Oxytocin

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Oxytocin, prepro- (neurophysin I) -human
Identifiers
Symbol(s) OXT OT
Entrez 5020
OMIM 167050
RefSeq NM_000915
UniProt P01178
Other data
Locus Chr. 20 p13
Oxytocin receptor -human
Identifiers
Symbol(s) OXTR
Entrez 5021
OMIM 167055
RefSeq NM_000916
UniProt P30559
Other data
Locus Chr. 3 p25


Oxytocin (Greek: "quick birth") is a mammalian hormone that is secreted into the bloodstream from the posterior pituitary gland, and that is also released into the brain, where it has effects on social behaviors. In pregnant women, it is secreted into the blood during labor in response to distention of the cervix and it stimulates contractions of the uterus to facilitate birth. During lactation, oxytocin is secreted in response to stimulation of the nipples by the sucking of the infant, and it stimulates milk let-down in the mammary gland. Oxytocin is also secreted during orgasm in both sexes; in men it facilitates movement of sperm. In the brain, it is involved in social recognition, bonding, sexual arousal, reproductive behaviors and appetite regulation. In some species, including rats, oxytocin also promotes sodium excretion (natriuresis) and inhibits sodium appetite.[1][2][3] [4]

Synthesis, storage and release

Oxytocin neurons immunolabelled (red) in the rat paraventricular nucleus.

Oxytocin is produced by enzymatic cleavage of a large precursor protein molecule, which is the product of oxytocin mRNA; it is made in magnocellular neurosecretory cells in the supraoptic nucleus and paraventricular nucleus of the hypothalamus and is released into the blood from the posterior lobe of the pituitary gland. Oxytocin is also made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord. In the posterior pituitary, oxytocin is packaged in large, dense-core vesicles, where it is bound to neurophysin; this is a large peptide fragment of the precursor molecule from which oxytocin is derived. The folding of the neurophysin molecule is thought to be important for packaging oxytocin into the neurosecretory vesicles.[5][6][7]

Secretion of oxytocin from the neurosecretory nerve endings is regulated by the electrical activity of the oxytocin cells in the hypothalamus. These cells generate action potentials that propagate down axons to the nerve endings in the pituitary. The endings contain large numbers of oxytocin-containing vesicles, which are released by exocytosis when the nerve terminals are depolarised by action potentials. [8]

Structure and relation to vasopressin

Oxytocin is a peptide of nine amino acids (a nonapeptide). The sequence is cysteine - tyrosine - isoleucine - glutamine - asparagine - cysteine - proline - leucine - glycine (CYIQNCPLG). The cysteine residues form a cystine (disulfide) bridge, and it has a molecular mass of 1007 daltons. One international unit (IU) of oxytocin is the equivalent of about 2 micrograms of pure peptide.

The structure of oxytocin is very similar to that of vasopressin (cysteine - tyrosine - phenylalanine - glutamine - asparagine - cysteine - proline - arginine - glycine), also a nonapeptide with a sulfur bridge whose sequence differs from oxytocin by two amino acids. The two genes, in mammals, seem to be located close to each other (less than 15,000 bases apart) on the same chromosome and are transcribed in opposite directions. This is not necessarily the case in all animals (e.g., Fugu). It is thought that the two genes resulted from a gene duplication event; the ancestral gene is estimated to be about 500 million years old and is found in cyclostomes (modern members of the Agnatha) [9] A table showing the sequences of members of the vasopressin/oxytocin superfamily and the species expressing them is present in the vasopressin article. Oxytocin and vasopressin were discovered, isolated and synthesized by Vincent du Vigneaud in 1953, work for which he received the Nobel Prize in Chemistry in 1955.[10]

Oxytocin and vasopressin are the only known hormones released by the human posterior pituitary gland to act at a distance. However, oxytocin neurons make other peptides, including cholecystokinin (CCK) and dynorphin, and other substances including nitric oxide and endocannabinoids that act locally. The magnocellular neurons that make oxytocin are adjacent to magnocellular neurons that make vasopressin, and are similar in many respects.

All eutherian mammals (i.e. all mammals in which the foetus is nurtured via a placenta) make oxytocin; most marsupials (metatheria) make a closely related hormone, mesotocin, which differs from oxytocin by a single amino acid and which is equally potent at the oxytocin receptor. Thus mesotocin in marsupials is thought to reflect a neutral mutation. Mesotocin is important in both lactation and parturition in marsupials as in eutherian mammals. All non-mammalian vertebrates also have two neurohypophysial hormones - one closely related in structure and function to oxytocin and one closely related to vasopressin.[11]

Actions

Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. All physiological effects of oxytocin are mediated by the binding of oxytocin to a specific, high affinity oxytocin receptor (OXTR).[12] This is a rhodopsin-type (class I) G-protein-coupled receptor which requires Mg2+ and cholesterol. The receptor is linked through G alpha(q/11) to phospholipase C, activation of PLC causes increased production of inositol trisphosphate (IP3) and diacyl glycerol. IP3 in turn activates receptors in the sarcoplasmic reticulum of myocytes (or endoplasmic reticulum of neurones) to release calcium into the cytosol. In myocytes, this can induce a further influx of calcium from the extracellular space, and the increased intracellular calcium, after binding to calmodulin, activates myosin light chain kinase to phosphorylate myosin light chains and cause the myocyte to contract. The human oxytocin receptor gene is located on chromosome 3p25.

Peripheral (hormonal) actions

The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. Oxytocin receptors are expressed by the myoepithelial cells of the mammary gland, and in both the myometrium and endometrium of the uterus at the end of pregnancy. In some mammals, oxytocin receptors are also found in the kidney and heart. Oxytocin is also expressed in the uterus of some species, including humans,[13] and in the enteric nervous system [14]

A "milk-ejection burst" of action potentials, recorded (with a microelectrode) from a single oxytocin neuron in the rat supraoptic nucleus. In a lactating rat, in response to suckling, oxytocin neurons display such bursts every few minutes.[15]
  • Letdown reflex – in lactating (breastfeeding) mothers, oxytocin acts at the mammary glands, causing milk to be 'let down' into a collecting chamber, from where it can be extracted by sucking at the nipple. Sucking by the infant at the nipple is relayed by spinal nerves to the caudal brainstem, and from there to the hypothalamus. The stimulation causes oxytocin neurons to fire action potentials in intermittent bursts; these bursts result in the secretion of pulses of oxytocin from the neurosecretory nerve terminals of the pituary gland. [16]

Oxytocin is secreted into the blood in very large pulses during labor, and at this time the uterus is highly sensitive to its actions as the result of a dramatic increase in the expression of oxytocin receptors in both the myometrium (the muscles of the uterus) and endometrium towards the end of pregnancy. The actions of oxytocin on the myometrium directly induce uterine contractions; the actions on the endometrium result in the production of prostaglandins, which also act on the myometrium to stimulate uterine contractions. Oxytocin release during breastfeeding causes mild but often painful uterine contractions during the first few weeks of lactation. This also helps in stopping bleeding from the point at which the placenta was attached after birth. However, in knockout mice lacking oxytocin and in mice lacking the oxytocin receptor, reproductive behavior and parturition are apparently normal, indicating that other physiological mechanisms can compensate for its absence in these functions. However, in these mice there is no milk let-down in response to suckling, so oxytocin is essential for this reflex.

  • Oxytocin is secreted into the blood at orgasm – in both males and females [18] In males, OXT may facilitate sperm transport in ejaculation. At ejaculation, oxytocin secretion stimulates contractions of the male reproductive tract (the seminiferous tubules, epididymis and the prostate gland). Oxytocin is also synthesized within the mammalian testis, epididymis and prostate and the presence of receptors through the reproductive tract supports a local action for this peptide. Oxytocin also modulates androgen levels in these tissues by stimulating the conversion of testosterone to dihydrotestostone (DHT) by 5-alpha-reductase. [19]
  • Due to its similarity to vasopressin, it can reduce the excretion of urine slightly. More important, in several species, oxytocin can stimulate sodium excretion from the kidneys (natriuresis).
  • Oxytocin and oxytocin receptors are also found in the heart in some rodents, and the hormone may play a role in the embryonal development of the heart by promoting cardiomyocyte differentiation [20][21], and may also be involved in regulating the secretion of atrial natriuretic peptide. [22]

However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.[23]

Actions of oxytocin within the brain

Oxytocin secreted from the pituitary gland cannot re-enter the brain because it cannot cross the blood-brain barrier. Instead, its behavioral effects are thought to reflect release from centrally-projecting neurons (which are different from the magnocellular neurones that project to the pituitary gland), and/or release from the cell bodies and dendrites of the magnocellular neurons. Oxytocin receptors are expressed by neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus, olfactory bulb, septum and areas of the caudal brainstem including the nucleus of the solitary tract[24] Some of these sites (the nucleus of the solitary tract and spinal cord) receive a very dense innervation from parvocellular oxytocin neurons, but others (amygdala and ventromedial nucleus of the hypothalamus) have very few oxytocin-containing fibres, despite a very dense distribution of receptors. This "mismatch" has led to the suggestion that cells at these sites may be responsive to oxytocin that may be released at distant sites but which diffuses through the brain extracellular space to reach these targets.

  • Milk ejection. Oxytocin release from the dendrites of oxytocin neurons in the hypothalamus has a key role in orchestrating the synchronised bursting pattern of activity of oxytocin neurons that underlies the suckling-induced milk-ejection reflex. [25]
  • Sexual arousal. Oxytocin injected into the cerebrospinal fluid causes erections in male rats. These actions are partly at the level of the spinal cord and partly at the level of the hypothalamus (especially the ventromedial nucleus of the hypothalamus). Oxytocin also facilitates sexual behavior (lordosis) in female rats by its actions at the ventromedial nucleus.[26][27]
  • Bonding. In the Prairie Vole, oxytocin released into the brain of the female during sexual activity is important for forming a monogamous pair bond with her sexual partner. Vasopressin appears to have a similar effect in males [28] In people, plasma concentrations of oxytocin have been reported to be higher amongst people who claim to be falling in love. Oxytocin has a role in social behaviors in many species, and so it seems likely that it has similar roles in humans. It has been suggested that deficiencies in oxytocin pathways in the brain might be a feature of autism.[29]
  • Maternal behavior. Sheep and rat females given oxytocin antagonists after giving birth do not exhibit typical maternal behavior. By contrast, virgin sheep females that have been treated with estrogen show maternal behavior towards foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise. [30]
  • Appetite regulation. Oxytocin given into the brain is a potent inhibitor of appetite, via its actions in the ventromedial nucleus and in the caudal brainstem (nucleus of the solitary tract)[31] [32][33]
  • Trust. Oxytocin seems to increase trust and reduce fear in humans. In a risky investment game, experimental subjects given nasally administered oxytocin displayed "the highest level of trust" twice as often as the control group. Subjects who were told that they were interacting with a computer showed no such reaction, leading to the conclusion that oxytocin was not merely affecting risk-aversion [35] Nasally-administered oxytocin has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses) [36]. There is no conclusive evidence for access of oxytocin to the brain through intranasal administration, however. To be determined is whether or not the oxytocin administered triggers the measured responses through peripheral actions, or at certain brain regions where the blood-brain barrier is absent (e.g. the area postrema).
  • Learning and MemoryThere have been reports that certain learning and memory functions are impaired by centrally-administered oxytocin. The interpretation of these findings is controversial.[37]

Uses

Synthetic oxytocin is sold as medication under the trade names Pitocin and Syntocinon, and also as generic oxytocin. Oxytocin is destroyed in the gastrointestinal tract, and so is normally administered by injection: it has a half-life of about three minutes in the blood. When given intravenously, oxytocin does not enter the brain in significant quantities - like most peptides, it is excluded by the blood-brain barrier. Drugs administered by nasal spray are thought to have better access to the CNS, and an oxytocin nasal spray has been used to stimulate breastfeeding; however, as noted above, there is as yet little evidence that it reaches the CNS in significant quantities.

Injected oxytocin analogues are used to induce labor and support labor in case of non-progression of parturition. [38][39] These have largely replaced ergotamine as the principal agent to increase uterine tone in acute postpartum haemorrhage. Oxytocin is also used in veterinary medicine to facilitate birth and to increase milk production. The tocolytic agent atosiban (Tractocile®) acts as an antagonist of oxytocin receptors. Atosiban is registered in many countries to suppress premature labour between 24 and 33 weeks of gestation, and has fewer side-effects than drugs previously used for this purpose (ritodrine, salbutamol and terbutaline).[40]

References

  1. ↑ Lee HJ et al. (2009) Oxytocin: the great facilitator of life. Prog Neurobiol 88:127-51. Review. PMID 19482229
  2. ↑ Neumann ID (2008) Brain oxytocin: a key regulator of emotional and social behaviours in both females and males J Neuroendocrinol 20:858-65. Review. PMID 18601710
  3. ↑ Arthur P et al. (2007) Oxytocin and parturition: a role for increased myometrial calcium and calcium sensitization? Front Biosci 12:619-33. Review. PMID 17127323
  4. ↑ Caldwell HK, Young WS III (2006) Oxytocin and vasopressin: genetics and behavioral implications. In Lim R. (ed.) Handbook of Neurochemistry and Molecular Neurobiology 3rd edition, Springer, New York, pp. 573-607. 320kb PDF
  5. ↑ de Bree FM (2000)Trafficking of the vasopressin and oxytocin prohormone through the regulated secretory pathway.J Neuroendocrinol 12:589-94.Review. PMID 10844588
  6. ↑ Armstrong WE, Stern JE (1998) Phenotypic and state-dependent expression of the electrical and morphological properties of oxytocin and vasopressin neurones Prog Brain Res 119:101-13. Review. PMID 10074783
  7. ↑ Pittman QJ et al. (1998) Electrophysiological studies of neurohypophysial neurons and peptides. Prog Brain Res 119:311-20. Review. PMID 10074796
  8. ↑ Armstrong WE et al. (2002) Plasticity in the electrophysiological properties of oxytocin neurons. Microsc Res Tech 56:73-80. Review. PMID 11810710
  9. ↑ Gimpl G, Fahrenholz F (2001) The oxytocin receptor system: structure, function, and regulation Physiol Rev 81: PMID 11274341
  10. ↑ Vincent du Vigneaud Nobelwinners.com
  11. ↑ Hoyle CH (1999) Neuropeptide families and their receptors: evolutionary perspectives. Brain Res 848:1-25. Review. PMID 10612694
  12. ↑ Gimpl G et al. (2008) Oxytocin receptors: ligand binding, signalling and cholesterol dependence Prog Brain Res 170:193-204. Review. PMID 18655883
  13. ↑ Zingg HH (2001) Oxytocin and uterine activity Front Horm Res 27:57-65. Review. PMID 11450435
  14. ↑ Welch MG et al. (2009) Expression and developmental regulation of oxytocin (OT) and oxytocin receptors (OTR) in the enteric nervous system (ENS) and intestinal epithelium. J Comp Neurol 512:256-70. Review. PMID 16512355
  15. ↑ Dyball REJ, Leng G (1986) Regulation of the milk ejection reflex in the rat J Physiol 380:239-56 PMID 3612564
  16. ↑ Hatton GI, Wang YF (2008) Neural mechanisms underlying the milk ejection burst and reflex Prog Brain Res 170:155-66. Review. PMID 18655880
  17. ↑ Kamel RM (2010) The onset of human parturition Arch Gynecol Obstet 281:975-82. Review. PMID 20127346
  18. ↑ Carmichael MS et al. (1987) Plasma oxytocin increases in the human sexual response J Clin Endocrinol Metab 64:27-31 PMID 3782434
  19. ↑ Thackare H et al. (2006) Oxytocin--its role in male reproduction and new potential therapeutic uses. Hum Reprod Update 12:437-48 PMID 16436468
  20. ↑ Paquin J et al.(2002) Oxytocin induces differentiation of P19 embryonic stem cells to cardiomyocytes Proc Natl Acad Sci USA 99:9550-5 PMID 12093924
  21. ↑ Jankowski et al. (2004) Oxytocin in cardiac ontogeny. Proc Natl Acad Sci USA 101:13074-9 PMID 15316117
  22. ↑ Antunes-Rodrigues J et al. (1997) The neuroendocrine control of atrial natriuretic peptide release.Mol Psychiatry 2:359-67. Review. PMID 9322224
  23. ↑ Takayanagi Y et al. (2005) Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice Proc Natl Acad Sci USA 102:16096-101 PMID 16249339
  24. ↑ Landgraf R, Neumann ID (2004) Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol 25:150-76 PMID 15589267
  25. ↑ Bealer SL et al. (2010) Oxytocin release in magnocellular nuclei: neurochemical mediators and functional significance during gestation Am J Physiol 299:R452-8. Review. PMID 20554931
  26. ↑ Baskerville TA, Douglas AJ (2010) Dopamine and oxytocin interactions underlying behaviors: potential contributions to behavioral disorders CNS Neurosci Ther 16:e92-123. Review. PMID 20557568
  27. ↑ Pfaus JG (2009) Pathways of sexual desire J Sex Med 6:1506-33. Review. PMID 19453889
  28. ↑ Debiec J (2005) Peptides of love and fear: vasopressin and oxytocin modulate the integration of information in the amygdala Bioessays 27:869-73. Review. PMID 16108061
    • Storm EE, Tecott LH (2005) Social circuits: peptidergic regulation of mammalian social behavior Neuron 47:483-6 Review. PMID 16102531
    • Keverne EB, Curley JP (2004) Vasopressin, oxytocin and social behaviour Curr Opin Neurobiol 14:777-83 PMID 15582383
    • Averbeck BB (2010) Oxytocin and the salience of social cues Proc Natl Acad Sci U S A 107:9033-4. PMID 20448196
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  29. ↑ Lim MM, Bielsky IF, Young LJ (2005) Neuropeptides and the social brain: potential rodent models of autism Int J Dev Neurosci 23:235-43. Review, PMID 15749248
  30. ↑ Poindron P (2005) Mechanisms of activation of maternal behaviour in mammals Reprod Nutr Dev 45:341-51 Review. PMID 15982459
  31. ↑ Olszewski PK et al. (2010) Molecular, immunohistochemical, and pharmacological evidence of oxytocin's role as inhibitor of carbohydrate but not fat intake Endocrinology 151:4736-44 PMID 20685878
  32. ↑ Douglas AJ et al. (2007) Neuroendocrine mechanisms of change in food intake during pregnancy: a potential role for brain oxytocin. Physiol Behav 91:352-65 Review. PMID 17512024
  33. ↑ Nishimori K et al. (2008) New aspects of oxytocin receptor function revealed by knockout mice: sociosexual behaviour and control of energy balance Prog Brain Res 170:79-90. Review. PMID 18655874
  34. ↑ Rotzinger S et al. (2010) Behavioral effects of neuropeptides in rodent models of depression and anxiety Peptides 31:736-56. Review. PMID 20026211
  35. ↑ Kosfeld M et al. (2005) Oxytocin increases trust in humans Nature 435:673-6 PMID 15931222
  36. ↑ Kirsch P et al. (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans J Neurosci 25:11489-93 PMID 16339042
  37. ↑ McEwen BB (2004) Brain-fluid barriers: relevance for theoretical controversies regarding vasopressin and oxytocin memory research. Adv Pharmacol 50:531-92, 655-708. Review. PMID 15350270
  38. ↑ Wei SQ et al. (2010) High-dose vs low-dose oxytocin for labor augmentation: a systematic review Am J Obstet Gynecol 203:296-304 Review. PMID 20451894
  39. ↑ Smith JG, Merrill DC (2006) Oxytocin for induction of labor Clin Obstet Gynecol 49:594-608. Review. PMID 16885666
  40. ↑ Blumenfeld YJ, Lyell DJ (2009) Prematurity prevention: the role of acute tocolysis Curr Opin Obstet Gynecol 21:136-41. Review. PMID 19996866
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