors have similar sequences to the vertebrate versions, but pharmacological differences have been seen. Invertebrate drug response has been far less characterized than mammalian pharmacology and the potential for species selective insecticides has been discussed.<ref>{{cite journal | vauthors = Cai M, Li Z, Fan F, Huang Q, Shao X, Song G | title = Design and synthesis of novel insecticides based on the serotonergic ligand 1-[(4-aminophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperazine (PAPP) | journal = Journal of Agricultural and Food Chemistry | volume = 58 | issue = 5 | pages = 2624–2629 | date = March 2010 | pmid = 20000410 | doi = 10.1021/jf902640u | bibcode = 2010JAFC...58.2624C }}</ref>

{{anchor|Hymenoptera}}

=====Hymenopterans=====

[[Wasp]]s and [[hornets]] have serotonin in their venom,<ref>{{cite book | vauthors = Manahan SE |title=Toxicological Chemistry and Biochemistry |edition=3rd |publisher=CRC Press |year=2002 |isbn=978-1-4200-3212-3 |page=393 }}</ref> which causes pain and inflammation<ref name="Chen_2010" >{{cite journal | vauthors = Chen J, Lariviere WR | title = The nociceptive and anti-nociceptive effects of bee venom injection and therapy: a double-edged sword | journal = Progress in Neurobiology | volume = 92 | issue = 2 | pages = 151–183 | date = October 2010 | pmid = 20558236 | pmc = 2946189 | doi = 10.1016/j.pneurobio.2010.06.006 }}</ref><ref name="Erspamer-1966" /> as do [[scorpion]]s.<ref>{{cite book | vauthors = Postma TL |chapter=Neurotoxic Animal Poisons and Venoms |chapter-url=http://www.sciencedirect.com/science/article/pii/B9780323052603500496 |pages=463–489 | veditors = Dobbs MR |year=2009 |title=Clinical Neurotoxicology |publisher=W.B. Saunders |doi=10.1016/B978-032305260-3.50049-6 |isbn=978-0-323-05260-3 }}</ref><ref name="Erspamer-1966" /> ''[[Pheidole dentata]]'' takes on more and more tasks in [[ant colony|the colony]] as it gets older, which requires it to respond to more and more [[olfaction|olfactory]] cues in the course of performing them. This olfactory response broadening was demonstrated to go along with increased serotonin and [[dopamine]], but not [[octopamine]] in 2006.<ref name="Gadenne-et-al-2016">{{cite journal | vauthors = Gadenne C, Barrozo RB, Anton S | title = Plasticity in Insect Olfaction: To Smell or Not to Smell? | journal = Annual Review of Entomology | volume = 61 | issue = 1 | pages = 317–333 | date = 2016-03-11 | pmid = 26982441 | doi = 10.1146/annurev-ento-010715-023523 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] | hdl-access = free | s2cid = 207568844 | hdl = 11336/19586 }}</ref>

=====Dipterans=====

If flies are fed serotonin, they are more aggressive; flies depleted of serotonin still exhibit aggression, but they do so much less frequently.<ref name="Dierick">{{cite journal | vauthors = Dierick HA, Greenspan RJ | title = Serotonin and neuropeptide F have opposite modulatory effects on fly aggression | journal = Nature Genetics | volume = 39 | issue = 5 | pages = 678–682 | date = May 2007 | pmid = 17450142 | doi = 10.1038/ng2029 | s2cid = 33768246 }}</ref> In [[Dipteran crop|their crops]] it plays a vital role in digestive motility produced by contraction. Serotonin that acts on the crop is exogenous to the crop itself and 2012 research suggested that it probably originated in the serotonin neural plexus in the thoracic-abdominal synganglion.<ref name="Stoffolano-Haselton-2013">{{cite journal | vauthors = Stoffolano JG, Haselton AT | title = The adult Dipteran crop: a unique and overlooked organ | journal = Annual Review of Entomology | volume = 58 | issue = 1 | pages = 205–225 | date = 2013-01-07 | pmid = 23317042 | doi = 10.1146/annurev-ento-120811-153653 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] | author-link = John Stoffolano }}</ref> In 2011 a ''[[Drosophila]]'' serotonergic mushroom body was found to work in concert with ''[[Amnesiac gene|Amnesiac]]'' to form memories.<ref name="Schoofs-et-al-2017" /> In 2007 serotonin was found to promote aggression in ''[[Diptera]]'', which was counteracted by [[neuropeptide F]] – a surprising find given that they both promote [[insect courtship|courtship]], which is usually similar to aggression in most respects.<ref name="Schoofs-et-al-2017" />

=== Vertebrates ===

Serotonin, also referred to as 5-hydroxytryptamine (5-HT), is a neurotransmitter most known for its involvement in mood disorders in humans. It is also a widely present neuromodulator among vertebrates and invertebrates.<ref name="Bacqué-Cazenave_2020">{{cite journal | vauthors = Bacqué-Cazenave J, Bharatiya R, Barrière G, Delbecque JP, Bouguiyoud N, Di Giovanni G, Cattaert D, De Deurwaerdère P | title = Serotonin in Animal Cognition and Behavior | journal = International Journal of Molecular Sciences | volume = 21 | issue = 5 | pages = 1649 | date = February 2020 | pmid = 32121267 | pmc = 7084567 | doi = 10.3390/ijms21051649 | doi-access = free }}</ref> Serotonin has been found having associations with many physiological systems such as cardiovascular, [[thermoregulation]], and behavioral functions, including: [[circadian rhythm]], appetite, aggressive and sexual behavior, sensorimotor reactivity and learning, and pain sensitivity.<ref name="Lucki_1998">{{cite journal | vauthors = Lucki I | title = The spectrum of behaviors influenced by serotonin | journal = Biological Psychiatry | volume = 44 | issue = 3 | pages = 151–162 | date = August 1998 | pmid = 9693387 | doi = 10.1016/s0006-3223(98)00139-5 | s2cid = 3001666 | doi-access = free }}</ref> Serotonin's function in neurological systems along with specific behaviors among vertebrates found to be strongly associated with serotonin will be further discussed. Two relevant case studies are also mentioned regarding serotonin development involving [[Teleost|teleost fish]] and [[Mouse|mice]].

In mammals, 5-HT is highly concentrated in the [[substantia nigra]], [[ventral tegmental area]] and [[raphe nuclei]]. Lesser concentrated areas include other brain regions and the spinal cord.<ref name="Bacqué-Cazenave_2020" /> 5-HT neurons are also shown to be highly branched, indicating that they are structurally prominent for influencing multiple areas of the [[Central nervous system|CNS]] at the same time, although this trend is exclusive solely to mammals.<ref name="Lucki_1998" />

====5-HT system in vertebrates====

[[Vertebrate]]s are multicellular organisms in the [[Chordate|phylum Chordata]] that possess a backbone and a [[nervous system]]. This includes mammals, fish, reptiles, birds, etc. In humans, the nervous system is composed of the [[Central nervous system|central]] and [[peripheral nervous system]], with little known about the specific mechanisms of neurotransmitters in most other vertebrates. However, it is known that while serotonin is involved in stress and behavioral responses, it is also important in [[cognitive functions]].<ref name="Bacqué-Cazenave_2020" /> Brain organization in most vertebrates includes 5-HT cells in the [[hindbrain]].<ref name="Bacqué-Cazenave_2020" /> In addition to this, 5-HT is often found in other sections of the brain in non-placental vertebrates, including the [[basal forebrain]] and [[Pretectal area|pretectum]].<ref name="Backström_2017">{{cite journal | vauthors = Backström T, Winberg S | title = Serotonin Coordinates Responses to Social Stress-What We Can Learn from Fish | journal = Frontiers in Neuroscience | volume = 11 | pages = 595 | date = 2017-10-25 | pmid = 29163002 | pmc = 5669303 | doi = 10.3389/fnins.2017.00595 | doi-access = free }}</ref> Since location of serotonin receptors contribute to behavioral responses, this suggests serotonin is part of specific pathways in non-placental vertebrates that are not present in amniotic organisms.<ref>{{cite journal | vauthors = Berger M, Gray JA, Roth BL | title = The expanded biology of serotonin | journal = Annual Review of Medicine | volume = 60 | issue = 1 | pages = 355–366 | date = 2009-02-01 | pmid = 19630576 | pmc = 5864293 | doi = 10.1146/annurev.med.60.042307.110802 }}</ref> Teleost fish and mice are organisms most often used to study the connection between serotonin and vertebrate behavior. Both organisms show similarities in the effect of serotonin on behavior, but differ in the mechanism in which the responses occur.

=====Dogs / canine species=====

There are few studies of serotonin in dogs. One study reported serotonin values were higher at dawn than at dusk.<ref>{{cite journal | vauthors = Alberghina D, Piccione G, Pumilia G, Gioè M, Rizzo M, Raffo P, Panzera M | title = Daily fluctuation of urine serotonin and cortisol in healthy shelter dogs and influence of intraspecific social exposure | journal = Physiology & Behavior | volume = 206 | pages = 1–6 | date = July 2019 | pmid = 30898540 | doi = 10.1016/j.physbeh.2019.03.016 | s2cid = 81965422 }}</ref> In another study, serum 5-HT levels did not seem to be associated with dogs' behavioural response to a stressful situation.<ref>{{cite journal | vauthors = Riggio G, Mariti C, Sergi V, Diverio S, Gazzano A | title = Serotonin and Tryptophan Serum Concentrations in Shelter Dogs Showing Different Behavioural Responses to a Potentially Stressful Procedure | journal = Veterinary Sciences | volume = 8 | issue = 1 | pages = 1 | date = December 2020 | pmid = 33374183 | pmc = 7824451 | doi = 10.3390/vetsci8010001 | doi-access = free }}</ref> Urinary serotonin/creatinine ratio in bitches tended to be higher 4 weeks after surgery. In addition, serotonin was positively correlated with both cortisol and progesterone but not with testosterone after ovariohysterectomy.<ref>{{cite journal | vauthors = Hydbring-Sandberg E, Larsson E, Madej A, Höglund OV | title = Short-term effect of ovariohysterectomy on urine serotonin, cortisol, testosterone and progesterone in bitches | journal = BMC Research Notes | volume = 14 | issue = 1 | pages = 265 | date = July 2021 | pmid = 34246304 | pmc = 8272283 | doi = 10.1186/s13104-021-05680-y | doi-access = free }}</ref>

=====Teleost fish=====

Like non-placental vertebrates, teleost fish also possess 5-HT cells in other sections of the brain, including the [[basal forebrain]].<ref name="Backström_2017" /> ''[[Zebrafish|Danio rerio]]'' (zebra fish) are a species of teleost fish often used for studying serotonin within the brain. Despite much being unknown about serotonergic systems in vertebrates, the importance in moderating stress and social interaction is known.<ref name="Winberg_2016">{{cite journal | vauthors = Winberg S, Thörnqvist PO | title = Role of brain serotonin in modulating fish behavior | journal = Current Zoology | volume = 62 | issue = 3 | pages = 317–323 | date = June 2016 | pmid = 29491919 | pmc = 5804243 | doi = 10.1093/cz/zow037 }}</ref> It is hypothesized that AVT and CRF cooperate with serotonin in the [https://link.springer.com/referenceworkentry/10.1007%2F978-1-4419-1005-9_460 hypothalamic-pituitary-interrenal axis].<ref name="Backström_2017" /> These [[neuropeptide]]s influence the [[Neuroplasticity|plasticity]] of the teleost, affecting its ability to change and respond to its environment. Subordinate fish in social settings show a drastic increase in 5-HT concentrations.<ref name="Winberg_2016" /> High levels of 5-HT long term influence the inhibition of aggression in subordinate fish.<ref name="Winberg_2016" />

=====Mice=====

Researchers at the Department of Pharmacology and Medical Chemistry used serotonergic drugs on male mice to study the effects of selected drugs on their behavior.<ref name="Olivier_1989">{{cite journal | vauthors = Olivier B, Mos J, van der Heyden J, Hartog J | title = Serotonergic modulation of social interactions in isolated male mice | journal = Psychopharmacology | volume = 97 | issue = 2 | pages = 154–156 | date = 1989-02-01 | pmid = 2498921 | doi = 10.1007/BF00442239 | s2cid = 37170174 }}</ref> Mice in isolation exhibit increased levels of [[Agonistic behaviour|agonistic behavior]] towards one another. Results found that serotonergic drugs reduce aggression in isolated mice while simultaneously increasing social interaction.<ref name="Olivier_1989" /> Each of the treatments use a different mechanism for targeting aggression, but ultimately all have the same outcome. While the study shows that serotonergic drugs successfully target serotonin receptors, it does not show specifics of the mechanisms that affect behavior, as all types of drugs tended to reduce aggression in isolated male mice.<ref name="Olivier_1989" /> Aggressive mice kept out of isolation may respond differently to changes in serotonin reuptake.

====Behavior====

Like in humans, serotonin is extremely involved in regulating behavior in most other vertebrates. This includes not only response and social behaviors, but also influencing mood. Defects in serotonin pathways can lead to intense variations in mood, as well as symptoms of mood disorders, which can be present in more than just humans.

=====Social interaction=====

One of the most researched aspects of social interaction in which serotonin is involved is aggression. Aggression is regulated by the 5-HT system, as serotonin levels can both induce or inhibit aggressive behaviors, as seen in mice (see section on Mice) and crabs.<ref name="Olivier_1989" /> While this is widely accepted, it is unknown if serotonin interacts directly or indirectly with parts of the brain influencing aggression and other behaviors.<ref name="Bacqué-Cazenave_2020" /> Studies of serotonin levels show that they drastically increase and decrease during social interactions, and they generally correlate with inhibiting or inciting aggressive behavior.<ref>{{cite journal | vauthors = Huber R, Smith K, Delago A, Isaksson K, Kravitz EA | title = Serotonin and aggressive motivation in crustaceans: altering the decision to retreat | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 11 | pages = 5939–5942 | date = May 1997 | pmid = 9159179 | pmc = 20885 | doi = 10.1073/pnas.94.11.5939 | doi-access = free | bibcode = 1997PNAS...94.5939H }}</ref> The exact mechanism of serotonin influencing social behaviors is unknown, as pathways in the 5-HT system in various vertebrates can differ greatly.<ref name="Bacqué-Cazenave_2020" />

=====Response to stimuli=====

Serotonin is important in environmental response pathways, along with other [[neurotransmitter]]s.<ref>{{cite journal | vauthors = Sanchez CL, Biskup CS, Herpertz S, Gaber TJ, Kuhn CM, Hood SH, Zepf FD | title = The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications | journal = The International Journal of Neuropsychopharmacology | volume = 18 | issue = 10 | pages = pyv050 | date = May 2015 | pmid = 25991656 | pmc = 4648158 | doi = 10.1093/ijnp/pyv050 }}</ref> Specifically, it has been found to be involved in auditory processing in social settings, as primary sensory systems are connected to social interactions.<ref name="Petersen_2017">{{cite journal | vauthors = Petersen CL, Hurley LM | title = Putting it in Context: Linking Auditory Processing with Social Behavior Circuits in the Vertebrate Brain | journal = Integrative and Comparative Biology | volume = 57 | issue = 4 | pages = 865–877 | date = October 2017 | pmid = 28985384 | pmc = 6251620 | doi = 10.1093/icb/icx055 }}</ref> Serotonin is found in the [[Inferior colliculus|IC structure]] of the midbrain, which processes specie specific and non-specific social interactions and vocalizations.<ref name="Petersen_2017" /> It also receives acoustic projections that convey signals to auditory processing regions.<ref name="Petersen_2017" /> Research has proposed that serotonin shapes the auditory information being received by the IC and therefore is influential in the responses to auditory stimuli.<ref name="Petersen_2017" /> This can influence how an organism responds to the sounds of predatory or other impactful species in their environment, as serotonin uptake can influence aggression or social interaction.

=====Mood=====

We can describe mood not as specific to an emotional status, but as associated with a relatively long-lasting emotional state. Serotonin's association with mood is most known for various forms of depression and bipolar disorders in humans.<ref name="Lucki_1998" /> Disorders caused by serotonergic activity potentially contribute to the many symptoms of major depression, such as overall mood, activity, suicidal thoughts and sexual and [[cognitive dysfunction]]. [[Selective serotonin reuptake inhibitor]]s (SSRI's) are a class of drugs demonstrated to be an effective treatment in major depressive disorder and are the most prescribed class of antidepressants. SSRI's function is to block the reuptake of serotonin, making more serotonin available to absorb by the receiving neuron. Animals have been studied for decades in order to understand depressive behavior among species. One of the most familiar studies, the forced swimming test (FST), was performed to measure potential antidepressant activity.<ref name="Lucki_1998" /> Rats were placed in an inescapable container of water, at which point time spent immobile and number of active behaviors (such as splashing or climbing) were compared before and after a panel of anti-depressant drugs were administered. Antidepressants that selectively inhibit NE reuptake were shown to reduce immobility and selectively increase climbing without affecting swimming. However, results of the SSRI's also show reduced immobility but increased swimming without affecting climbing. This study demonstrated the importance of behavioral tests for antidepressants, as they can detect drugs with an effect on core behavior along with behavioral components of species.<ref name="Lucki_1998" />

===Growth and reproduction===

In the nematode ''[[Caenorhabditis elegans|C.&nbsp;elegans]]'', artificial depletion of serotonin or the increase of octopamine cues behavior typical of a low-food environment: ''C.&nbsp;elegans'' becomes more active, and mating and egg-laying are suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal.<ref name="pmid18522834">{{cite journal | vauthors = Srinivasan S, Sadegh L, Elle IC, Christensen AG, Faergeman NJ, Ashrafi K | title = Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms | journal = Cell Metabolism | volume = 7 | issue = 6 | pages = 533–544 | date = June 2008 | pmid = 18522834 | pmc = 2495008 | doi = 10.1016/j.cmet.2008.04.012 }}</ref> Serotonin is necessary for normal nematode male mating behavior,<ref name="pmid8254383">{{cite journal | vauthors = Loer CM, Kenyon CJ | title = Serotonin-deficient mutants and male mating behavior in the nematode Caenorhabditis elegans | journal = The Journal of Neuroscience | volume = 13 | issue = 12 | pages = 5407–5417 | date = December 1993 | pmid = 8254383 | pmc = 6576401 | doi = 10.1523/JNEUROSCI.13-12-05407.1993 }}</ref> and the inclination to leave food to search for a mate.<ref name="pmid15329389">{{cite journal | vauthors = Lipton J, Kleemann G, Ghosh R, Lints R, Emmons SW | title = Mate searching in Caenorhabditis elegans: a genetic model for sex drive in a simple invertebrate | journal = The Journal of Neuroscience | volume = 24 | issue = 34 | pages = 7427–7434 | date = August 2004 | pmid = 15329389 | pmc = 6729642 | doi = 10.1523/JNEUROSCI.1746-04.2004 }}</ref> The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects [[insulin]]-like signaling and the [[TGF beta signaling pathway]],<ref name="Murakami H 2007">{{cite journal | vauthors = Murakami H, Murakami S | title = Serotonin receptors antagonistically modulate Caenorhabditis elegans longevity | journal = Aging Cell | volume = 6 | issue = 4 | pages = 483–488 | date = August 2007 | pmid = 17559503 | doi = 10.1111/j.1474-9726.2007.00303.x | s2cid = 8345654 | doi-access = free }}</ref> which control long-term adaption.

In the [[Drosophila melanogaster|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.<ref name="pmid18628395">{{cite journal | vauthors = Kaplan DD, Zimmermann G, Suyama K, Meyer T, Scott MP | title = A nucleostemin family GTPase, NS3, acts in serotonergic neurons to regulate insulin signaling and control body size | journal = Genes & Development | volume = 22 | issue = 14 | pages = 1877–1893 | date = July 2008 | pmid = 18628395 | pmc = 2492735 | doi = 10.1101/gad.1670508 }}</ref><ref name="pmid18628391">{{cite journal | vauthors = Ruaud AF, Thummel CS | title = Serotonin and insulin signaling team up to control growth in Drosophila | journal = Genes & Development | volume = 22 | issue = 14 | pages = 1851–1855 | date = July 2008 | pmid = 18628391 | pmc = 2735276 | doi = 10.1101/gad.1700708 }}</ref> Serotonin has also been identified as the trigger for [[swarm behavior]] in locusts.<ref name="Anstey" /> In humans, though insulin regulates blood sugar and [[insulin-like growth factor|IGF]] regulates growth, serotonin controls the release of both hormones, modulating insulin release from the [[beta cell]]s in the [[pancreas]] through serotonylation of GTPase signaling proteins.<ref name="pmid19859528">{{cite journal | vauthors = Paulmann N, Grohmann M, Voigt JP, Bert B, Vowinckel J, Bader M, Skelin M, Jevsek M, Fink H, Rupnik M, Walther DJ | title = Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation | journal = PLOS Biology | volume = 7 | issue = 10 | pages = e1000229 | date = October 2009 | pmid = 19859528 | pmc = 2760755 | doi = 10.1371/journal.pbio.1000229 | veditors = O'Rahilly S | doi-access = free }}</ref> Exposure to [[SSRI]]s during [[gestation|pregnancy]] reduces fetal growth.<ref name="pmid19262294">{{cite journal | vauthors = Davidson S, Prokonov D, Taler M, Maayan R, Harell D, Gil-Ad I, Weizman A | title = Effect of exposure to selective serotonin reuptake inhibitors in utero on fetal growth: potential role for the IGF-I and HPA axes | journal = Pediatric Research | volume = 65 | issue = 2 | pages = 236–241 | date = February 2009 | pmid = 19262294 | doi = 10.1203/PDR.0b013e318193594a | doi-access = free }}</ref>

Genetically altered ''C.&nbsp;elegans'' worms that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a [[dauer larva|dormant larval state]].<ref name="pmid19851507">{{cite journal | vauthors = Ben Arous J, Laffont S, Chatenay D | title = Molecular and sensory basis of a food related two-state behavior in C. elegans | journal = PLOS ONE | volume = 4 | issue = 10 | pages = e7584 | date = October 2009 | pmid = 19851507 | pmc = 2762077 | doi = 10.1371/journal.pone.0007584 | veditors = Brezina V | doi-access = free | bibcode = 2009PLoSO...4.7584B }}</ref><ref name="pmid10676966">{{cite journal | vauthors = Sze JY, Victor M, Loer C, Shi Y, Ruvkun G | title = Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant | journal = Nature | volume = 403 | issue = 6769 | pages = 560–564 | date = February 2000 | pmid = 10676966 | doi = 10.1038/35000609 | s2cid = 4394553 | bibcode = 2000Natur.403..560S }}</ref>

===Aging and age-related phenotypes===

{{See also|Aging brain#Serotonin}}

Serotonin is known to regulate aging, learning, and memory. The first evidence comes from the study of longevity in [[Caenorhabditis elegans|''C.&nbsp;elegans'']].<ref name="Murakami H 2007"/> During early phase of aging{{vague|date=September 2017}}, the level of serotonin increases, which alters locomotory behaviors and associative memory.<ref>{{cite journal | vauthors = Murakami H, Bessinger K, Hellmann J, Murakami S | title = Manipulation of serotonin signal suppresses early phase of behavioral aging in Caenorhabditis elegans | journal = Neurobiology of Aging | volume = 29 | issue = 7 | pages = 1093–1100 | date = July 2008 | pmid = 17336425 | doi = 10.1016/j.neurobiolaging.2007.01.013 | s2cid = 37671716 }}</ref> The effect is restored by mutations and drugs (including [[mianserin]] and [[methiothepin]]) that inhibit [[serotonin receptors]]. 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|date=September 2017}} phase of aging.

==Biochemical mechanisms==

===Biosynthesis===

[[File:Serotonin biosynthesis.svg|thumb|right|340px|alt= On top an L-tryptophan molecule with an arrow down to a 5-HTP molecule. [[Tryptophan hydroxylase]] catalyses this reaction with help of O₂ and [[tetrahydrobiopterin]], which becomes water and [[dihydrobiopterin]]. From the 5-HTP molecule goes an arrow down to a serotonin molecule. Aromatic L-amino acid decarboxylase or 5-Hydroxytryptophan decarboxylase catalyses this reaction with help of [[pyridoxal phosphate]]. From the serotonin molecule goes an arrow to a 5-HIAA molecule at the bottom of the image. Monoamine oxidase catalyses this reaction, in the process O₂ and water is consumed, and ammonia and hydrogen peroxide is produced.|The pathway for the synthesis of serotonin from tryptophan]]

In animals and humans, serotonin is [[Biosynthesis|synthesized]] from the [[amino acid]] <small>L</small>-[[tryptophan]] by a short [[metabolic pathway]] consisting of two [[enzyme]]s, [[tryptophan hydroxylase]] (TPH) and [[Aromatic L-amino acid decarboxylase|aromatic amino acid decarboxylase]] (DDC), and the coenzyme [[pyridoxal phosphate]]. 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 [[Biological tissue|tissues]], and [[TPH2]], which is a neuron-specific [[Protein isoform|isoform]].<ref name="pmid14597720">{{cite journal | vauthors = Côté F, Thévenot E, Fligny C, Fromes Y, Darmon M, Ripoche MA, Bayard E, Hanoun N, Saurini F, Lechat P, Dandolo L, Hamon M, Mallet J, Vodjdani G | title = Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 23 | pages = 13525–13530 | date = November 2003 | pmid = 14597720 | pmc = 263847 | doi = 10.1073/pnas.2233056100 | first14 = G | doi-access = free | bibcode = 2003PNAS..10013525C }}</ref>

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. ''Aspergillus 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.<ref>{{cite journal | vauthors = Alarcón J, Cid E, Lillo L, Céspedesa C, Aguila S, Alderete JB | title = Biotransformation of indole derivatives by mycelial cultures | journal = Zeitschrift für Naturforschung C | volume = 63 | issue = 1–2 | pages = 82–84 | year = 2008 | pmid = 18386493 | doi = 10.1515/znc-2008-1-215 | s2cid = 29472174 | doi-access = free }}</ref>

[[File:Biosynthesis and breakdown of serotonin and the catecholamines, and the metabolic block in AADC deficiency.png|thumb|Process]]

Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system, because it does not cross the [[blood–brain barrier]].<ref name="pmid18043762" /> However, [[tryptophan]] and its [[metabolite]] [[5-hydroxytryptophan]] (5-HTP), from which serotonin is synthesized, do cross the blood–brain barrier. These agents are available as [[dietary supplement]]s and in various foods, 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 [[tumor]]s or [[cancer]]s, and levels of these substances may be measured in the urine to test for these tumors.

==Analytical chemistry==

[[Indium tin oxide]] is recommended for the [[electrode]] material in [[electrochemistry|electrochemical]] investigation of concentrations produced, detected, or consumed by [[microbe]]s.<ref name="Sismaet-Goluch-2018">{{cite journal | vauthors = Sismaet HJ, Goluch ED | title = Electrochemical Probes of Microbial Community Behavior | journal = Annual Review of Analytical Chemistry | volume = 11 | issue = 1 | pages = 441–461 | date = June 2018 | pmid = 29490192 | doi = 10.1146/annurev-anchem-061417-125627 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] | quote-page = 449 | s2cid = 3632265 | doi-access = free | bibcode = 2018ARAC...11..441S | quote = Table 1{{spaces|5}}The respective potential peaks for various electroactive biomolecules that are produced or consumed by microbes reported in the literature{{sup|a}} ... Serotonin {{!}} Indium tin oxide {{!}} +0.67 {{!}} 66 }}</ref> A mass spectrometry technique was developed in 1994 to measure the [[molecular weight]] of both natural and synthetic serotonins.<ref name="Henson-et-al-1999">{{cite journal | vauthors = Henson JM, Butler MJ, Day AW | title = THE DARK SIDE OF THE MYCELIUM: Melanins of Phytopathogenic Fungi | journal = Annual Review of Phytopathology | volume = 37 | issue = 1 | pages = 447–471 | year = 1999 | pmid = 11701831 | doi = 10.1146/annurev.phyto.37.1.447 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] }}</ref>

==History and etymology==

It had been known to physiologists for over a century that a vasoconstrictor material appears in serum when blood was allowed to clot.<ref name="Anthony_1984">{{cite journal | vauthors = Anthony M | title = Serotonin antagonists | journal = Australian and New Zealand Journal of Medicine | volume = 14 | issue = 6 | pages = 888–895 | date = December 1984 | pmid = 6398056 | doi = 10.1111/j.1445-5994.1984.tb03802.x | s2cid = 28327178 }}</ref> In 1935, Italian [[Vittorio Erspamer]], working in Pavia, 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".<ref name="Erspamer_1954">{{cite journal | vauthors = Erspamer V | title = Pharmacology of indole-alkylamines | journal = Pharmacological Reviews | volume = 6 | issue = 4 | pages = 425–487 | date = December 1954 | pmid = 13236482 }}</ref><ref name="pmid17526278">{{cite journal | vauthors = Negri L | title = [Vittorio Erspamer (1909-1999)] | journal = Medicina Nei Secoli | volume = 18 | issue = 1 | pages = 97–113 | year = 2006 | pmid = 17526278 | url = https://www.medicinaneisecoli.it/index.php/MedSecoli/article/view/491 }}</ref> In 1948, [[Maurice M. Rapport]], [[Arda Green]], and [[Irvine Page]] of the [[Cleveland Clinic]] discovered a vasoconstrictor substance in [[blood plasma|blood serum]], and since it was a serum agent affecting vascular tone, they named it serotonin.<ref name="pmid18100415">{{cite journal | vauthors = Rapport MM, Green AA, Page IH | title = Serum vasoconstrictor, serotonin; isolation and characterization | journal = The Journal of Biological Chemistry | volume = 176 | issue = 3 | pages = 1243–1251 | date = December 1948 | pmid = 18100415 | doi = 10.1016/S0021-9258(18)57137-4 | doi-access = free }}</ref>

In 1952, 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.<ref name="pmid13035756">{{cite journal | vauthors = Feldberg W, Toh CC | title = Distribution of 5-hydroxytryptamine (serotonin, enteramine) in the wall of the digestive tract | journal = The Journal of Physiology | volume = 119 | issue = 2–3 | pages = 352–362 | date = February 1953 | pmid = 13035756 | pmc = 1392800 | doi = 10.1113/jphysiol.1953.sp004850 }}</ref> Synonyms of serotonin include: 5-hydroxytriptamine, enteramine, substance DS, and 3-(β-aminoethyl)-5-hydroxyindole.<ref>SciFinder – Serotonin Substance Detail. Accessed (4 November 2012).{{full citation needed|date=October 2017}}</ref> In 1953, [[Betty Twarog]] and Page discovered serotonin in the central nervous system.<ref>{{cite journal | vauthors = Twarog BM, Page IH | title = Serotonin content of some mammalian tissues and urine and a method for its determination | journal = The American Journal of Physiology | volume = 175 | issue = 1 | pages = 157–161 | date = October 1953 | pmid = 13114371 | doi = 10.1152/ajplegacy.1953.175.1.157 | doi-access = free }}</ref> Page regarded Erspamer's work on ''[[Octopus vulgaris]]'', ''[[Discoglossus pictus]]'', ''[[Hexaplex trunculus]]'', ''[[Bolinus brandaris]]'', ''[[Sepia (cephalopod)|Sepia]]'', ''[[Mytilus (bivalve)|Mytilus]]'', and ''[[Ostrea]]'' as valid and fundamental to understanding this newly identified substance, but regarded his earlier results in various models – especially those from rat blood – to be too confounded by the presence of other bioactive chemicals, including some other vasoactives.<ref name="Page-1954">{{cite journal | vauthors = Page IH | title = Serotonin (5-hydroxytryptamine) | journal = Physiological Reviews | volume = 34 | issue = 3 | pages = 563–588 | date = July 1954 | pmid = 13185755 | doi = 10.1152/physrev.1954.34.3.563 | publisher = [[American Physiological Society]] | author-link = Irvine Page }}</ref>

==Notes==

{{Reflist|group=Note}}

==References==

{{Reflist|30em}}

==Further reading==

{{Refbegin}}

* {{cite journal | vauthors = Gutknecht L, Jacob C, Strobel A, Kriegebaum C, Müller J, Zeng Y, Markert C, Escher A, Wendland J, Reif A, Mössner R, Gross C, Brocke B, Lesch KP | title = Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation | journal = The International Journal of Neuropsychopharmacology | volume = 10 | issue = 3 | pages = 309–320 | date = June 2007 | pmid = 17176492 | doi = 10.1017/S1461145706007437 | doi-access = free }}

{{Refend}}

==External links==

{{Commons category}}

* [http://gmd.mpimp-golm.mpg.de/Spectrums/a1a3167e-cbab-45fd-adb6-9addc14e0ec2.aspx 5-Hydroxytryptamine MS Spectrum]

* [http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=SRO Serotonin bound to proteins] in the [[Protein Data Bank|PDB]]

* [http://www.psychotropical.com/ PsychoTropicalResearch] Extensive reviews on serotonergic drugs and Serotonin Syndrome.

* [https://www.chm.bris.ac.uk/motm/serotonin/home1.htm Molecule of the Month: Serotonin] at [[University of Bristol]]

* 60-Second Psych: [https://www.scientificamerican.com/podcast/episode/68FC98F1-E48A-251D-8F65277181DB9A4E/ No Fair! My Serotonin Level Is Low], [[Scientific American]]

* [http://www.clinlabnavigator.com/Tests/Serotonin.html Serotonin Test Interpretation on ClinLab Navigator].

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{{Serotonin receptor modulators}}

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