Editing Serotonin (section)

==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 | bibcode = 2011JNAtP..74.2304P }}</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>

Serotonin occurs in several hallucinogenic mushrooms of the genus ''[[Panaeolus]]''.<ref name="Tyler1958">{{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>

===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 | bibcode = 2003JExpB.206..223N }}</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]] | bibcode = 2009AnRvP..47..207R | 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-HT<sub>1</sub> receptors]] predominates in subordinate animals, while [[5-HT2 receptor|5-HT<sub>2</sub> 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.