World Library  
Flag as Inappropriate
Email this Article


Article Id: WHEBN0000028764
Reproduction Date:

Title: Serotonin  
Author: World Heritage Encyclopedia
Language: English
Subject: E-55888, PNU-181731, PHA-57378, LP-44, LY-215,840
Collection: Biogenic Amines, Hydroxyarenes, Neurotransmitters, Serotonin, Serotonin Receptor Agonists, Serotonin Releasing Agents, Taar1 Agonists, Tryptamine Alkaloids
Publisher: World Heritage Encyclopedia


Skeletal formula of serotonin
Ball-and-stick model of the serotonin molecule
Space-filling model of the serotonin molecule
CAS number  YesY
ChemSpider  YesY
IUPHAR ligand
Jmol-3D images Image 1
Molecular formula C10H12N2O
Molar mass 176.215 g/mol
Appearance White powder
Melting point 167.7 °C (333.9 °F; 440.8 K) 121–122 °C (ligroin)[1]
Boiling point 416 ± 30 °C (at 760 Torr)[2]
Solubility in water slightly soluble
Acidity (pKa) 10.16 in water at 23.5 °C[3]
Dipole moment 2.98 D
MSDS External MSDS
LD50 750 mg/kg (subcutaneous, rat),[4] 4500 mg/kg (intraperitoneal, rat),[5] 60 mg/kg (oral, rat)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 YesY   YesY/N?)

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract (GI tract), platelets, and the central nervous system (CNS) of animals, including humans. It is popularly thought to be a contributor to feelings of well-being and happiness.[6]

Approximately 90% of the [7][8] The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.

Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they release serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing. There are various serotonin receptors.

Serotonin is metabolized mainly to 5-HIAA, chiefly by the liver. Metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic acid derivative. The latter is then excreted by the kidneys. One type of tumor, called carcinoid, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing (serotonin itself does not cause flushing. Potential causes of flushing in carcinoid syndrome include bradykinins, prostaglandins, tachykinins, substance P, and/or histamine), diarrhea, and heart problems. Because of serotonin's growth-promoting effect on cardiac myocytes,[9] a serotonin-secreting carcinoid tumour may cause a tricuspid valve disease syndrome, due to the proliferation of myocytes onto the valve.

In addition to animals, serotonin is found in fungi and plants.[10] Serotonin's presence in insect venoms and plant spines serves to cause pain, which is a side-effect of serotonin injection. Serotonin is produced by pathogenic amoebae, and its effect on the gut causes diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.


  • Functions 1
    • Receptors 1.1
    • Gauge of food availability (appetite) 1.2
      • Effects of food content 1.2.1
      • In the digestive tract (emetic) 1.2.2
      • Gauge of social situation 1.2.3
    • Growth and reproduction 1.3
    • Aging and age-related phenotypes 1.4
    • Bone metabolism 1.5
    • Organ development 1.6
    • Cardiovascular growth factor 1.7
    • Deficiency 1.8
  • In the brain 2
    • Gross anatomy 2.1
    • Microanatomy 2.2
      • Receptors 2.2.1
      • Termination 2.2.2
      • Serotonylation 2.2.3
  • Biosynthesis 3
  • Drugs targeting the 5-HT system 4
    • Psychedelic drugs 4.1
    • Antidepressants 4.2
      • Serotonin syndrome 4.2.1
    • Antiemetics 4.3
  • In unicellular organisms 5
  • In plants 6
    • Methyl-tryptamines and hallucinogens 6.1
  • Insect venom 7
  • History 8
  • Notes 9
  • References 10
  • External links 11


Serotonin is a neurotransmitter and is found in all

  • 5-Hydroxytryptamine MS Spectrum
  • Serotonin bound to proteins in the PDB
  • PsychoTropicalResearch Extensive reviews on serotonergic drugs and Serotonin Syndrome.
  • Molecule of the Month: Serotonin at University of Bristol
  • 60-Second Psych: No Fair! My Serotonin Level Is Low, Scientific American
  • Serotonin Test Interpretation on ClinLab Navigator.
  • Gutknecht L, Jacob C, Strobel A et al. (June 2007). "Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation". The International Journal of Neuropsychopharmacology 10 (3): 309–20.  
  • The Psychobiology of Serotonin Deficiency Syndrome

External links

  1. ^ Pietra, S.;Farmaco, Edizione Scientifica 1958, Vol. 13, pp. 75–9.
  2. ^ Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994–2011 ACD/Labs)
  3. ^ Mazák, K.; Dóczy, V.; Kökösi, J.; Noszál, B. (2009). "Proton Speciation and Microspeciation of Serotonin and 5-Hydroxytryptophan". Chemistry & Biodiversity 6 (4): 578–90.  
  4. ^ Erspamer, Vittorio (1952). Ricerca Scientifica 22: 694–702. 
  5. ^ Tammisto, Tapani (1968). Annales Medicinae Experimentalis et Biologiea Fenniae 46 (3, Pt. 2): 382–4. 
  6. ^ Young SN (2007). "How to increase serotonin in the human brain without drugs". Rev. Psychiatr. Neurosci. 32 (6): 394–99.  
  7. ^ King MW. "Serotonin". The Medical Biochemistry Page. Indiana University School of Medicine. Retrieved 1 December 2009. 
  8. ^ Berger M, Gray JA, Roth BL; Gray; Roth (2009). "The expanded biology of serotonin". Annu. Rev. Med. 60: 355–66.  
  9. ^ Bianchi, P. (2005). "A new hypertrophic mechanism of serotonin in cardiac myocytes: Receptor-independent ROS generation". The FASEB Journal.  
  10. ^ Kang K, Park S, Kim YS, Lee S, Back K; Park; Kim; Lee; Back (2009). "Biosynthesis and biotechnological production of serotonin derivatives". Appl. Microbiol. Biotechnol. 83 (1): 27–34.  
  11. ^ . n.p., 20 June. 2010. Web. 11 Aug. 2013.LiveStrongCoila, Bridgett. "Effects of Serotonin on the Body."
  12. ^ Roth, BL; Driscol, J (12 January 2011). Database"i"PDSP K. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 17 December 2013. 
  13. ^
  14. ^ Gonzalez, R; Chávez-Pascacio, K; Meneses, A (September 2013). "Role of 5-HT5A receptors in the consolidation of memory". Behavioural Brain Research 252: 246–251.  
  15. ^ Jonz, Michael G.Riga, EkateriniMercier, A. JoffrePotter, John W. "Effects Of 5-HT (Serotonin) On Reproductive Behaviour In Heterodera Schachtii (Nematoda)." Canadian Journal Of Zoology 79.9 (2001): 1727. Canadian Reference Centre. Web. 11 August 2013.
  16. ^ Sawin ER, Ranganathan R, Horvitz HR; Ranganathan; Horvitz (2000). "C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway". Neuron 26 (3): 619–31.  
  17. ^ Niacaris T, Avery L; Avery (2003). "Serotonin regulates repolarization of the C. elegans pharyngeal muscle". J. Exp. Biol. 206 (Pt 2): 223–31.  
  18. ^ Stahl SM, Mignon L, Meyer JM; Mignon; Meyer (2009). "Which comes first: atypical antipsychotic treatment or cardiometabolic risk?". Acta Psychiatr Scand 119 (3): 171–9.  
  19. ^ Buckland PR, Hoogendoorn B, Guy CA, Smith SK, Coleman SL, O'Donovan MC; Hoogendoorn; Guy; Smith; Coleman; O'Donovan (2005). "Low gene expression conferred by association of an allele of the 5-HT2C receptor gene with antipsychotic-induced weight gain". Am J Psychiatry 162 (3): 613–5.  
  20. ^ Holmes MC, French KL, Seckl JR; French; Seckl (1997). "Dysregulation of diurnal rhythms of serotonin 5-HT2C and corticosteroid receptor gene expression in the hippocampus with food restriction and glucocorticoids". J. Neurosci. 17 (11): 4056–65.  
  21. ^ Leibowitz SF (1990). "The role of serotonin in eating disorders". Drugs. 39 Suppl 3: 33–48.  
  22. ^ Wurtman, RJ; Hefti, F; Melamed, E (1980). "Precursor control of neurotransmitter synthesis". Pharmacol Rev 32: 315–35. 
  23. ^ a b c Young SN (2007). "How to increase serotonin in the human brain without drugs". J Psychiatry Neurosci 32 (6): 394–9.  
  24. ^ "Insulin Resistance". 
  25. ^ "Insulin Resistance and Diabetes". 
  26. ^ Grossman, Mary H.; Hart, Cheryle R. (2008). The Feel-Good Diet. New York: McGraw-Hill. p. 64.  
  27. ^ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 187.  
  28. ^ de Wit R, Aapro M, Blower PR; Aapro; Blower (2005). "Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients?". Cancer Chemother Pharmacol 56 (3): 231–8.  
  29. ^ Kravitz EA (1988). "Hormonal control of behavior: amines and the biasing of behavioral output in lobsters". Science 241 (4874): 1775–81.  
  30. ^ Yeh SR, Fricke RA, Edwards DH; Fricke; Edwards (1996). "The effect of social experience on serotonergic modulation of the escape circuit of crayfish". Science 271 (5247): 366–9.  
  31. ^ McGuire, Michael (2013) "Believing,the neuroscience of fantasies, fears and confictions" (Prometius Books)
  32. ^ Caspi N, Modai I, Barak P, Waisbourd A, Zbarsky H, Hirschmann S, Ritsner M.; Modai; Barak; Waisbourd; Zbarsky; Hirschmann; Ritsner (Mar 2001). "Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study". Int Clin Psychopharmacol. 16 (2): 111–5.  
  33. ^ Basky, Greg (2000). "Suicide linked to serotonin gene".  
  34. ^ Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL; Bengel; Heils; Sabol; Greenberg; Petri; Benjamin; Müller; Hamer; Murphy (1996). "Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region". Science 274 (5292): 1527–31.  
  35. ^ Srinivasan S, Sadegh L, Elle IC, Christensen AG, Faergeman NJ, Ashrafi K; Sadegh; Elle; Christensen; Faergeman; Ashrafi (2008). "Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms". Cell Metab. 7 (6): 533–44.  
  36. ^ Loer CM, Kenyon CJ; Kenyon (1993). "Serotonin-deficient mutants and male mating behavior in the nematode Caenorhabditis elegans". J. Neurosci. 13 (12): 5407–17.  
  37. ^ Lipton J, Kleemann G, Ghosh R, Lints R, Emmons SW; Kleemann; Ghosh; Lints; Emmons (2004). "Mate searching in Caenorhabditis elegans: a genetic model for sex drive in a simple invertebrate". J. Neurosci. 24 (34): 7427–34.  
  38. ^ Murakami, H; Murakami, S (2007). "Serotonin receptors antagonistically modulate Caenorhabditis elegans longevity". Aging cell 6 (4): 483–8.  
  39. ^ Murakami H, Murakami S; Murakami (August 2007). "Serotonin receptors antagonistically modulate Caenorhabditis elegans longevity". Aging Cell 6 (4): 483–8.  
  40. ^ Murakami H, Bessinger K, Hellmann J, Murakami S; Bessinger; Hellmann; Murakami (July 2008). "Manipulation of serotonin signal suppresses early phase of behavioral aging in Caenorhabditis elegans". Neurobiol. Aging 29 (7): 1093–100.  
  41. ^ Frost M, Andersen TE, Yadav V, Brixen K, Karsenty G, Kassem M; Andersen; Yadav; Brixen; Karsenty; Kassem (2010). "Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin". J Bone Miner Res. 25 (3): 673–5.  
  42. ^ Rosen CJ (2009). "Breaking into bone biology: serotonin's secrets". Nat Med. 15 (2): 145–6.  
  43. ^ Mödder UI, Achenbach SJ, Amin S, Riggs BL, Melton LJ 3rd, Khosla S; Achenbach; Amin; Riggs; Melton Lj; Khosla (2010). "Relation of serum serotonin levels to bone density and structural parameters in women". J Bone Miner Res. 25 (2): 415–22.  
  44. ^ Frost M, Andersen T, Gossiel F, Hansen S, Bollerslev J, Van Hul W, Eastell R, Kassem M, Brixen K.; Andersen; Gossiel; Hansen; Bollerslev; Van Hul; Eastell; Kassem; Brixen (2011). "Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high bone mass phenotype due to a mutation in Lrp5". J Bone Miner Res. 26 (8): 1721–8.  
  45. ^ Kode A, Mosialou I, Silva BC, Rached MT, Zhou B, Wang J, Townes TM, Hen R, Depinho RA, Guo XE, Kousteni S.; Mosialou; Silva; Rached; Zhou; Wang; Townes; Hen; Depinho; Guo; Kousteni (2012). "FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin". J Clin Invest. 122 (10): 3490–503.  
  46. ^ Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P.; Balaji; Suresh; Liu; Lu; Li; Guo; Mann; Balapure; Gershon; Medhamurthy; Vidal; Karsenty; Ducy (2010). "Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis". Nat Med. 16 (3): 308–12.  
  47. ^ Ozanne, S.E.; Hales, C.N. (2004). "Lifespan: catch-up growth and obesity in male mice". Nature. 427 (6973): 411–2.  
  48. ^ Lewis, D.S.; Bertrand, H.A.; McMahan, C.A.; McGill Jr, Mcgill H.C.; Carey, K.D.; Masoro, E.J. (1986). "Preweaning food intake influences the adiposity of young adult baboons". J Clin Invest 78 (4): 899–905.  
  49. ^ Hahn, P. (1984). "Effect of litter size on plasma cholesterol and insulin and some liver and adipose tissue enzymes in adult rodents". J Nutr. 114 (7): 1231–4.  
  50. ^ Popa D, Léna C, Alexandre C, Adrien J; Léna; Alexandre; Adrien (April 2008). "Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: evidence from sleep, stress, and behavior". The Journal of Neuroscience 28 (14): 3546–54.  
  51. ^ Maciag D, Simpson KL, Coppinger D et al. (January 2006). "Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry". Neuropsychopharmacology 31 (1): 47–57.  
  52. ^ Maciag D, Williams L, Coppinger D, Paul IA; Williams; Coppinger; Paul (February 2006). "Neonatal citalopram exposure produces lasting changes in behavior that are reversed by adult imipramine treatment". European Journal of Pharmacology 532 (3): 265–9.  
  53. ^ Holden C (October 2004). "Neuroscience. Prozac treatment of newborn mice raises anxiety". Science 306 (5697): 792.  
  54. ^ Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA; Zhou; Lira; Hen; Gingrich (October 2004). "Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice". Science 306 (5697): 879–81.  
  55. ^ Kaplan DD, Zimmermann G, Suyama K, Meyer T, Scott MP; Zimmermann; Suyama; Meyer; Scott (2008). "A nucleostemin family GTPase, NS3, acts in serotonergic neurons to regulate insulin signaling and control body size". Genes Dev. 22 (14): 1877–93.  
  56. ^ Ruaud AF, Thummel CS; Thummel (2008). "Serotonin and insulin signaling team up to control growth in Drosophila". Genes Dev. 22 (14): 1851–5.  
  57. ^ Anstey ML, Rogers SM, Ott SR, Burrows M, Simpson SJ; Rogers; Ott; Burrows; Simpson (2009). "Serotonin mediates behavioral gregarization underlying swarm formation in desert locusts". Science 323 (5914): 627–30.  
  58. ^ a b c Paulmann N, Grohmann M, Voigt JP, Bert B, Vowinckel J, Bader M, Skelin M, Jevsek M, Fink H, Rupnik M, Walther DJ; Grohmann; Voigt; Bert; Vowinckel; Bader; Skelin; Jevsek; Fink; Rupnik; Walther (2009). O'Rahilly, Steve, ed. "Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation". PLoS Biol. 7 (10): e1000229.  
  59. ^ Davidson S, Prokonov D, Taler M, Maayan R, Harell D, Gil-Ad I, Weizman A; Prokonov; Taler; Maayan; Harell; Gil-Ad; Weizman (2009). "Effect of exposure to selective serotonin reuptake inhibitors in utero on fetal growth: potential role for the IGF-I and HPA axes". Pediatr. Res. 65 (2): 236–41.  
  60. ^ a b Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA; Graf; Aleil; Walther; Tian; Jochum; Gachet; Bader; Clavien (2006). "Platelet-derived serotonin mediates liver regeneration". Science 312 (5770): 104–7.  
  61. ^ Matondo RB, Punt C, Homberg J, Toussaint MJ, Kisjes R, Korporaal SJ, Akkerman JW, Cuppen E, de Bruin A; Punt; Homberg; Toussaint; Kisjes; Korporaal; Akkerman; Cuppen; De Bruin (2009). "Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration". Am. J. Physiol. Gastrointest. Liver Physiol. 296 (4): G963–8.  
  62. ^ Collet C, Schiltz C, Geoffroy V, Maroteaux L, Launay JM, de Vernejoul MC; Schiltz; Geoffroy; Maroteaux; Launay; De Vernejoul (2008). "The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation". FASEB J. 22 (2): 418–27.  
  63. ^ a b Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G; Ryu; Suda; Tanaka; Gingrich; Schütz; Glorieux; Chiang; Zajac; Insogna; Mann; Hen; Ducy; Karsenty (2008). "Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum". Cell 135 (5): 825–37.  
  64. ^ a b McDuffie JE, Motley ED, Limbird LE, Maleque MA; Motley; Limbird; Maleque (2000). "5-hydroxytryptamine stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures". J. Cardiovasc. Pharmacol. 35 (3): 398–402.  
  65. ^ Marieb, Elaine Nicpon (2009). Essentials of human anatomy & physiology (Eighth ed.). San Francisco: Pearson/Benjamin Cummings. p. 336.  
  66. ^ a b Baskin SI (1991). Principles of cardiac toxicology. Boca Raton: CRC Press.  
  67. ^ Jähnichen S, Horowski R, Pertz H. Receptors"2B"Pergolide and Cabergoline But not Lisuride Exhibit Agonist Efficacy at Serotonin 5-HT. Retrieved 3 February 2010. 
  68. ^ Adverse Drug Reactions Advisory Committee,  
  69. ^ Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E; Andersohn; Suissa; Haverkamp; Garbe (2007). "Dopamine agonists and the risk of cardiac-valve regurgitation". N. Engl. J. Med. 356 (1): 29–38.  
  70. ^ Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G; Antonini; Gatto; Gentile; Tesei; Pezzoli (2007). "Valvular heart disease and the use of dopamine agonists for Parkinson's disease". N. Engl. J. Med. 356 (1): 39–46.  
  71. ^ "Food and Drug Administration Public Health Advisory". 29 March 2007. Retrieved 7 February 2010. 
  72. ^ "MedWatch – 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents". U.S.  
  73. ^ Ben Arous J, Laffont S, Chatenay D; Laffont; Chatenay (2009). Brezina, Vladimir, ed. "Molecular and sensory basis of a food related two-state behavior in C. elegans". PLoS ONE 4 (10): e7584.  
  74. ^ Sze JY, Victor M, Loer C, Shi Y, Ruvkun G; Victor; Loer; Shi; Ruvkun (2000). "Food and metabolic signaling defects in a Caenorhabditis elegans serotonin-synthesis mutant". Nature 403 (6769): 560–4.  
  75. ^ a b Côté F, Thévenot E, Fligny C et al. (2003). "Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function". Proc. Natl. Acad. Sci. U.S.A. 100 (23): 13525–30.  
  76. ^ Alenina N, Kikic D, Todiras M, Mosienko V, Qadri F, Plehm R, Boyé P, Vilianovitch L, Sohr R, Tenner K, Hörtnagl H, Bader M; Kikic; Todiras; Mosienko; Qadri; Plehm; Boyé; Vilianovitch; Sohr; Tenner; Hörtnagl; Bader (2009). "Growth retardation and altered autonomic control in mice lacking brain serotonin". Proc. Natl. Acad. Sci. U.S.A. 106 (25): 10332–7.  
  77. ^ Savelieva KV, Zhao S, Pogorelov VM et al. (2008). Bartolomucci, Alessandro, ed. "Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants". PLoS ONE 3 (10): e3301.  
  78. ^ 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".  
  79. ^ Paterson DS, Trachtenberg FL, Thompson EG, Belliveau RA, Beggs AH, Darnall R, Chadwick AE, Krous HF, Kinney HC; Trachtenberg; Thompson; Belliveau; Beggs; Darnall; Chadwick; Krous; Kinney (2006). "Multiple serotonergic brainstem abnormalities in sudden infant death syndrome". JAMA 296 (17): 2124–32.  
  80. ^ Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois JM, Nomikos GG, Greengard P; Chergui; Rachleff; Flajolet; Zhang; El Yacoubi; Vaugeois; Nomikos; Greengard (2006). "Alterations in 5-HT1B receptor function by p11 in depression-like states". Science 311 (5757): 77–80.  
  81. ^ a b Badawy, Abdulla (2000). "Serotonin:the stuff of romance". The Biochemist: 15–17. 
  82. ^ Frazer, A.; and Hensler, J. G. (1999). "Understanding the neuroanatomical organization of serotonergic cells in the brain provides insight into the functions of this neurotransmitter". In  
  83. ^ 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.)
  84. ^ Hannon J, Hoyer D; Hoyer (2008). "Molecular biology of 5-HT receptors". Behav. Brain Res. 195 (1): 198–213.  
  85. ^ Walther DJ, Peter JU, Winter S, Höltje M, Paulmann N, Grohmann M, Vowinckel J, Alamo-Bethencourt V, Wilhelm CS, Ahnert-Hilger G, Bader M; Peter; Winter; Höltje; Paulmann; Grohmann; Vowinckel; Alamo-Bethencourt; Wilhelm; Ahnert-Hilger; Bader (2003). "Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release". Cell 115 (7): 851–62.  
  86. ^ Watts SW, Priestley JR, Thompson JM; Priestley; Thompson (2009). Kreindler, James L., ed. "Serotonylation of vascular proteins important to contraction". PLoS ONE 4 (5): e5682.  
  87. ^ Alarcon, J (2008). "Biotransformation of indole derivatives by mycelial cultures". Zeitschrift für Naturforschung.C, A journal of biosciences 63: 82. 
  88. ^ Titeler M, Lyon RA, Glennon RA; Lyon; Glennon (1988). "Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens". Psychopharmacology (Berl.) 94 (2): 213–6.  
  89. ^ Nichols DE (2000). "Role of serotonergic neurons and 5-HT receptors in the action of hallucinogens". In Baumgarten HG, Gothert M. Serotoninergic Neurons and 5-HT Receptors in the CNS. Santa Clara, CA: Springer-Verlag TELOS.  
  90. ^ Kapur S, Seeman P; Seeman (2002). "NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia". Mol. Psychiatry 7 (8): 837–44.  
  91. ^ Johnson MP, Hoffman AJ, Nichols DE; Hoffman; Nichols (1986). "Effects of the enantiomers of MDA, MDMA and related analogues on [3H]serotonin and [3H]dopamine release from superfused rat brain slices". Eur. J. Pharmacol. 132 (2–3): 269–76.  
  92. ^ Willner, Paul; Hale, A.; Argyropoulos, S. (May 2005). "Dopaminergic mechanism of antidepressant action in depressed patients". Journal of Affective Disorders 86 (1): 37–45.  
  93. ^ Benmansour S, Cecchi M, Morilak DA, Gerhardt GA, Javors MA, Gould GG, Frazer A; Cecchi; Morilak; Gerhardt; Javors; Gould; Frazer (1999). "Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level". J. Neurosci. 19 (23): 10494–501.  
  94. ^ Beitchman J, Baldassarra L, Mik H, De Luca V, King N, Bender D, Ehtesham S, Kennedy J; Baldassarra; Mik; De Luca; King; Bender; Ehtesham; Kennedy (2011). "Serotonin Transporter Polymorphisms and Persistent, Pervasive Childhood Aggression". The American Journal of Psychiatry 163 (6): 1103–5.  
  95. ^ Pezawas, Lukas; Meyer-Lindenberg, Andreas; Drabant, Emily M; Verchinski, Beth A; Munoz, Karen E; Kolachana, Bhaskar S; Egan, Michael F; Mattay, Venkata S; Hariri, Ahmad R; Weinberger, Daniel R (2005). "5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: A genetic susceptibility mechanism for depression". Nature Neuroscience 8 (6): 828–34.  
  96. ^ Schinka, J A; Busch, R M; Robichaux-Keene, N (2004). "A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety". Molecular Psychiatry 9 (2): 197–202.  
  97. ^ Crockett MJ, Clark L, Tabibnia G, Lieberman MD, Robbins TW; Clark; Tabibnia; Lieberman; Robbins (2008). "Serotonin modulates behavioral reactions to unfairness". Science 320 (5884): 1739.  
  98. ^ 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.  
  99. ^ Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM; Isbister; Sibbritt; Dawson; Whyte (2003). "The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity". QJM 96 (9): 635–42.  
  100. ^ Johnson DJ, Sanderson H, Brain RA, Wilson CJ, Solomon KR; Sanderson; Brain; Wilson; Solomon (2007). "Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae". Ecotoxicol. Environ. Saf. 67 (1): 128–39.  
  101. ^ McGowan K, Kane A, Asarkof N, Wicks J, Guerina V, Kellum J, Baron S, Gintzler AR, Donowitz M; Kane; Asarkof; Wicks; Guerina; Kellum; Baron; Gintzler; Donowitz (1983). "Entamoeba histolytica causes intestinal secretion: role of serotonin". Science 221 (4612): 762–4.  
  102. ^ McGowan K, Guerina V, Wicks J, Donowitz M; Guerina; Wicks; Donowitz (1985). "Secretory hormones of Entamoeba histolytica". Ciba Found. Symp. 112: 139–54.  
  103. ^ Banu N, Zaidi KR, Mehdi G, Mansoor T; Zaidi; Mehdi; Mansoor (2005). "Neurohumoral alterations and their role in amoebiasis" (PDF). Indian J. Clin Biochem 20 (2): 142–5.  
  104. ^ Acharya DP, Sen MR, Sen PC; Sen; Sen (1989). "Effect of exogenous 5-hydroxytryptamine on pathogenicity of Entamoeba histolytica in experimental animals". Indian J. Exp. Biol. 27 (8): 718–20.  
  105. ^ Schröder P, Abele C, Gohr P, Stuhlfauth-Roisch U, Grosse W.; Abele; Gohr; Stuhlfauth-Roisch; Grosse (1999). "Latest on enzymology of serotonin biosynthesis in walnut seeds". Adv Exp Med Biol. Advances in Experimental Medicine and Biology 467: 637–644.  
  106. ^ Feldman JM, Lee EM; Lee (October 1985). "Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid". The American Journal of Clinical Nutrition 42 (4): 639–43.  
  107. ^ Pénez N, Culioli G, Pérez T, Briand JF, Thomas OP, Blache Y; Culioli; Pérez; Briand; Thomas; Blache (October 2011). "Antifouling properties of simple indole and purine alkaloids from the Mediterranean gorgonian Paramuricea clavata". Journal of Natural Products 74 (10): 2304–8.  
  108. ^ Guillén-Casla V, Rosales-Conrado N, León-González ME, Pérez-Arribas LV, Polo-Díez LM; Rosales-Conrado; León-González; Pérez-Arribas; Polo-Díez (April 2012). "Determination of serotonin and its precursors in chocolate samples by capillary liquid chromatography with mass spectrometry detection". Journal of Chromatography A 1232: 158–65.  
  109. ^ Tyler VE (September 1958). "Occurrence of serotonin in a hallucinogenic mushroom". Science 128 (3326): 718.  
  110. ^ Stanley E. Manahan, Toxicological Chemistry and Biochemistry, Third Edition. CRC Press, 2002. ISBN 9781420032123
  111. ^ Michael R. Dobbs Clinical Neurotoxicology: Syndromes, Substances, Environments, Expert Consult. Elsevier Health Sciences, 2009. ISBN 9780323070997
  112. ^ Negri L (2006). "[Vittorio Erspamer (1909–1999)]". Med Secoli (in Italian) 18 (1): 97–113.  
  113. ^ Rapport MM, Green AA, Page IH; Green; Page (December 1948). "Serum vasoconstrictor, serotonin; isolation and characterization". The Journal of Biological Chemistry 176 (3): 1243–51.  
  114. ^ FELDBERG W, TOH CC; Toh (February 1953). "Distribution of 5-hydroxytryptamine (serotonin, enteramine) in the wall of the digestive tract". The Journal of Physiology 119 (2–3): 352–62.  
  115. ^ SciFinder – Serotonin Substance Detail. Accessed (4 November 2012).
  116. ^ Twarog BM, Page IH; Page (October 1953). "Serotonin content of some mammalian tissues and urine and a method for its determination". The American Journal of Physiology 175 (1): 157–61.  


  1. ^ References are ignored for the functions of these receptors due to the fact they appear on the WorldHeritage pages for the specific receptor in question


In 1952, enteramine was shown to be the same substance as serotonin, and as the broad range of physiological roles was elucidated, the abbreviation 5-HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field.[114] Synonyms of serotonin include: 5-hydroxytriptamine, thrombotin, enteramin, substance DS, and 3-(β-Aminoethyl)-5-hydroxyindole.[115] In 1953, Betty Twarog and Page discovered serotonin in the central nervous system.[116]

In 1935, Italian Vittorio Erspamer showed an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later, Erspamer was able to show it was a previously unknown amine, which he named "enteramine".[112] In 1948, Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin.[113]


Wasps and hornets have serotonin in their venom,[110]:393-394 as do scorpions.[111]:468

Insect venom

Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH2) and (OH) groups, are N-oxides, or miss the OH group. These compounds do reach the brain, although some portion of them are metabolized by monoamine oxidase enzymes (mainly MAO-A) in the liver. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff. These compounds are widely present in the leaves of many plants, and may serve as deterrents for animal ingestion. Serotonin occurs in several mushrooms of the genus Panaeolus.[109]

Methyl-tryptamines and hallucinogens

Unlike its precursors, 5-HTP and tryptophan, serotonin does not cross the blood–brain barrier, which means ingesting serotonin in the diet has no immediate effect on brain serotonin levels.

Serotonin and tryptophan have been found in chocolate with varying cocoa contents. The highest serotonin content (2.93 µg/g) was found in chocolate with 85% cocoa, and the highest tryptophan content (13.27–13.34 µg/g) was found in 70–85% cocoa. The intermediate in the synthesis from tryptophan to serotonin, 5-hydroxytryptophan, was not found.[108]

Serotonin is one compound of the poison contained in stinging nettles (Urtica dioica), where it causes pain on injection in the same manner as its presence in insect venoms (see above). It is also naturally found in Paramuricea clavata, or the Red Sea Fan.[107]

However, since serotonin is a major gastrointestinal tract modulator, it may be produced by plants in fruits 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 mushrooms, fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genera. Serotonin concentrations of 3–30 mg/kg have been found in plantains, pineapples, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.[106]

In drying seeds, 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 L-tryptophan, which is then decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by a cytochrome P450 monooxygenase, yielding serotonin.[105]

In plants

Serotonin is used by a variety of single-cell organisms for various purposes. SSRIs have been found to be toxic to algae.[100] The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.[101][102] Patients infected with E. histolytica have been found to have highly elevated serum serotonin levels, which returned to normal following resolution of the infection.[103] E. histolytica also responds to the presence of serotonin by becoming more virulent.[104] This means serotonin secretion not only serves to increase the spread of enteamoebas by giving the host diarrhea but also serves to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing. Outside a host, the density of entoamoebas is low, hence also the serotonin concentration. Low serotonin signals to the entoamoebas 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 serotonin concentration increases.

In unicellular organisms

Some 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 postoperative nausea and vomiting.


Extremely high levels of serotonin can cause a condition known as serotonin syndrome, with toxic and potentially fatal effects. In practice, such toxic levels are essentially impossible to reach through an overdose of a single antidepressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI.[98] The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at nontoxic levels.[99]

Serotonin syndrome

Although phobias and depression might be attenuated by serotonin-altering drugs, this does not mean the individual's situation has been improved, but only the individual's perception of the environment. Sometimes, a lower serotonin level might be beneficial, for example in the ultimatum game, where players with normal serotonin levels are more prone to accept unfair offers than participants whose serotonin levels have been artificially lowered.[97]

Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases. This has been connected to the observation that the benefit of SSRIs may decrease in selected patients after a long-term treatment. A switch in medication will usually resolve this issue (up to 70% of the time).[93] The antidepressants mirtazapine and mianserin (5HT2 and 5HT3 receptors antagonists) have mood-elevating effects. This provides evidence for the theory that serotonin is most likely used to regulate the extent or intensity of moods, rather than level directly correlating with mood. In fact, the 5-HTTLPR gene codes for the number of serotonin transporters in the brain, with more serotonin transporters causing decreased duration and magnitude of serotonergic signaling.[94] The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety.[95][96] Therefore, increasing levels of extracellular serotonin may be associated with increased affect, for good or for worse.

Drugs that alter serotonin levels are used in treating depression, generalized anxiety disorder and social phobia. Monoamine oxidase inhibitors (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 synaptic cleft longer. The tricyclic antidepressants (TCAs) inhibit the reuptake of both serotonin and norepinephrine. The newer selective serotonin reuptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs. The side-effects that have become apparent recently include a decrease in bone mass in elderly and increased risk for osteoporosis. However, it is not yet clear whether it is due to SSRI action on peripheral serotonin production and or action in the gut or in the brain.[63] There is investigation into whether SSRIs benefits to mood are somehow related to dopamine receptor sensitivity indirectly influenced by antidepressant mechanisms. In one study, patients with depression taking an SSRI were given low dose D2 receptor antagonist administration, and reported negative effect on mood.[92]


The psychedelic drugs psilocin/psilocybin, DMT, mescaline, phencyclidine and LSD are agonists, primarily at 5HT2A/2C receptors.[88][89][90] The empathogen-entactogen MDMA releases serotonin from synaptic vesicles of neurons.[91]

Psychedelic drugs

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.

Drugs targeting the 5-HT system

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.

Serotonin can be synthesized from tryptophan in the lab using Aspergillus niger and Psilocybe coprophila as catalysts. The first phase to 5-hydroxytryptophan would require letting tryptophan sit in ethanol and water for 7 days, then mixing in enough HCl (or other acid) to bring the pH to 3, and then adding NaOH to make a pH of 13 for 1 hour. Asperigillus niger would be the catalyst for this first phase. The second phase to synthesizing tryptophan itself from the 5-hydroxytryptophan intermediate would require adding ethanol and water, and letting sit for 30 days this time. The next two steps would be the same as the first phase: adding HCl to make the pH = 3, and then adding NaOH to make the pH very basic at 13 for 1 hour. This phase uses the Psilocybe coprophila as the catalyst for the reaction.[87]

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 neuron-specific isoform.[75]

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

On top a L-tryptophan molecule with an arrow down to a 5-HTP molecule. Tryptophan hydroxylase catalyses this reaction with help of O2 and tetrahydrobiopterin, which becomes water and dihydrobiopterin. From the 5-HTP molecule goes an arrow down to a serotonin molecule. Aromatic L-amino acid decarboxylase or 5-Hydroxytryptophan decarboxylase catalyses this reaction with help of pyridoxal phosphate. From the serotonin molecule goes an arrow to a 5-HIAA molecule at the bottom ot the image. Monoamine oxidase catalyses this reaction, in the process O2 and water is consumed, and ammonia and hydrogen peroxide is produced.


Serotonin can also signal through a nonreceptor mechanism called serotonylation, in which serotonin modifies proteins.[58] This process underlies serotonin effects upon platelet-forming cells (thrombocytes) in which it links to the modification of signaling enzymes called GTPases that then trigger the release of vesicle contents by exocytosis.[85] A similar process underlies the pancreatic release of insulin.[58] The effects of serotonin upon vascular smooth muscle tone (this is the biological function from which serotonin originally got its name) depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.[86]


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 some SSRIs, such as fluoxetine and sertraline, inhibit PMAT but at IC50 values which surpass the therapeutic plasma concentrations by up to four orders of magnitude; therefore, SSRI monotherapy is "ineffective" in PMAT inhibition. At present, no known pharmaceuticals are known to 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 μmoles/L).

Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is accomplished 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 and selective serotonin reuptake inhibitors (SSRIs). A 2006 study conducted by the University of Washington suggested a newly discovered monoamine transporter, known as PMAT, may account for "a significant percentage of 5-HT clearance".[64]


The 5-HT receptors, the receptors for serotonin, 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.[84]


Serotonin is released into the space between neurons, and diffuses over a relatively wide gap (>20 µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.


The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.[82] There are 7 or 8 raphe nuclei (some scientists chose to group the nuclei raphes lineares into one nucleus), all of which located along the midline of the brainstem, and centered around the reticular formation.[83] 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.

Gross anatomy

 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 axons upwards to the whole cerebrum, and one collection next to the cerebellum that sends axons downwards the spinal cord. Slightly forward the upper serotonergic neurons is the ventral tegmental area (VTA), the dopaminergic neurons there sends axons to the nucleus accumbens, hippocampus and the frontal cortex. Over the VTA is another collection of dopamine cells, the substansia nigra, which send axons to the striatum.
Serotonin system, contrasted with the dopamine system

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 axons upwards to the whole cerebrum, and one collection next to the cerebellum that sends axons downwards the spinal cord. Slightly forward the upper serotonergic neurons is the ventral tegmental area (VTA), the dopaminergic neurons there sends axons to the nucleus accumbens, hippocampus and the frontal cortex. Over the VTA is another collection of dopamine cells, the substansia nigra, which send axons to the striatum.

In the brain

Consumption of an average amount of alcohol (.8g/kg of body weight) shows to decrease tryptophan by about 25%, leading to a similar decrease in serotonin. The sexual and impulsive behavior resulting from an intoxicated state is at least partially an effect of the decrease in serotonin because serotonin regulates these behaviors.[81]

Depletion of serotonin is common between disorders such as obsessive-compulsive disorder, depression, and anxiety. However, Dr. Marazziti and his researchers at the University of Pisa in Italy, found that depletion of serotonin also occurs in people who have recently fallen in love. This leads to the obsessive component associated with early stages of love.[81]

Recent research conducted at Rockefeller University shows, in both patients who suffer from depression and mice that model the disorder, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.[80]

In humans, defective signaling of serotonin in the brain may be the root cause of sudden infant death syndrome (SIDS). Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy[78] genetically modified lab mice to produce low levels of the neurotransmitter 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 low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may have caused sudden death.[60] If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).[79]

Genetically altered mice that lack TPH2 are normal when they are born. However, after three days, they appear to be smaller and weaker, and have softer skin than their siblings. In a purebred strain, 50% of the mutants died during the first four weeks, but in a mixed strain, 90% survived. Normally, the mother weans the litter after three weeks, but the mutant animals needed five weeks. After that, they caught up in growth and had normal mortality rates. Subtle changes in the autonomic nervous system are present, but the most obvious difference from normal mice is the increased aggressiveness and impairment in maternal care of young.[76] Despite the blood–brain barrier, the loss of serotonin production in the brain is partially compensated by intestinal serotonin. The behavioural changes become greatly enhanced if one crosses TPH1- with TPH2-lacking mice and gets animals that lack TPH entirely.[77]

Serotonin in mammals is made by two different tryptophan hydroxylases: TPH1 produces serotonin in the pineal gland and the enterochromaffin cells, while TPH2 produces it in the raphe nuclei and in the myenteric plexus. Genetically altered mice lacking TPH1 develop progressive loss of heart strength early on. They have pale skin and breathing difficulties, are easily tired, and eventually die of heart failure.[75]

Genetically altered C. elegans worms that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a dormant larval state.[73][74]


Two independent studies published in the New England Journal of Medicine in January 2007, implicated pergolide, along with cabergoline, in causing valvular heart disease.[69][70] As a result of this, the FDA removed pergolide from the U.S. market in March 2007.[71] (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).[72]

Some serotonergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as cardiac valve fibrosis.[66] In the past, three groups of serotonergic drugs have been epidemiologically linked with these syndromes. They are the serotonergic vasoconstrictive antimigraine drugs (ergotamine and methysergide),[66] 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.[67] As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was declining in use since reported in 2003 to be associated with cardiac fibrosis.[68]

Serotonin, in addition, evokes endothelial nitric oxide synthase activation and stimulates, through a 5-HT1B receptor-mediated mechanism, the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.[64] In blood, serotonin is collected from plasma by platelets, which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing.[65]

Cardiovascular growth factor

In the fruitfly, where insulin both regulates blood sugar and acts as a growth factor, serotonergic neurons regulate the adult body size by affecting insulin secretion.[55][56] Serotonin has also been identified as the trigger for swarm behavior in locusts.[57] In humans, though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones, so serotonin suppresses insulin release from the beta cells in the pancreas,[58] and exposure to SSRIs reduces fetal growth.[59] Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors.[60] Serotonin present in the blood then stimulates cellular growth to repair liver damage.[61] 5HT2B receptors also activate osteocytes, which build up bone[62] However, serotonin also inhibits osteoblasts, through 5-HT1B receptors.[63]

Since serotonin signals resource availability it is not surprising that it affects organ development. Many human and animal studies have shown that nutrition in early life can influence, in adulthood, such things as body fatness, blood lipids, blood pressure, atherosclerosis, behavior, learning and longevity.[47][48][49] Rodent experiments shows that early life exposure to SSRI:s makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes,[50][51] which are reversed by treatment with antidepressants.[52] By treating normal and knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.[53][54]

Organ development

In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass.[41][42][43][44] Mice that lack brain serotonin have osteopenia, while mice that lack gut serotonin have high bone density. In humans, increased blood serotonin levels have been shown to be significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through 5-HT1B receptors, it negatively regulates bone mass, while it does so positively through 5-HT2B receptors and 5-HT2C receptors. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events.[45] These studies have opened a new area of research in bone metabolism that can be potentially harnessed to treat bone mass disorders.[46]

Bone metabolism

Serotonin is known to regulate aging, learning and memory. The first evidence comes from the study of longevity in C. elegans.[39] During early phase of aging, the level of serotonin increases, which alters locomotory behaviors and associative memory.[40] 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 phase of aging.

Aging and age-related phenotypes

In the nematode C. elegans, artificial depletion of serotonin or the increase of octopamine cues behavior typical of a low-food environment: C. 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.[35] Serotonin is necessary for normal nematode male mating behavior,[36] and the inclination to leave food to search for a mate.[37] 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,[38] which control long-term adaption.

Growth and reproduction

In humans, levels of 5-HT1A receptor activation in the brain show negative correlation with aggression,[32] and a mutation in the gene that codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype.[33] Serotonin in the brain is not usually degraded after use, but is collected by serotonergic neurons by serotonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy.[34]

With Macaque monkeys, it has been found that alpha males have twice the level of serotonin released in the brain, as measured by the levels of 5-Hydoxyindolacetic acid (5-HIAA) in the cerebro-spinal fluid, than that found in subordinate males and females. Dominance and high levels of cerebro-serotonon levels seem to go hand in hand. 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 rose to double that found in subdominant males and females. The reason why serotonin levels are only high in dominant males but not dominant females has not yet been established.[31]

If a lobster is injected with serotonin, it behaves as if it were alpha, while octopamine causes subordinate behavior.[29] A crayfish that is frightened may 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 receptors (5-HT receptors) that have opposing effects on the fight-or-flight response. The effect of 5-HT1 receptors predominates in subordinate animals, while 5-HT2 receptors predominates in dominants.[30]

How much food an animal gets not only depends on food availability but also depends on the animal's ability to compete with others. This is especially true for social animals, where the stronger individuals might steal food from the weaker (this is not to say anti-social animals do not concern themselves with the needs of others and do not steal food from others). Thus, serotonin is not only involved in the perception of food availability but also involved in social rank.

Gauge of social situation

If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting.[27] The enterochromaffin cells not only react to bad food but are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.[28]

The gut is surrounded by enterochromaffin cells, which release serotonin in response to food in the lumen. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin.

In the digestive tract (emetic)

Consuming purified tryptophan increases brain serotonin whereas eating foods containing tryptophan do not.[22] This is because the transport system which brings tryptophan across the blood-brain barrier is also selective for the other amino acids which are contained in protein food sources.[23] High plasma levels of other large neutral amino acids prevents the plasma concentration of tryptophan from increasing brain concentration levels.[23] Research also suggests eating a diet rich in carbohydrates and low in protein will increase serotonin by secreting insulin, which helps in amino acid competition.[23] However, increasing insulin for a long period may trigger the onset of insulin resistance, obesity, type 2 diabetes, and lower serotonin levels.[24][25] Muscles use 12 of the 13 amino acid groups (not using tryptophan), allowing more muscular individuals to produce more serotonin.[26]

Effects of food content

When humans smell food, dopamine is released to increase the appetite. But, unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs that block 5-HT2C receptors make the body unable to recognize when it is no longer hungry or otherwise in need of nutrients, and are associated with increased weight gain,[18] especially in people with a low number of receptors.[19] The expression of 5-HT2C receptors in the hippocampus follows a diurnal rhythm,[20] just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest.[21]

Serotonin functions as a neurotransmitter in the nervous systems of simple, as well as complex, animals. For example, in the roundworm Caenorhabditis elegans, which feeds on bacteria, serotonin is released as a signal in response to positive events, e.g., finding a new source of food or in male animals finding a female with which to mate.[15] 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.[16] The released serotonin activates the muscles used for feeding, while octopamine suppresses them.[17] Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability.

Gauge of food availability (appetite)

Binding profile of serotonin
Receptor Ki (nM)[12] Receptor function[Note 1]
5-HT1 receptor family signals via Gi/o inhibition of adenylyl cyclase.
5-HT1A 3.17 Memory (agonists ↓); learning (agonists ↓); anxiety (agonists ↓); depression (agonists ↓); positive, negative, and cognitive symptoms of schizophrenia (partial agonists ↓); analgesia (agonists ↑); aggression (agonists ↓); dopamine release in the prefrontal cortex (agonists ↑); serotonin release and synthesis (agonists ↓)
5-HT1B 4.32 Vasoconstriction (agonists ↑); aggression (agonists ↓); bone mass (↓). Serotonin autoreceptor.
5-HT1D 5.03 Vasoconstriction (agonists ↑)
5-HT1E 7.53
5-HT1F 10
5-HT2 receptor family signals via Gq activation of phospholipase C.
5-HT2A 11.55 Psychedelia (agonists ↑; antagonists ↑); depression (agonists & antagonists ↓); anxiety (antagonists ↓); positive and negative symptoms of schizophrenia (antagonists ↓); norepinephrine release from the locus coeruleus (antagonists ↑); glutamate release in the prefrontal cortex
5-HT2B 8.71 Cardiovascular functioning (agonists increase risk of pulmonary hypertension), empathy (via the spindle neurons or Von Economo neurons[13])
5-HT2C 5.02 Dopamine release into the mesocorticolimbic pathway (agonists ↓); acetylcholine release in the prefrontal cortex (agonists ↑); appetite (agonists ↓); antipsychotic effects (agonists ↑); antidepressant effects (agonists & antagonists ↑)
Other 5-HT receptors
5-HT3 ? Emesis (agonists ↑); anxiolysis (antagonists ↑)
5-HT4 125.89 Movement of food across the GI tract (agonists ↑); memory & learning (agonists ↑); antidepressant effects (agonists ↑). Signalling via Gαq activation of adenylyl cyclase.
5-HT5A 251.2 Memory consolidation.[14] Signals via Gi/o inhibition of adenylyl cyclase
5-HT6 98.41 Cognition (antagonists ↑); antidepressant effects (agonists & antagonists ↑). Gs signalling via activating adenylyl cyclase.
5-HT7 8.11 Cognition (antagonists ↑); antidepressant effects (antagonists ↑). Acts by Gs signalling via activating adenylyl cyclase.



This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.

Copyright © World Library Foundation. All rights reserved. eBooks from Project Gutenberg are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.