Serotonin

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'''Serotonin'''
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Pubchem(5202)
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A biochemical messenger and regulator, synthesized from the essential amino acid L-TRYPTOPHAN. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (RECEPTORS, SEROTONIN) explain the broad physiological actions and distribution of this biochemical mediator.Serotonin is also found in many [[mushrooms]] and [[plant]]s, including [[fruit]]s and [[vegetable]]s.
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==Description==
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A biochemical messenger and regulator, synthesized from the essential   amino acid L-TRYPTOPHAN. In humans it is found primarily in the   central nervous system, gastrointestinal tract, and blood platelets.   Serotonin mediates several important physiological functions including   neurotransmission, gastrointestinal motility, hemostasis, and   cardiovascular integrity. Multiple receptor families (RECEPTORS,   SEROTONIN) explain the broad physiological actions and distribution of   this biochemical mediator.
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==General Properties==
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<b>*Molecular Weight</b>
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== Function ==
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[[File:5-HT numbered.svg|thumb|left|200px|A hydroxy-group at carbon 5 of the carbon skeleton of <small>L</small>-tryptophan without a [[carboxyl group]] gives serotonin its descriptive chemical name, ''5-hydroxytryptamine''.]]
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176.22
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In the [[central nervous system]], serotonin plays an important role as a [[neurotransmitter]] in the modulation of [[anger]], [[aggression]], [[Thermoregulation|body temperature]], [[Mood (psychology)|mood]], [[sleep]], [[human sexuality]], [[appetite]], and [[metabolism]], as well as stimulating [[vomiting]].<ref>[http://drugs.emedtv.com/dolasetron/dolasetron.html Dolasetron<!-- Bot generated title -->]</ref>
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<b>*Molecular Formula</b>
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Serotonin has broad activities in the brain, and genetic variation in serotonin receptors and the [[serotonin transporter]], which facilitates reuptake of serotonin into presynapses, have been implicated in neurological diseases. Drugs targeting serotonin-induced pathways are being used in the treatment of many psychiatric disorders, and one focus of clinical research is the influence of genetics on serotonin action and metabolism in psychiatric settings. Such studies have revealed that the variation in the promoter region of the serotonin transporter protein accounts for nearly 10% of total variance in anxiety-related personality,<ref> {{Cite journal | author = Lesch, K.; Bengel, D.; Heils, A.; Sabol, S. Z.; Greenberg, B. D.; Petri, S.; Clemens, R.; Müller, J. B.; Hamer, D. H.; Murphy, D. L. | title = Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region | journal = [[Science]] | year = 1996 | volume =  274 | pages =  1527–31 | doi = 10.1126/science.274.5292.1527 | pmid = 8929413}}</ref> and the effect of this gene on [[Major depressive disorder|depression]] was found to interact with the environment.<ref>{{Cite journal | author = Caspi, A.; Sugden, K.; Moffitt, T. E.; Taylor, A.; Craig, I. W.; Harrington, W.; McClay, J.; Mill, J.; Martin, J.; Braithwaite, A.; Poulton, R. | title = Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene | journal = [[Science]] | year = 2003 | volume = 301 | pages = 386–89 | doi = 10.1126/science.1083968 | pmid = 12869766}}</ref>
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C<sub>1</sub><sub>0</sub>H<sub>1</sub><sub>2</sub>N<sub>2</sub>O
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Levels of serotonin in the brain show association with aggression <ref> {{Cite journal | author = 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 =  Int Clin Psychopharmacol. | year = 2001 Mar | volume =  16(2) | pages =  111-5 | doi =  | pmid = 11236069}}</ref>, and  a mutation in the gene which codes for the [[5-HT2A receptor|5-HT<sub>2A</sub>]] receptor may double the risk of suicide for those with that genotype.<ref>{{Cite journal
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| author = [[Greg Basky|Basky, Greg]]
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| title = Suicide linked to serotonin gene
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| journal = [[CMAJ]]
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| month = May
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| year = 2000
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| volume = 162
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| issue = 9
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| url = http://www.cmaj.ca/cgi/content/full/162/9/1343-a
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}}</ref>
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<b>*IUPAC NAME</b>
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Using the [[ultimatum game]] as model, it was shown that people whose serotonin levels have been artificially lowered will reject unfair offers more often than players with normal serotonin levels.<ref>{{Cite journal
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|author=Crockett, M. J.; Clark, L.; Tabibnia, G.; Lieberman, M. D.; Robbins, T. W. |title=Serotonin modulates behavioral reactions to unfairness |journal=Science (journal) |volume=320 |issue=5884 |page=1739 |year=2008 |month=June |pmid=18535210 |pmc=2504725 |doi=10.1126/science.1155577
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}}</ref>
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3-(2-aminoethyl)-1H-indol-5-ol
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In addition, serotonin is also a [[Periphery|peripheral]] signal mediator. It is found extensively in the human [[gastrointestinal tract]] as about 80-90% of the body's total serotonin is found in the enterochromaffin cells in the gut.<ref>[http://web.indstate.edu/thcme/mwking/nerves.html Indiana State University]</ref><ref>[http://www.clinlabnavigator.com/Tests/Serotonin.html] Serotonin tests info, Accessed May 6, 2008</ref> In the blood, the major storage site is [[platelet]]s, which collect serotonin for use in mediating post-injury [[vasoconstriction]].<ref>''Essentials of Human Anatomy & Physiology'', Eighth Edition, p. 336</ref>
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<b>*Canonical Smiles</b>
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Recent research suggests that serotonin plays an important role in [[liver]] regeneration and acts as a [[mitogen]] (induces cell division) throughout the body.  Recent research also suggests that intestinal serotonin may inhibit bone formation.<ref>http://www.sciencedaily.com/releases/2008/11/081126122209.htm</ref><ref>Cell 135, 825–837, November 28, 2008</ref>
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C1=CC2=C(C=C1O)C(=CN2)CCN
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===Serotonin and SIDS===
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<b>*Isomeric Smiles</b>
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Defective signalling of serotonin in the brain may be the root cause of [[sudden infant death syndrome]] (SIDS), Italian researchers have found. Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy,<ref> {{Cite journal | author = Audero, Enrica; Coppi, Elisabetta; Mlinar, Boris; Rossetti, Tiziana; Caprioli, Antonio; Al Banchaabouchi, Mumna; Corradetti, Renato; Gross, Cornelius | title = Sporadic Autonomic Dysregulation and Death Associated with Excessive Serotonin Autoinhibition | journal = [[Science]] | year = 2008 | volume =  321 | pages =  130–133 | doi = 10.1126/science.1157871 | pmid = 18599790}}</ref> genetically modified lab mice to produce low levels of the brain signaling protein serotonin. The results showed the mice suffered drops in heart rate and other symptoms of SIDS, and many of the animals died at an early age.
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Researchers now believe that low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may have caused sudden death, researchers said in the July 4, 2008 issue of Science.<ref>{{cite journal
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| author = Lesurtel, M. ''et al.''
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| year = 2006
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| title = Platelet-derived serotonin mediates liver regeneration
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| journal = [[Science (journal)|Science]]
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| volume = 312
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| issue = 5770
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| pages = 104–7
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| pmid = 16601191
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| doi = 10.1126/science.1123842
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}}</ref>
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==Anatomy==
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=== Gross anatomy ===
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The neurons of the [[raphe nuclei]] are the principal source of 5-HT release in the brain.<ref>{{cite book
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| author = [[Alan Frazer|Frazer, A.]]; and [[Julie G. Hensler|Hensler, J. G.]]
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| editor = [[George J. Siegel|Siegel, G. J.]]
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| others = Agranoff, Bernard W.; Fisher, Stephen K.; Albers, R. Wayne; Uhler, Michael D.
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| title = Basic Neurochemistry
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| url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm
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| edition = Sixth
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| year = 1999
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| publisher = Lippincott Williams and Wilkins
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| isbn = 0-397-51820-X
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| chapter = Understanding the neuroanatomical organization of serotonergic cells in the brain provides insight into the functions of this neurotransmitter
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| chapterurl = http://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
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| 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.
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}}</ref>
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The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the [[brainstem]], centered around the [[reticular formation]].<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>
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==PhysioChemical Properties==
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Axons from the neurons of the raphe nuclei form a [[neurotransmitter system]], reaching large areas of the brain. Axons of neurons in the ''caudal'' [[raphe nuclei]] terminate in the following locations:
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<b>*Melting Point</b>
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* [[Deep cerebellar nuclei]]
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* [[Cerebellar cortex]]
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* [[Spinal cord]]
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167.5(EXP)
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On the other hand, axons of neurons in the ''rostral'' [[raphe nuclei]] terminate in e.g.:
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<b>*LogP</b>
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* [[Thalamus]]
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* [[Striatum]]
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* [[Hypothalamus]]
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* [[Nucleus accumbens]]
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* [[Neocortex]]
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* [[Cingulate gyrus]]
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* [[Cingulum]]
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* [[Hippocampus]]
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* [[Amygdala]]</div>
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0.21(EXP)
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Thus, activation of this serotonin system has effects on large areas of the brain.
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<b>*Water Solubility</b>
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=== Microanatomy ===
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2.00E+04(EXP)
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Serotonin is released from serotonergic varicosities (swellings) into the extra neuronal space, but not from synaptic terminal [[bouton]]s as other neurotransmitters. {{Fact|date=June 2008}} Serotonin diffuses over a relatively wide gap (>20µm) to activate [[5-HT receptor]]s located on the [[dendrite]]s, cell bodies and [[presynaptic terminal]]s of adjacent neurons.
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==External Links==
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==== Receptors ====
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*[http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5202]Pubchem
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{{main|5-HT receptor}}
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*[http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=2QEH]]2QEH,[[http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3BRN]]3BRN,
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*[http://www.genome.jp/dbget-bin/www_bget?compound+C00780]KEGG Compound
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*[http://www.hmdb.ca/metabolites/HMDB00259]Human Metabolome DataBase
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[[5-HT receptor]]s are the [[receptor (biochemistry)|receptors]] for serotonin. They 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, dissociatives and deliriants|hallucinogenic drugs]]. With the exception of the [[5-HT3|5-HT<sub>3</sub> receptor]], a ligand gated [[ion channel]], all other 5-HT receptors are [[G-protein-coupled receptor|G protein coupled seven transmembrane]] (or ''heptahelical'') receptors that activate an [[intracellular]] [[second messenger]] cascade. {{Fact|date=June 2008}}
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[[Categories:Hormones]]
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==== Termination ====
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Serotonergic action is terminated primarily via [[reuptake|uptake]] of 5-HT from the synapse. This is through the specific [[monoamine transporter]] for 5-HT, [[Serotonin transporter|SERT]], on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including [[MDMA]] (ecstasy), [[amphetamine]], [[cocaine]], [[dextromethorphan]] (an [[antitussive]]), [[tricyclic antidepressants]] (TCAs) and [[selective serotonin reuptake inhibitor]]s (SSRIs).
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Interestingly, a 2006 study conducted by the [[University of Washington]] suggested that a newly discovered monoamine transporter, known as PMAT, may account for 'a significant percentage of 5-HT clearance.<ref>{{cite book
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| author = Mingyan Zhou, Karen Engel,1 and Joanne Wang*
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| editor = ?
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| others = ?
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| title = Biochemical Pharmacology
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| url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1828907
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| edition = Vol 73 Issue 1
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| year = 2007
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| publisher = Elsevier Inc.
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| isbn = ?
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| chapter = Evidence for Significant Contribution of a Newly Identified Monoamine Transporter (PMAT) to Serotonin Uptake in the Human Brain
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| doi = 10.1016/j.bcp.2006.09.008
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| pmid = 1828907
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}}</ref>' Contrasting with the high-affinity  SERT, the PMAT has been identified as a low affinity transporter with an apparent K<sub>m</sub> of 114 micromoles/L for serotonin; 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, <blockquote>''"..resulting in roughly comparable uptake efficiencies to SERT in heterologous expression systems."''</blockquote> The study also suggests that some SSRIs, such as fluoxetine and sertraline, inhibit PMAT but at IC<sub>50</sub> values which surpass therapeutic plasma concentrations by up to four magnitudes of ten; ergo, SSRI monotherapy is ''ineffective'' in PMAT inhibition. At present, there are no known pharmaceuticals which would appreciably inhibit PMAT at normal therapeutic doses. The PMAT also suggestively transports dopamine and norepinephrine albeit at K<sub>m</sub> values even higher than that of 5-HT (330–15,000 micromoles/L).
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===Endothelial cell function and Serotonin ===
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5-hydroxytryptamine evokes [[endothelium|endothelial]] [[nitric oxide synthase]] activation and stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.<ref>{{Cite journal
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| author = McDuffie, J. E.
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| title = -hydroxytryptamine stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures
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| journal = J. Cardiovasc. Pharmacol.
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| month = March
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| year = 2000
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| volume = 35
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| issue = 3
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| url = http://www.cardiovascularpharm.com/pt/re/jcardiopharm/abstract.00005344-200003000-00008.htm;jsessionid=LLhXJN6PTXBlSKWpG3mTNChLl7C4wQZFQF2yyFWnlQLcdph7zkQq!-1990489359!181195628!8091!-1}}</ref>
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== Biosynthesis ==
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[[Image:Serotonin biosynthesis.svg|thumb|right|400px|The pathway for the synthesis of serotonin from tryptophan]]
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In animals including humans, serotonin is [[Biosynthesis|synthesized]] from the [[amino acid]] <small>L</small>-[[tryptophan]] by a short [[metabolic pathway]] consisting of two [[enzyme]]s: [[tryptophan hydroxylase]] (TPH) and [[Aromatic L-amino acid decarboxylase|amino acid decarboxylase]] (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several [[Biological tissue|tissues]], and TPH2, which is a brain-specific [[Protein isoform|isoform]]. There is evidence that [[polymorphism (biology)|genetic polymorphisms]] in both these subtypes influence susceptibility to anxiety and depression in humans. There is also evidence that [[ovarian hormones]] can affect the expression of TPH in various species, suggesting a possible mechanism for [[postpartum depression]] and [[premenstrual stress syndrome]].{{Fact|date=January 2009}} Serotonin biosynthesis in plants likewise begins with <small>L</small>-tryptophan, which is however first [[Decarboxylation|decarboxylated]] by [[tryptophan decarboxylase]] to give tryptamine, which is then [[Hydroxylation|hydroxylated]] by the [[cytochrome P450 monooxygenase]], [[tryptamine 5-hydroxylase]], yielding serotonin.<ref name="Schröder et al">{{cite journal|author=Schröder P, Abele C, Gohr P, Stuhlfauth-Roisch U, Grosse W.|year= 1999|title=Latest on enzymology of serotonin biosynthesis in walnut seeds|journal=Adv Exp Med Biol.|volume=467|pages=637-644|pmid=10721112}}</ref>
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Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the [[blood-brain barrier]]. However, tryptophan and its [[metabolite]] [[5-hydroxytryptophan]] (5-HTP), from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as [[dietary supplement]]s and may be effective serotonergic agents.
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One product of serotonin breakdown is [[5-Hydroxyindoleacetic acid]] (5 HIAA), which is excreted in the [[urine]]. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain [[tumor]]s or [[cancer]]s, and levels of these substances may be measured in the urine to test for these tumors.
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== Drugs targeting the 5-HT system ==
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Several classes of [[drugs]] target the 5-HT system including some [[antidepressant]]s, [[antipsychotic]]s, [[anxiolytic]]s, [[antiemetic]]s, and [[migraine|antimigraine drugs]] as well as the [[psychedelic drug]]s and [[empathogen]]s.
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=== Psychedelic drugs ===
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The [[psychedelic drug]]s [[psilocin]]/[[psilocybin]], [[dimethyltryptamine|DMT]], [[mescaline]], and [[LSD]] mimic the action of serotonin primarily at [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]]. The [[empathogen]] [[MDMA]] (ecstasy) releases serotonin from synaptic vesicles of neurons.
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=== Antidepressants ===
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The [[MAOI]]s prevent the breakdown of [[monoamine neurotransmitter]]s (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of [[hypertensive emergency]] triggered by foods with high [[tyramine]] content and certain drugs.
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Some drugs inhibit the re-uptake of serotonin, making it stay in the synapse longer. The [[tricyclic antidepressants]] (TCAs) inhibit the re-uptake of both serotonin and [[norepinephrine]]. The newer [[Selective and non-selective|selective]] serotonin re-uptake inhibitors ([[SSRI]]s) have fewer  side-effects and fewer interactions with other drugs.
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SSRI medications have been shown to lower serotonin levels below initial level over time, despite initial increases in serotonin.<ref name="benmansour">Benmansour, Saloua ''et al.'', Effects of Chronic Antidepressant Treatments on Serotonin Transporter Function, Density, and mRNA Level. Journal of Neuroscience, 1999, 19(23):10494-10501.  http://www.jneurosci.org/cgi/content/full/19/23/10494 </ref>  This decrease in level did not rectify after the medicine was discontinued. However, the novel antidepressant [[Tianeptine]], selective serotonin reuptake ''enhancer'', has mood elevating effects. This has given evidence to the theory that serotonin is most likely used to regulate the extent or intensity of moods, and that low levels are what's associated with SSRI sexual dysfunction and/or "mood blunting" experienced by people on these medications.
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=== Antiemetics ===
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[[5-HT3 antagonist|5-HT<sub>3</sub> antagonist]]s such as [[ondansetron]], [[granisetron]], and [[tropisetron]] are important [[antiemetic]] agents. They are particularly important in treating the [[nausea]] and [[vomiting]] that occur during anticancer [[chemotherapy]] using cytotoxic drugs. Another application is in the treatment of post-operative nausea and vomiting. Applications to the treatment of depression and other mental and psychological conditions have also been investigated with some positive results.
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== Pathology ==
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If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of [[sudden infant death syndrome]] (SIDS).<ref name="SIDS">{{cite journal |author=Paterson, D. S.; Trachtenberg, F. L.; Thompson, E.G.; ''et al.'' |title=Multiple serotonergic brainstem abnormalities in sudden infant death syndrome |journal=JAMA |volume=296 |issue=17 |pages=2124–32 |year=2006 |month=November |pmid=17077377 |doi=10.1001/jama.296.17.2124 |url=
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}}</ref><ref>[http://www.sciencedaily.com/releases/2007/03/070309103136.htm Sciencedaily Report ''Anger and Aggression in Women: Blame It On Genetics'']</ref> Low levels of serotonin may also be associated with [[Relationship between religion and science#Scientific study of religion|intense spiritual experiences]].<ref>Farde, Lars; and Borg, Jacqueline; Section of psychiatry at Karolinska Institutet in Stockholm, Sweden 2003, [http://ajp.psychiatryonline.org/cgi/content/full/160/11/1965? the study] and a [http://www.beliefnet.com/story/140/story_14076_1.html vulgarized article]</ref>
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Recent research conducted at [[Rockefeller University]] shows that both in patients who suffer from depression and in mice that model the disorder, levels of the [[p11 protein]] are decreased. This protein is related to serotonin transmission within the brain.<ref>{{cite journal
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| author = Svenningsson, P. ''et al.''
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| year = 2006
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| title = Alterations in 5-HT1B receptor function by p11 in depression-like states
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| journal = Science
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| volume = 311
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| issue = 5757
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| pages = 77–80
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| pmid = 16400147
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| doi = 10.1126/science.1117571 <!--Retrieved from CrossRef by DOI bot-->
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}}</ref>
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[[Obsessive-compulsive disorder]] (OCD) can be a debilitating disorder with the following two anxiety-related essential features: obsessions (undesirable, recurrent, disturbing thoughts) and compulsions (repetitive or ritualized behaviors). SSRIs, and other medicines which alter serotonin levels, have been approved to be used to treat symptoms of OCD.
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=== Serotonin syndrome ===
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{{main|serotonin syndrome}}
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Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a condition known as [[serotonin syndrome]]. In practice, such toxic levels are essentially impossible to reach through an [[overdose]] of a single anti-depressant drug, but require a combination of serotonergic agents, such as an [[SSRI]] with an [[MAOI]].<ref>{{cite journal |author=Isbister, G. K.; Bowe, S. J.; Dawson, A.; Whyte, I. M. |title=Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose |journal=J. Toxicol. Clin. Toxicol. |volume=42 |issue=3 |pages=277–85 |year=2004 |pmid=15362595 |doi= |url=}}</ref> The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels.<ref>{{cite journal |author=Dunkley, E. J.; Isbister, G. K.; Sibbritt, D.; Dawson, A. H.; Whyte, I. M. |title=The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity |journal=QJM |volume=96 |issue=9 |pages=635–42 |year=2003 |month=September |pmid=12925718 |doi= |url=http://qjmed.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12925718}}</ref> For example, recreational doses of [[MDMA]] (ecstasy) will generally cause such symptoms but only rarely lead to true [[toxicity]].{{Fact|date=February 2008}}
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=== Chronic diseases resulting from serotonin 5-HT<sub>2B</sub> overstimulation ===
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{{main|Cardiac fibrosis}}
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In blood, serotonin stored in platelets is active wherever platelets bind, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic, to aid healing. Because of these effects, overdoses of serotonin, or serotonin agonist drugs, may cause acute or chronic pulmonary hypertension from pulmonary vasoconstriction, or else syndromes of [[retroperitoneal fibrosis]] or cardiac valve fibrosis ([[endocardial fibrosis]]) from overstimulation of serotonic growth receptors on fibrocytes.{{Fact|date=April 2008}}
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Serotonin itself may cause a syndrome of cardiac fibrosis when it is eaten in large quantities in the diet (the Matoki banana of East Africa) or when it is over-secreted by certain mid-gut [[carcinoid]] tumors.{{Fact|date=April 2008}} The valvular fibrosis in such cases is typically on the right side of the heart, since excess serotonin in the serum outside platelets is metabolized in the lungs, and does not reach the left circulation.{{Fact|date=April 2008}}
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Serotonergic [[agonist]] drugs in overdose in experimental animals not only cause acute (and sometimes fatal) [[pulmonary hypertension]], but there is epidemiologic evidence that chronic use of certain of these drugs produce a chronic pulmonary hypertensive syndrome in humans.{{Fact|date=April 2008}} Some serotonergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of [[retroperitoneal fibrosis]], as well as [[cardiac fibrosis|cardiac valve fibrosis]].<ref name=Baskin>{{cite book |title=Principles of Cardiac Toxicology
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|author=Baskin, Steven I. |year=1991 |publisher=CRC Press |location= |isbn=0849388090 |pages= |url=http://books.google.com/books?id=AW7M6jBixj4C&pg=PA626&lpg=PA626&dq=ergotamine+endocardial+fibrosis&source=web&ots=BrjNzsIc-N&sig=X-WM0TaoW6I5nkx6xiTsxJYvLHo.}}</ref>
 +
 
 +
In the past, three groups of serotonergic drugs have been epidemiolgically linked with these syndromes. They are the serotonergic vasoconstrictive anti-migraine drugs ([[ergotamine]] and [[methysergide]]),<ref name=Baskin/> the serotonergic appetite suppressant drugs ([[fenfluramine]], [[chlorphentermine]], and [[aminorex]]), and certain anti-parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT<sub>2B</sub> receptors. These include [[pergolide]] and [[cabergoline]], but not the more dopamine-specific [[lisuride]].<ref> Jähnichen, S.; Horowski, R.; Pertz, H. {{PDFlink|[http://userpage.fu-berlin.de/~hpertz/Presentation001.pdf "Pergolide and Cabergoline But not Lisuride Exhibit Agonist Efficacy at Serotonin 5-HT<sub>2B</sub> Receptors".]|515&nbsp;KB}} Presentation. Retrieved on [[2007-03-30]].</ref> As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is [[pergolide]]. The drug was in decreasing use since reported in 2003 to be associated with cardiac fibrosis.<ref>{{cite journal | url = http://www.tga.gov.au/adr/aadrb/aadr0408.htm | year = 2004 | month = August | title = Cardiac valvulopathy with pergolide | author = [[Adverse Drug Reactions Advisory Committee|ADRAC]] | journal = Aust Adv Drug React Bull | volume = 23 | issue = 4}} [http://www.tga.gov.au/adr/aadrb/aadr0408.htm Free full text] from the [[Australia]]n [[Therapeutic Goods Administration]]</ref> Two independent studies published in the [[New England Journal of Medicine]] in January 2007, implicated pergolide along with [[cabergoline]] in causing [[valvular heart disease]].<ref>{{citation| last1=Schade| first1=Rene| last2=Andersohn |first2=Frank |last3=Suissa |first3=Samy |last4=Haverkamp |first4=Wilhelm |last5=Garbe |first5=Edeltraut |title=Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation |journal=New England Journal of Medicine |volume=356 |issue=1 |pages=29–38 |date=[[2007-01-04]] |year=2007 |url=http://content.nejm.org/cgi/content/full/356/1/29 |doi= |id= |pmid=17202453}}</ref><ref>{{citation| last1=Zanettini| first1=Renzo| last2=Antonini |first2=Angelo |last3=Gatto |first3=Gemma |last4=Gentile |first4=Rosa |last5=Tesei |first5=Silvana |last6=Pezzoli |first6=Gianna |title=Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson's Disease |journal=New England Journal of Medicine |volume=356 |issue=1 |pages=39–46 |date=[[2007-01-04]] |year=2007 |url=http://content.nejm.org/cgi/content/full/356/1/39 |doi= |id= |pmid=17202454}}</ref> As a result of this, the [[Food and Drug Administration|FDA]] removed pergolide from the U.S. market in March, 2007.<ref>{{cite web |url=http://www.fda.gov/cder/drug/advisory/pergolide.htm |title=Food and Drug Administration Public Health Advisory |date=[[2007-03-29]] |accessdate=2007-04-27}}</ref> (Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).<ref name="FDAwithdraw">{{cite web | url = http://www.fda.gov/medwatch/safety/2007/safety07.htm#Pergolide | title = MedWatch - 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents | publisher = U.S. [[Food and Drug Administration]] | date = March 29, 2007 | accessdate = 2007-03-30}}</ref>
 +
 
 +
Because neither the amino acid [[L-tryptophan]] nor the [[SSRI]]-class antidepressants raise blood serotonin levels {{Fact|date=April 2008}}, they are not under suspicion to cause the syndromes described. However, since 5-hydroxytryptophan ([[5-HTP]]) does raise blood serotonin levels, it is under some of the same scrutiny as actively serotonergic drugs.{{Fact|date=April 2008}}
 +
 
 +
== In unicellular organisms ==
 +
 
 +
Serotonin is used by a variety of single-cell organisms for various purposes. Selective serotonin re-uptake inhibitors (SSRIs) have been found to be toxic to algae.<ref>{{cite journal |author=Johnson, D. J.; Sanderson, H.; Brain, R. A.; Wilson, C. J.; Solomon, K. R. |title=Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae |journal=Ecotoxicol. Environ. Saf. |volume=67 |issue=1 |pages=128–39 |year=2007 |pmid=16753215 |doi=10.1016/j.ecoenv.2006.03.016}}</ref> The gastrointestinal parasite ''[[Entamoeba histolytica]]'' secretes serotonin, causing a sustained secretory diarrhea in some patients.<ref>{{cite journal |author=McGowan, K.; Kane, A.; Asarkof, N. ''et al.'' |title=Entamoeba histolytica causes intestinal secretion: role of serotonin |journal=Science |volume=221 |issue=4612 |pages=762–4 |year=1983 |pmid=6308760| doi = 10.1126/science.6308760 <!--Retrieved from CrossRef by DOI bot-->}}</ref><ref>{{cite journal |author=McGowan, K.; Guerina, V.; Wicks, J.; Donowitz, M. |title=Secretory hormones of Entamoeba histolytica |journal=Ciba Found. Symp. |volume=112 |issue= |pages=139–54 |year=1985 |pmid=2861068 |doi=}}</ref> Patients infected with ''[[Entamoeba histolytica]]'' have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.<ref>{{cite journal |author=Banu, Naheed ''et al.'' |title=Neurohumoral alterations and their role in amoebiasis |journal=Indian J. Clin Biochem |volume=20 |issue=2 |pages=142–5 |year=2005 |url=http://medind.nic.in/iaf/t05/i2/iaft05i2p142.pdf |format=PDF| doi = 10.1007/BF02867414 <!--Retrieved from CrossRef by DOI bot-->}}</ref> ''[[Entamoeba histolytica]]'' also responds to the presence of serotonin by becoming more virulent.<ref>{{cite journal |author=Acharya, D. P.; Sen, M. R.; Sen, P. C. |title=Effect of exogenous 5-hydroxytryptamine on pathogenicity of Entamoeba histolytica in experimental animals |journal=Indian J. Exp. Biol. |volume=27 |issue=8 |pages=718–20 |year=1989 |pmid=2561282 |doi=}}</ref>
 +
 
 +
== In plants ==
 +
 
 +
Serotonin is found in [[mushroom]]s and [[plant]]s, including [[fruits]] and [[vegetable]]s. The highest values of 25–400 mg/kg have been found in nuts of the [[walnut]] (''Juglans'') and [[hickory]] (''Carya'') genuses. Serotonin concentrations of 3–30 mg/kg have been found in [[plantain]], [[pineapple]], [[banana]], [[kiwifruit]], [[plum]]s, and [[tomato]]es. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.<ref>{{cite journal |author=Feldman, J. M.; Lee, E. M. |title=Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid |journal=Am. J. Clin. Nutr. |volume=42 |issue=4 |pages=639–43 |year=1985 |month=October |pmid=2413754 |doi= |url=http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=2413754}}</ref> Serotonin is one compound of the poison contained in [[stinging nettle]]s (''Urtica dioica''). It should be noted that serotonin, unlike its precursors 5-HTP and tryptophan, does not cross the [[Blood-brain barrier|blood–brain barrier]], which means that ingesting serotonin in the diet has no effect on brain serotonin levels.
 +
Several plants contain serotonin together with a family of related [[tryptamine]]s that are [[methyl]]ated at the [[amine|amino]] (NH<sub>2</sub>) and [[hydroxy]] (OH) groups, are [[amine oxide|''N''-oxides]], or miss the OH group. Examples are plants from the ''[[Anadenanthera]]'' genus that are used in the [[hallucinogen]]ic [[yopo]] snuff.
 +
 
 +
== In animals ==
 +
 
 +
Serotonin as a [[neurotransmitter]] is found in all animals, including [[insect]]s. Several [[bufo alvarius|toad venom]]s, as well as that of the [[Brazilian wandering spider]] and [[stingray]], contain serotonin and related [[tryptamine]]s. It has also been identified as the trigger for swarm behaviour in locusts<ref>http://news.bbc.co.uk/2/hi/science/nature/7858996.stm
 +
</ref>.
 +
 
 +
== History ==
 +
 
 +
Isolated and named in 1948 by Maurice M. Rapport, Arda Green, and [[Irvine Page]] of the [[Cleveland Clinic]],<ref>{{Cite journal
 +
| author = Rapport, Maurice M.; Green, Arda A.; Page, Irvine H.
 +
| year = 1948 |month=December |pmid=18100415
 +
| title = Serum vasoconstrictor (serotonin). IV. Isolation and characterization
 +
| journal = [[J. Biol. Chem.]]
 +
| volume = 176
 +
| issue = 3
 +
| pages = 1243–51
 +
}}</ref>
 +
the name ''serotonin'' is something of a [[misnomer]] and reflects the circumstances of the compound's discovery. It was initially identified as a vasoconstrictor substance in [[Blood plasma|blood serum]] – hence ''serotonin'', a serum agent affecting vascular tone. This agent was later chemically identified as 5-hydroxytryptamine (5-HT) by Rapport, and, as the broad range of physiological roles were elucidated, 5-HT became the preferred name in the pharmacological field.
 +
 
 +
== Increasing serotonin levels ==
 +
 
 +
Serotonin levels may be increased by supplement of tryptophan. However, increasing foods rich in tryptophan (eg, meats, proteins) do not increase serotonin levels, due to competition with other amino acids.<ref name=Young>{{cite journal |author=Young, S. N. |title=How to increase serotonin in the human brain without drugs |journal=J. Psychiatry Neurosci. |volume=32 |issue=6 |pages=394–9 |year=2007 |month=November |pmid=18043762 |pmc=2077351 |doi= |url=http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-32/issue-6/pdf/pg394.pdf|format=PDF|accessdate=2008-12-30}}</ref> What is required to increase serotonin production is an increase in the ratio of tryptophan to phenylalanine and leucine. Fruits with a good ratio include dates, papaya and banana. Foods with a lower ratio inhibit the production of serotonin. These include whole wheat and rye bread<ref>[http://www.selfgrowth.com/articles/Nutritional_Pharmacology_of_Sleep_Depression.html Nutritional Pharmacology Of Sleep & Depression<!-- Bot generated title -->]</ref>
 +
Much research has indicated that vigorous aerobic exercise improves mood, believed to be facilitated by an increase in serotonin levels.<ref>[http://serendip.brynmawr.edu/bb/neuro/neuro99/web1/Byrd.html Serotonin and Its Uses<!-- Bot generated title -->]</ref> Research also suggests that eating a diet rich in whole grain carbohydrates and low in protein will increase serotonin by secreting insulin, which helps in amino acid competition.<ref name=Young/> However, increasing insulin for a long period of time can sometimes onset [[insulin resistance]], which is related to [[obesity]], [[type 2 diabetes]], and lower serotonin levels.  It is also believed that muscles use many of the amino acids except tryptophan, allowing men to have more serotonin than women.<ref>http://books.google.com/books?id=2PxhgaCThccC&pg=PA49&lpg=PA49&dq=insulin+resistance+and+serotonin&source=web&ots=udW-o42zjY&sig=rtcdA8TTAkuxSxwvrR4TxYcnF30&hl=en&sa=X&oi=book_result&resnum=3&ct=result#PPA64,M1</ref> Bright [[light therapy]] is another popular method which prevents the conversion of serotonin to [[melatonin]].<ref>[http://apollohealth.com/light_therapy_education.html Education : Philips<!-- Bot generated title -->]</ref> A similar effect is obtained by spending more time in natural sunlight. Recently, acupuncture has been shown to stimulate the release of serotonin levels in lab animals.<ref>[http://www.sasappa.co.jp/online/abstract/tmp/1/208/html/0112080405.html Acupuncture Stimulates the Release of Serotonin, but Not Dopamine, in the Rat Nucleus Accumbens<!-- Bot generated title -->]</ref>
 +
 +
 
 +
'''KEGG Pathway'''(C00780)
 +
*Tryptophan metabolism
 +
*Neuroactive ligand-receptor interaction
 +
*Gap junction
 +
*Serotonin receptor agonists/antagonists
 +
{| border="1;width:100%; height:200px;style=text-align:center"
 +
|+'''List of PDB files having estriol as a Ligand:'''
 +
|-
 +
! style="background:brown; color:white" |MMDB ID
 +
! style="background:brown; color:white" |PDB ID
 +
! style="background:brown; color:white" |Reference
 +
|-
 +
|59445
 +
|2QEH
 +
|Mans BJ, Calvo E, Ribeiro JM, Andersen JFThe Crystal Structure of D7r4, a Salivary Biogenic Amine-binding Protein from the Malaria Mosquito Anopheles gambiaeJ. Biol. Chem. v282, p.36626-36633
 +
|-
 +
|63512
 +
|3BRN
 +
|Mans BJ, Ribeiro JM, Andersen JFStructure, function, and evolution of biogenic amine-binding proteins in soft ticksJ. Biol. Chem. v283, p.18721-18733
 +
|-
 +
|}
 +
{| border="1;width:100%; height:200px;style=text-align:center"
 +
|+'''Physiochemical properties of Estriol:'''
 +
|-
 +
! style="background:brown; color:white" |Physical Property
 +
! style="background:brown; color:white" |Value
 +
! style="background:brown; color:white" |Units
 +
! style="background:brown; color:white" |Temp (deg C)
 +
! style="background:brown; color:white" |Source
 +
|-
 +
|Melting Point
 +
|167.5
 +
|deg C
 +
|
 +
|EXP
 +
|-
 +
|pKa Dissociation Constant
 +
|9.97
 +
|(none)
 +
|25
 +
|EXP
 +
|-
 +
|log P (octanol-water)
 +
|0.21
 +
|(none)
 +
|  
 +
|EXP
 +
|-
 +
|Water Solubility
 +
|2.00E+04
 +
|mg/L
 +
|27
 +
|EXP
 +
|-
 +
|Vapor Pressure
 +
|1.91E-06
 +
|mm Hg
 +
|25
 +
|EST
 +
|-
 +
|Henry's Law Constant
 +
|1.39E-14
 +
|atm-m3/mole
 +
|25
 +
|EST
 +
|-
 +
|Atmospheric OH Rate Constant
 +
|2.33E-10
 +
|cm3/molecule-sec
 +
|25
 +
|EST
 +
|-
 +
|}
 +
{| border="1;width:100%; height:200px;style=text-align:center"
 +
|+'''Toxicity:'''
 +
|-
 +
! style="background:brown; color:white" |Organism
 +
! style="background:brown; color:white" |Test Type 
 +
! style="background:brown; color:white" |Route 
 +
! style="background:brown; color:white" |Reported Dose (Normalized Dose)
 +
! style="background:brown; color:white" |Effect
 +
! style="background:brown; color:white" |Source
 +
|-
 +
|cat
 +
|LDLo
 +
|intravenous
 +
|5mg/kg (5mg/kg)
 +
|CARDIAC: OTHER CHANGES
 +
 
 +
LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION
 +
|Farmakologiya i Toksikologiya Vol. 26, Pg. 10, 1963.
 +
|-
 +
|guinea pig
 +
|LD50
 +
|intravenous
 +
|12800ug/kg (12.8mg/kg)
 +
| 
 +
|Archives Internationales de Pharmacodynamie et de Therapie. Vol. 168, Pg. 373, 1967.
 +
|-
 +
|mouse
 +
|LD50
 +
|intramuscular
 +
|750mg/kg (750mg/kg)  
 +
|
 +
|Archives Internationales de Pharmacodynamie et de Therapie. Vol. 112, Pg. 319, 1957.
 +
|-
 +
|mouse
 +
|LD50
 +
|intraperitoneal
 +
|160mg/kg (160mg/kg)
 +
| 
 +
|Indian Journal of Physiology and Pharmacology. Vol. 17, Pg. 31, 1973.
 +
|-
 +
|mouse
 +
|LD50
 +
|intravenous
 +
|81mg/kg (81mg/kg)
 +
|BEHAVIORAL: TREMOR
 +
 
 +
BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD
 +
|Farmakologiya i Toksikologiya Vol. 26, Pg. 10, 1963.
 +
|-
 +
|mouse
 +
|LD50
 +
|oral
 +
|60mg/kg (60mg/kg)  
 +
|Meditsinskii Zhurnal Uzbekistana. Vol. (3), Pg. 61, 1985.
 +
|-
 +
|mouse
 +
|LD50
 +
|subcutaneous
 +
|601mg/kg (601mg/kg)
 +
|BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY)
 +
 
 +
BEHAVIORAL: ATAXIA
 +
 
 +
GASTROINTESTINAL: "HYPERMOTILITY, DIARRHEA"
 +
|Farmakologiya i Toksikologiya Vol. 26, Pg. 10, 1963.
 +
|-
 +
|mouse
 +
|LD50
 +
|unreported
 +
|250mg/kg (250mg/kg)
 +
|  
 +
|"CRC Handbook of Antibiotic Compounds," Vols.1- , Berdy, J., Boca Raton, FL, CRC Press, 1980Vol. 8(1), Pg. 122, 1982.
 +
|-
 +
|rat
 +
|LD50
 +
|intravenous
 +
|30mg/kg (30mg/kg)
 +
| 
 +
|Psychopharmacology Service Center, Bulletin. Vol. 2, Pg. 17, 1963.
 +
|-
 +
|rat
 +
|LD50
 +
|subcutaneous
 +
|285mg/kg (285mg/kg)  
 +
|
 +
|Psychopharmacology Service Center, Bulletin. Vol. 2, Pg. 17, 1963.
 +
|-
 +
|}

Current revision

Show 3-D Structure

Serotonin Pubchem(5202)

A biochemical messenger and regulator, synthesized from the essential amino acid L-TRYPTOPHAN. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (RECEPTORS, SEROTONIN) explain the broad physiological actions and distribution of this biochemical mediator.Serotonin is also found in many mushrooms and plants, including fruits and vegetables.

Contents

[edit] Function

[[File:5-HT numbered.svg|thumb|left|200px|A hydroxy-group at carbon 5 of the carbon skeleton of L-tryptophan without a carboxyl group gives serotonin its descriptive chemical name, 5-hydroxytryptamine.]]

In the central nervous system, serotonin plays an important role as a neurotransmitter in the modulation of anger, aggression, body temperature, mood, sleep, human sexuality, appetite, and metabolism, as well as stimulating vomiting.<ref>Dolasetron</ref>

Serotonin has broad activities in the brain, and genetic variation in serotonin receptors and the serotonin transporter, which facilitates reuptake of serotonin into presynapses, have been implicated in neurological diseases. Drugs targeting serotonin-induced pathways are being used in the treatment of many psychiatric disorders, and one focus of clinical research is the influence of genetics on serotonin action and metabolism in psychiatric settings. Such studies have revealed that the variation in the promoter region of the serotonin transporter protein accounts for nearly 10% of total variance in anxiety-related personality,<ref> Lesch, K.; Bengel, D.; Heils, A.; Sabol, S. Z.; Greenberg, B. D.; Petri, S.; Clemens, R.; Müller, J. B.; Hamer, D. H.; Murphy, D. L. (1996). "Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region". Science 274: 1527–31. doi:10.1126/science.274.5292.1527. PMID 8929413. </ref> and the effect of this gene on depression was found to interact with the environment.<ref>Caspi, A.; Sugden, K.; Moffitt, T. E.; Taylor, A.; Craig, I. W.; Harrington, W.; McClay, J.; Mill, J.; Martin, J.; Braithwaite, A.; Poulton, R. (2003). "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene". Science 301: 386–89. doi:10.1126/science.1083968. PMID 12869766. </ref>

Levels of serotonin in the brain show association with aggression <ref> Caspi N, Modai I, Barak P, Waisbourd A, Zbarsky H, Hirschmann S, Ritsner M. (2001 Mar). "Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study". Int Clin Psychopharmacol. 16(2): 111-5. PMID 11236069. </ref>, and a mutation in the gene which codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype.<ref>Basky, Greg (May 2000). "Suicide linked to serotonin gene". CMAJ 162 (9). </ref>

Using the ultimatum game as model, it was shown that people whose serotonin levels have been artificially lowered will reject unfair offers more often than players with normal serotonin levels.<ref>Crockett, M. J.; Clark, L.; Tabibnia, G.; Lieberman, M. D.; Robbins, T. W. (June 2008). "Serotonin modulates behavioral reactions to unfairness". Science (journal) 320 (5884). doi:10.1126/science.1155577. PMID 18535210. </ref>

In addition, serotonin is also a peripheral signal mediator. It is found extensively in the human gastrointestinal tract as about 80-90% of the body's total serotonin is found in the enterochromaffin cells in the gut.<ref>Indiana State University</ref><ref>[1] Serotonin tests info, Accessed May 6, 2008</ref> In the blood, the major storage site is platelets, which collect serotonin for use in mediating post-injury vasoconstriction.<ref>Essentials of Human Anatomy & Physiology, Eighth Edition, p. 336</ref>

Recent research suggests that serotonin plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout the body. Recent research also suggests that intestinal serotonin may inhibit bone formation.<ref>http://www.sciencedaily.com/releases/2008/11/081126122209.htm</ref><ref>Cell 135, 825–837, November 28, 2008</ref>

[edit] Serotonin and SIDS

Defective signalling of serotonin in the brain may be the root cause of sudden infant death syndrome (SIDS), Italian researchers have found. Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy,<ref> Audero, Enrica; Coppi, Elisabetta; Mlinar, Boris; Rossetti, Tiziana; Caprioli, Antonio; Al Banchaabouchi, Mumna; Corradetti, Renato; Gross, Cornelius (2008). "Sporadic Autonomic Dysregulation and Death Associated with Excessive Serotonin Autoinhibition". Science 321: 130–133. doi:10.1126/science.1157871. PMID 18599790. </ref> genetically modified lab mice to produce low levels of the brain signaling protein serotonin. The results showed the mice suffered drops in heart rate and other symptoms of SIDS, and many of the animals died at an early age.

Researchers now believe that low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may have caused sudden death, researchers said in the July 4, 2008 issue of Science.<ref>Lesurtel, M. et al. (2006). "Platelet-derived serotonin mediates liver regeneration". Science 312 (5770): 104–7. doi:10.1126/science.1123842. PMID 16601191. </ref>

[edit] Anatomy

[edit] Gross anatomy

The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.<ref>Template:Cite book</ref> The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation.<ref>|The Raphe nuclei group of neurons are located along the brain stem from the labels 'Mid Brain' to 'Oblongata', centered on the pons. (See relevant image.)</ref>

Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching large areas of the brain. Axons of neurons in the caudal raphe nuclei terminate in the following locations:

On the other hand, axons of neurons in the rostral raphe nuclei terminate in e.g.:

Thus, activation of this serotonin system has effects on large areas of the brain.

[edit] Microanatomy

Serotonin is released from serotonergic varicosities (swellings) into the extra neuronal space, but not from synaptic terminal boutons as other neurotransmitters. Template:Fact Serotonin diffuses over a relatively wide gap (>20µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.

[edit] Receptors

Main article: 5-HT receptor

5-HT receptors are the receptors for serotonin. They are located on the cell membrane of 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 hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade. Template:Fact

[edit] Termination

Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).

Interestingly, a 2006 study conducted by the University of Washington suggested that a newly discovered monoamine transporter, known as PMAT, may account for 'a significant percentage of 5-HT clearance.<ref>Template:Cite book</ref>' Contrasting with the high-affinity SERT, the PMAT has been identified as a low affinity transporter with an apparent Km of 114 micromoles/L for serotonin; 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."
The study also suggests that some SSRIs, such as fluoxetine and sertraline, inhibit PMAT but at IC50 values which surpass therapeutic plasma concentrations by up to four magnitudes of ten; ergo, SSRI monotherapy is ineffective in PMAT inhibition. At present, there are no known pharmaceuticals which would appreciably inhibit PMAT at normal therapeutic doses. The PMAT also suggestively transports dopamine and norepinephrine albeit at Km values even higher than that of 5-HT (330–15,000 micromoles/L).

[edit] Endothelial cell function and Serotonin

5-hydroxytryptamine evokes endothelial nitric oxide synthase activation and stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.<ref>McDuffie, J. E. (March 2000). "-hydroxytryptamine stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures". J. Cardiovasc. Pharmacol. 35 (3). </ref>

[edit] Biosynthesis

Image:Serotonin biosynthesis.svg
The pathway for the synthesis of serotonin from tryptophan

In animals including humans, serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a brain-specific isoform. There is evidence that genetic polymorphisms in both these subtypes influence susceptibility to anxiety and depression in humans. There is also evidence that ovarian hormones can affect the expression of TPH in various species, suggesting a possible mechanism for postpartum depression and premenstrual stress syndrome.Template:Fact Serotonin biosynthesis in plants likewise begins with L-tryptophan, which is however first decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by the cytochrome P450 monooxygenase, tryptamine 5-hydroxylase, yielding serotonin.<ref name="Schröder et al">Schröder P, Abele C, Gohr P, Stuhlfauth-Roisch U, Grosse W. (1999). "Latest on enzymology of serotonin biosynthesis in walnut seeds". Adv Exp Med Biol. 467: 637-644. PMID 10721112. </ref>

Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as dietary supplements and may be effective serotonergic agents.

One product of serotonin breakdown is 5-Hydroxyindoleacetic acid (5 HIAA), which is excreted in the urine. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors.

[edit] Drugs targeting the 5-HT system

Several classes of drugs target the 5-HT system including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs as well as the psychedelic drugs and empathogens.

[edit] Psychedelic drugs

The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD mimic the action of serotonin primarily at 5-HT2A receptor. The empathogen MDMA (ecstasy) releases serotonin from synaptic vesicles of neurons.

[edit] Antidepressants

The MAOIs prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content and certain drugs.

Some drugs inhibit the re-uptake of serotonin, making it stay in the synapse longer. The tricyclic antidepressants (TCAs) inhibit the re-uptake of both serotonin and norepinephrine. The newer selective serotonin re-uptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs.

SSRI medications have been shown to lower serotonin levels below initial level over time, despite initial increases in serotonin.<ref name="benmansour">Benmansour, Saloua et al., Effects of Chronic Antidepressant Treatments on Serotonin Transporter Function, Density, and mRNA Level. Journal of Neuroscience, 1999, 19(23):10494-10501. http://www.jneurosci.org/cgi/content/full/19/23/10494 </ref> This decrease in level did not rectify after the medicine was discontinued. However, the novel antidepressant Tianeptine, selective serotonin reuptake enhancer, has mood elevating effects. This has given evidence to the theory that serotonin is most likely used to regulate the extent or intensity of moods, and that low levels are what's associated with SSRI sexual dysfunction and/or "mood blunting" experienced by people on these medications.

[edit] Antiemetics

5-HT3 antagonists such as ondansetron, granisetron, and tropisetron are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in the treatment of post-operative nausea and vomiting. Applications to the treatment of depression and other mental and psychological conditions have also been investigated with some positive results.

[edit] Pathology

If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).<ref name="SIDS">Paterson, D. S.; Trachtenberg, F. L.; Thompson, E.G.; et al. (November 2006). "Multiple serotonergic brainstem abnormalities in sudden infant death syndrome". JAMA 296 (17): 2124–32. doi:10.1001/jama.296.17.2124. PMID 17077377. </ref><ref>Sciencedaily Report Anger and Aggression in Women: Blame It On Genetics</ref> Low levels of serotonin may also be associated with intense spiritual experiences.<ref>Farde, Lars; and Borg, Jacqueline; Section of psychiatry at Karolinska Institutet in Stockholm, Sweden 2003, the study and a vulgarized article</ref>

Recent research conducted at Rockefeller University shows that both in patients who suffer from depression and in mice that model the disorder, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.<ref>Svenningsson, P. et al. (2006). "Alterations in 5-HT1B receptor function by p11 in depression-like states". Science 311 (5757): 77–80. doi:10.1126/science.1117571. PMID 16400147. </ref>

Obsessive-compulsive disorder (OCD) can be a debilitating disorder with the following two anxiety-related essential features: obsessions (undesirable, recurrent, disturbing thoughts) and compulsions (repetitive or ritualized behaviors). SSRIs, and other medicines which alter serotonin levels, have been approved to be used to treat symptoms of OCD.

[edit] Serotonin syndrome

Main article: serotonin syndrome

Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a condition known as serotonin syndrome. In practice, such toxic levels are essentially impossible to reach through an overdose of a single anti-depressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI.<ref>Isbister, G. K.; Bowe, S. J.; Dawson, A.; Whyte, I. M. (2004). "Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose". J. Toxicol. Clin. Toxicol. 42 (3): 277–85. PMID 15362595. </ref> The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels.<ref>Dunkley, E. J.; Isbister, G. K.; Sibbritt, D.; Dawson, A. H.; Whyte, I. M. (September 2003). "The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity". QJM 96 (9): 635–42. PMID 12925718. </ref> For example, recreational doses of MDMA (ecstasy) will generally cause such symptoms but only rarely lead to true toxicity.Template:Fact

[edit] Chronic diseases resulting from serotonin 5-HT2B overstimulation

Main article: Cardiac fibrosis

In blood, serotonin stored in platelets is active wherever platelets bind, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic, to aid healing. Because of these effects, overdoses of serotonin, or serotonin agonist drugs, may cause acute or chronic pulmonary hypertension from pulmonary vasoconstriction, or else syndromes of retroperitoneal fibrosis or cardiac valve fibrosis (endocardial fibrosis) from overstimulation of serotonic growth receptors on fibrocytes.Template:Fact

Serotonin itself may cause a syndrome of cardiac fibrosis when it is eaten in large quantities in the diet (the Matoki banana of East Africa) or when it is over-secreted by certain mid-gut carcinoid tumors.Template:Fact The valvular fibrosis in such cases is typically on the right side of the heart, since excess serotonin in the serum outside platelets is metabolized in the lungs, and does not reach the left circulation.Template:Fact

Serotonergic agonist drugs in overdose in experimental animals not only cause acute (and sometimes fatal) pulmonary hypertension, but there is epidemiologic evidence that chronic use of certain of these drugs produce a chronic pulmonary hypertensive syndrome in humans.Template:Fact Some serotonergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as cardiac valve fibrosis.<ref name=Baskin>Template:Cite book</ref>

In the past, three groups of serotonergic drugs have been epidemiolgically linked with these syndromes. They are the serotonergic vasoconstrictive anti-migraine drugs (ergotamine and methysergide),<ref name=Baskin/> the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride.<ref> Jähnichen, S.; Horowski, R.; Pertz, H. Template:PDFlink Presentation. Retrieved on 2007-03-30.</ref> As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was in decreasing use since reported in 2003 to be associated with cardiac fibrosis.<ref>ADRAC (August 2004). "Cardiac valvulopathy with pergolide". Aust Adv Drug React Bull 23 (4).  Free full text from the Australian Therapeutic Goods Administration</ref> Two independent studies published in the New England Journal of Medicine in January 2007, implicated pergolide along with cabergoline in causing valvular heart disease.<ref>Template:Citation</ref><ref>Template:Citation</ref> As a result of this, the FDA removed pergolide from the U.S. market in March, 2007.<ref>Template:Cite web</ref> (Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).<ref name="FDAwithdraw">Template:Cite web</ref>

Because neither the amino acid L-tryptophan nor the SSRI-class antidepressants raise blood serotonin levels Template:Fact, they are not under suspicion to cause the syndromes described. However, since 5-hydroxytryptophan (5-HTP) does raise blood serotonin levels, it is under some of the same scrutiny as actively serotonergic drugs.Template:Fact

[edit] In unicellular organisms

Serotonin is used by a variety of single-cell organisms for various purposes. Selective serotonin re-uptake inhibitors (SSRIs) have been found to be toxic to algae.<ref>Johnson, D. J.; Sanderson, H.; Brain, R. A.; Wilson, C. J.; Solomon, K. R. (2007). "Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae". Ecotoxicol. Environ. Saf. 67 (1): 128–39. doi:10.1016/j.ecoenv.2006.03.016. PMID 16753215. </ref> The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.<ref>McGowan, K.; Kane, A.; Asarkof, N. et al. (1983). "Entamoeba histolytica causes intestinal secretion: role of serotonin". Science 221 (4612): 762–4. doi:10.1126/science.6308760. PMID 6308760. </ref><ref>McGowan, K.; Guerina, V.; Wicks, J.; Donowitz, M. (1985). "Secretory hormones of Entamoeba histolytica". Ciba Found. Symp. 112: 139–54. PMID 2861068. </ref> Patients infected with Entamoeba histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.<ref>Banu, Naheed et al. (2005). "Neurohumoral alterations and their role in amoebiasis" (PDF). Indian J. Clin Biochem 20 (2): 142–5. doi:10.1007/BF02867414. </ref> Entamoeba histolytica also responds to the presence of serotonin by becoming more virulent.<ref>Acharya, D. P.; Sen, M. R.; Sen, P. C. (1989). "Effect of exogenous 5-hydroxytryptamine on pathogenicity of Entamoeba histolytica in experimental animals". Indian J. Exp. Biol. 27 (8): 718–20. PMID 2561282. </ref>

[edit] In plants

Serotonin is found in mushrooms and plants, including fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genuses. Serotonin concentrations of 3–30 mg/kg have been found in plantain, pineapple, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.<ref>Feldman, J. M.; Lee, E. M. (October 1985). "Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid". Am. J. Clin. Nutr. 42 (4): 639–43. PMID 2413754. </ref> Serotonin is one compound of the poison contained in stinging nettles (Urtica dioica). It should be noted that serotonin, unlike its precursors 5-HTP and tryptophan, does not cross the blood–brain barrier, which means that ingesting serotonin in the diet has no effect on brain serotonin levels. Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH2) and hydroxy (OH) groups, are N-oxides, or miss the OH group. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff.

[edit] In animals

Serotonin as a neurotransmitter is found in all animals, including insects. Several toad venoms, as well as that of the Brazilian wandering spider and stingray, contain serotonin and related tryptamines. It has also been identified as the trigger for swarm behaviour in locusts<ref>http://news.bbc.co.uk/2/hi/science/nature/7858996.stm </ref>.

[edit] History

Isolated and named in 1948 by Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic,<ref>Rapport, Maurice M.; Green, Arda A.; Page, Irvine H. (December 1948). "Serum vasoconstrictor (serotonin). IV. Isolation and characterization". J. Biol. Chem. 176 (3): 1243–51. PMID 18100415. </ref> the name serotonin is something of a misnomer and reflects the circumstances of the compound's discovery. It was initially identified as a vasoconstrictor substance in blood serum – hence serotonin, a serum agent affecting vascular tone. This agent was later chemically identified as 5-hydroxytryptamine (5-HT) by Rapport, and, as the broad range of physiological roles were elucidated, 5-HT became the preferred name in the pharmacological field.

[edit] Increasing serotonin levels

Serotonin levels may be increased by supplement of tryptophan. However, increasing foods rich in tryptophan (eg, meats, proteins) do not increase serotonin levels, due to competition with other amino acids.<ref name=Young>Young, S. N. (November 2007). "How to increase serotonin in the human brain without drugs" (PDF). J. Psychiatry Neurosci. 32 (6): 394–9. PMID 18043762. PMC:2077351. Retrieved on 2008-12-30.</cite> </ref> What is required to increase serotonin production is an increase in the ratio of tryptophan to phenylalanine and leucine. Fruits with a good ratio include dates, papaya and banana. Foods with a lower ratio inhibit the production of serotonin. These include whole wheat and rye bread<ref>Nutritional Pharmacology Of Sleep & Depression</ref> Much research has indicated that vigorous aerobic exercise improves mood, believed to be facilitated by an increase in serotonin levels.<ref>Serotonin and Its Uses</ref> Research also suggests that eating a diet rich in whole grain carbohydrates and low in protein will increase serotonin by secreting insulin, which helps in amino acid competition.<ref name=Young/> However, increasing insulin for a long period of time can sometimes onset insulin resistance, which is related to obesity, type 2 diabetes, and lower serotonin levels. It is also believed that muscles use many of the amino acids except tryptophan, allowing men to have more serotonin than women.<ref>http://books.google.com/books?id=2PxhgaCThccC&pg=PA49&lpg=PA49&dq=insulin+resistance+and+serotonin&source=web&ots=udW-o42zjY&sig=rtcdA8TTAkuxSxwvrR4TxYcnF30&hl=en&sa=X&oi=book_result&resnum=3&ct=result#PPA64,M1</ref> Bright light therapy is another popular method which prevents the conversion of serotonin to melatonin.<ref>Education : Philips</ref> A similar effect is obtained by spending more time in natural sunlight. Recently, acupuncture has been shown to stimulate the release of serotonin levels in lab animals.<ref>Acupuncture Stimulates the Release of Serotonin, but Not Dopamine, in the Rat Nucleus Accumbens</ref>


KEGG Pathway(C00780)

  • Tryptophan metabolism
  • Neuroactive ligand-receptor interaction
  • Gap junction
  • Serotonin receptor agonists/antagonists
List of PDB files having estriol as a Ligand:
MMDB ID PDB ID Reference
59445 2QEH Mans BJ, Calvo E, Ribeiro JM, Andersen JFThe Crystal Structure of D7r4, a Salivary Biogenic Amine-binding Protein from the Malaria Mosquito Anopheles gambiaeJ. Biol. Chem. v282, p.36626-36633
63512 3BRN Mans BJ, Ribeiro JM, Andersen JFStructure, function, and evolution of biogenic amine-binding proteins in soft ticksJ. Biol. Chem. v283, p.18721-18733
Physiochemical properties of Estriol:
Physical Property Value Units Temp (deg C) Source
Melting Point 167.5 deg C EXP
pKa Dissociation Constant 9.97 (none) 25 EXP
log P (octanol-water) 0.21 (none) EXP
Water Solubility 2.00E+04 mg/L 27 EXP
Vapor Pressure 1.91E-06 mm Hg 25 EST
Henry's Law Constant 1.39E-14 atm-m3/mole 25 EST
Atmospheric OH Rate Constant 2.33E-10 cm3/molecule-sec 25 EST
Toxicity:
Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
cat LDLo intravenous 5mg/kg (5mg/kg) CARDIAC: OTHER CHANGES

LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION

Farmakologiya i Toksikologiya Vol. 26, Pg. 10, 1963.
guinea pig LD50 intravenous 12800ug/kg (12.8mg/kg) Archives Internationales de Pharmacodynamie et de Therapie. Vol. 168, Pg. 373, 1967.
mouse LD50 intramuscular 750mg/kg (750mg/kg) Archives Internationales de Pharmacodynamie et de Therapie. Vol. 112, Pg. 319, 1957.
mouse LD50 intraperitoneal 160mg/kg (160mg/kg) Indian Journal of Physiology and Pharmacology. Vol. 17, Pg. 31, 1973.
mouse LD50 intravenous 81mg/kg (81mg/kg) BEHAVIORAL: TREMOR

BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD

Farmakologiya i Toksikologiya Vol. 26, Pg. 10, 1963.
mouse LD50 oral 60mg/kg (60mg/kg) Meditsinskii Zhurnal Uzbekistana. Vol. (3), Pg. 61, 1985.
mouse LD50 subcutaneous 601mg/kg (601mg/kg) BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY)

BEHAVIORAL: ATAXIA

GASTROINTESTINAL: "HYPERMOTILITY, DIARRHEA"

Farmakologiya i Toksikologiya Vol. 26, Pg. 10, 1963.
mouse LD50 unreported 250mg/kg (250mg/kg) "CRC Handbook of Antibiotic Compounds," Vols.1- , Berdy, J., Boca Raton, FL, CRC Press, 1980Vol. 8(1), Pg. 122, 1982.
rat LD50 intravenous 30mg/kg (30mg/kg) Psychopharmacology Service Center, Bulletin. Vol. 2, Pg. 17, 1963.
rat LD50 subcutaneous 285mg/kg (285mg/kg) Psychopharmacology Service Center, Bulletin. Vol. 2, Pg. 17, 1963.

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