Editing Serotonin (section)

===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>