Editing Serotonin (section)

==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 | doi-access = free | 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 | doi = 10.1016/S0031-6997(25)00462-4 | 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 [[serotonin receptor]]s 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 drug]]s. There are currently 14{{nbsp}}known serotonin receptors, including the serotonin [[5-HT1 receptor|5-HT<sub>1</sub>]] (<sub>[[5-HT1A receptor|1A]]</sub>, <sub>[[5-HT1B receptor|1B]]</sub>, <sub>[[5-HT1D receptor|1D]]</sub>, <sub>[[5-HT1E receptor|1E]]</sub>, <sub>[[5-HT1F receptor|1F]]</sub>), [[5-HT2 receptor|5-HT<sub>2</sub>]] (<sub>[[5-HT2A receptor|2A]]</sub>, <sub>[[5-HT2B receptor|2B]]</sub>, <sub>[[5-HT2C receptor|2C]]</sub>), [[5-HT3 receptor|5-HT<sub>3</sub>]], [[5-HT4 receptor|5-HT<sub>4</sub>]], [[5-HT5 receptor|5-HT<sub>5</sub>]] (<sub>[[5-HT5A receptor|5A]]</sub>, <sub>[[5-HT5B receptor|5B]]</sub>), [[5-HT6 receptor|5-HT<sub>6</sub>]], and [[5-HT7 receptor|5-HT<sub>7</sub> receptor]]s. Except for the serotonin [[5-HT3|5-HT<sub>3</sub> 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> The 5-HT<sub>5B</sub> receptor is present in rodents but not in humans.

In addition to the serotonin receptors, serotonin is an [[agonist]] of the [[trace amine-associated receptor 1]] (TAAR1) in some species.<ref name="GainetdinovHoenerBerry2018">{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}</ref><ref name="SimmlerBuchyChaboz2016">{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA| archive-url = https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | archive-date = 9 May 2025 }}</ref> It is a weak TAAR1 [[partial agonist]] in rats, but is inactive at the TAAR1 in mice and humans.<ref name="GainetdinovHoenerBerry2018" /><ref name="SimmlerBuchyChaboz2016" />

The [[cryo-EM]] [[protein–ligand complex|structure]]s of the serotonin 5-HT<sub>2A</sub> receptor with serotonin, as well as with various [[serotonergic psychedelic]]s, have been solved and published by [[Bryan L. Roth]] and colleagues.<ref name="GumpperJainKim2025">{{cite journal | vauthors = Gumpper RH, Jain MK, Kim K, Sun R, Sun N, Xu Z, DiBerto JF, Krumm BE, Kapolka NJ, Kaniskan HÜ, Nichols DE, Jin J, Fay JF, Roth BL | title = The structural diversity of psychedelic drug actions revealed | journal = Nature Communications | volume = 16 | issue = 1 | pages = 2734 | date = March 2025 | pmid = 40108183 | doi = 10.1038/s41467-025-57956-7 | pmc = 11923220 | bibcode = 2025NatCo..16.2734G }}</ref><ref name="GumpperDiBertoJain2022">{{cite conference | vauthors = Gumpper RH, DiBerto J, Jain M, Kim K, Fay J, Roth BL | title = Structures of Hallucinogenic and Non-Hallucinogenic Analogues of the 5-HT2A Receptor Reveals Molecular Insights into Signaling Bias | conference = University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center | date = September 2022 | url = https://www.med.unc.edu/pharm/wp-content/uploads/sites/930/2022/07/COMPLETE-PHARM-RETREAT-PROGRAM-2022-UPDATE.pdf#page=37}}</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''<sub>m</sub> 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|IC<sub>50</sub>]] 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<sub>i</sub> (nM)<ref>{{cite web | title = PDSP K<sub>i</sub> 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-HT<sub>1</sub> receptor family signals via [[Gi alpha subunit|G<sub>i/o</sub>]] inhibition of [[adenylyl cyclase]].
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 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<sub>1B</sub>]] || 4.32 || Vasoconstriction (agonists ↑); aggression (agonists ↓); bone mass (↓). Serotonin autoreceptor.
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || 5.03 || Vasoconstriction (agonists ↑)
|-
| [[5-HT1E receptor|5-HT<sub>1E</sub>]] || 7.53 ||
|-
| [[5-HT1F receptor|5-HT<sub>1F</sub>]] || 10 ||
|-
| colspan ="3" align="center" | 5-HT<sub>2</sub> receptor family signals via [[Gq alpha subunit|G<sub>q</sub>]] activation of [[phospholipase C]].
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 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<sub>2A</sub> 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<sub>2B</sub>]] || 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<sub>2C</sub>]] || 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-HT<sub>3</sub>]] || 593 || Emesis (agonists ↑); anxiolysis (antagonists ↑).
|-
| [[5-HT4 receptor|5-HT<sub>4</sub>]] || 125.89 || Movement of food across the GI tract (agonists ↑); memory & learning (agonists ↑); antidepressant effects (agonists ↑). Signalling via [[Gs alpha subunit|G<sub>αs</sub>]] activation of adenylyl cyclase.
|-
| [[5-HT5A receptor|5-HT<sub>5A</sub>]] || 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<sub>i/o</sub>]] inhibition of [[adenylyl cyclase]].
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]] || 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<sub>s</sub>]] signalling via activating [[adenylyl cyclase]].
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]] || 8.11 || Cognition (antagonists ↑); antidepressant effects (antagonists ↑). Acts by [[Gs alpha subunit|G<sub>s</sub>]] 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.

It is the dorsal part of the raphe nucleus that contains neurons projecting to the central nervous system. Serotonin-releasing neurons in this area receive input from a large number of areas, notably from [[prefrontal cortex]], [[lateral habenula]], [[preoptic area]], [[substantia nigra]] and [[amygdala]].<ref>{{cite journal | vauthors = Zhou L, Liu MZ, Li Q, Deng J, Mu D, Sun YG | title = Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus | journal = Cell Reports | volume = 18 | issue = 12 | pages = 3018–3032 | date = March 2017 | pmid = 28329692 | doi = 10.1016/j.celrep.2017.02.077 | doi-access = free }}</ref> These neurons are thought to communicate the expectation of rewards in the near future, a quantity called state value in [[reinforcement learning]].<ref>{{cite journal | vauthors = Harkin EF, Grossman CD, Cohen JY, Béïque JC, Naud R | title = A prospective code for value in the serotonin system | journal = Nature | date = March 2025 | pmid = 40140568 | doi = 10.1038/s41586-025-08731-7 }}</ref>

====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 | pmc = 11457822 }}</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<sub>2C</sub> 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<sub>2C</sub> 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<sub>1A</sub> 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<sub>2A</sub>]] 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<sub>1B</sub> receptors]], it negatively regulates bone mass, while it does so positively through [[5-HT2B receptor|5-HT<sub>2B</sub> receptors]] and [[5-HT2C receptor|5-HT<sub>2C</sub> 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<sub>2A</sub>]] and [[5-HT2B receptor|5-HT<sub>2B</sub> 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<sub>2B</sub> 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<sub>1B</sub> 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>

====Adipose tissue====
Serotonin also regulates white and brown adipose tissue function, and adipocytes are capable of producing 5-HT separately from the gut. Serotonin increases lipogenesis through [[5-HT2A receptor|HTR2A]] in white adipose tissue, and suppressed thermogenesis in brown adipose tissue via Htr3.<ref>{{cite journal | vauthors = Oh CM, Namkung J, Go Y, Shong KE, Kim K, Kim H, Park BY, Lee HW, Jeon YH, Song J, Shong M, Yadav VK, Karsenty G, Kajimura S, Lee IK, Park S, Kim H | title = Regulation of systemic energy homeostasis by serotonin in adipose tissues | journal = Nature Communications | volume = 6 | pages = 6794 | date = April 2015 | pmid = 25864946 | doi = 10.1038/ncomms7794 | pmc = 4403443 | bibcode = 2015NatCo...6.6794O }}</ref>