Oxytocin

From Wikipedia, the free encyclopedia

Jump to: navigation, search
Oxytocin
Systematic (IUPAC) name
3-(19-amino-13-sec-butyl-7-

(carboxymethyl)-4-(2-(1-(carboxymethylamino)-5- guanidino-1-oxopentan-2-ylcarbamoyl) pyrrolidine-1-carbonyl)-16-(4-hydroxybenzyl)- 6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17- pentaazacycloicosan-10-yl)propanoic acid
Identifiers
CAS number 50-56-6
ATC code H01BB02
PubChem 439302
DrugBank BTD00016
ChemSpider 388434
Chemical data
Formula C43H66N12O12S2 
Mol. mass 1007.19 g/mol
Pharmacokinetic data
Bioavailability nil
Protein binding 30%
Metabolism hepatic oxytocinases
Half life 1–6 min
Excretion Biliary and renal
Therapeutic considerations
Pregnancy cat.

A(AU)
Legal status

POM(UK) ℞-only(US)
Routes Intranasal, IV, IM

Oxytocin (IPA: /ˌɔk.sɪ.ˈtoʊ.sɪn/) is a mammalian hormone that also acts as a neurotransmitter in the brain.

It is best known for its roles in female reproduction: it is released in large amounts after distension of the cervix and vagina during labor, and after stimulation of the nipples, facilitating birth and breastfeeding, respectively. Recent studies have begun to investigate oxytocin's role in various behaviors, including social recognition, bonding, anxiety, trust, and maternal behaviors.

Contents

[edit] Synthesis, storage and release

Oxytocin is made in magnocellular neurosecretory cells of the supraoptic and paraventricular nuclei of the hypothalamus and is stored in Herring bodies at the axon terminals in the posterior pituitary. It is then released into the blood from the posterior lobe (neurohypophysis) 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. Depending on the species, oxytocin-expressing cells are located in other areas, including the amygdala and bed nucleus of the stria terminalis. It is postulated that trusting behavior is somehow influenced by these oxytocin stimulated neurons.

In the pituitary gland, oxytocin is packaged in large, dense-core vesicles, where it is bound to neurophysin I as shown in the inset of the figure; neurophysin is a large peptide fragment of the larger precursor protein molecule from which oxytocin is derived by enzymatic cleavage.

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.

Oxytocin is also synthesized by corpora lutea of several species, including ruminants and primates. Along with estrogen, it is involved in inducing the endometrial synthesis of Prostaglandin-F2alpha to cause regression of the corpus luteum.

[edit] 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 sulfur bridge. Oxytocin has a molecular mass of 1007 daltons. One international unit (IU) of oxytocin is the equivalent of about 2 micrograms of pure peptide.

Oxytocin structure. Inset shows oxytocin bound to neurophysin

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 2 amino acids. 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 isolated and synthesized by Vincent du Vigneaud in 1953, work for which he received the Nobel Prize in Chemistry in 1955.

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 corticotropin-releasing hormone (CRH) and dynorphin, for example, that act locally. The magnocellular neurons that make oxytocin are adjacent to magnocellular neurons that make vasopressin, and are similar in many respects.

[edit] Actions

oxytocin, prepro- (neurophysin I)
Identifiers
Symbol OXT
Alt. Symbols OT
Entrez 5020
HUGO 8528
OMIM 167050
RefSeq NM_000915
UniProt P01178
Other data
Locus Chr. 20 p13

Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. The actions of oxytocin are mediated by specific, high affinity oxytocin receptors. The oxytocin receptor is a G-protein-coupled receptor which requires Mg2+ and cholesterol. It belongs to the rhodopsin-type (class I) group of G-protein-coupled receptors.

[edit] Peripheral (hormonal) actions

The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. (See oxytocin receptor for more detail on its action.)

  • 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 compressing the areola and sucking at the nipple. Sucking by the infant at the nipple is relayed by spinal nerves to the hypothalamus. The stimulation causes neurons that make oxytocin to fire action potentials in intermittent bursts; these bursts result in the secretion of pulses of oxytocin from the neurosecretory nerve terminals of the pituitary gland.
  • Uterine contraction – important for cervical dilation before birth and causes contractions during the second and third stages of labor. Oxytocin release during breastfeeding causes mild but often painful uterine contractions during the first few weeks of lactation. This also serves to assist the uterus in clotting the placental attachment point postpartum. However, in knockout mice lacking the oxytocin receptor, reproductive behavior and parturition is normal.[1]
  • The relationship between oxytocin and human sexual response is unclear. At least two non-controlled studies have found increases in plasma oxytocin at orgasm – in both men and women.[2][3] The authors of one of these studies speculated that oxytocin's effects on muscle contractibility may facilitate sperm and egg transport.[2] Murphy et al. (1987), studying men, found that oxytocin levels were raised throughout sexual arousal and there was no acute increase at orgasm. [4] A more recent study of men found an increase in plasma oxytocin immediately after orgasm, but only in a portion of their sample that did not reach statistical significance. The authors noted that these changes "may simply reflect contractile properties on reproductive tissue."[5]
  • Due to its similarity to vasopressin, it can reduce the excretion of urine slightly. More importantly, in several species, oxytocin can stimulate sodium excretion from the kidneys (natriuresis), and in humans, high doses of oxytocin can result in hyponatremia.
  • 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. [6][7] However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.[1]
  • Modulation of hypothalamic-pituitary-adrenal axis activity. Oxytocin, under certain circumstances, indirectly inhibits release of adrenocorticotropic hormone and cortisol and, in those situations, may be considered an antagonist of vasopressin. [8]

[edit] Actions of oxytocin within the brain

Oxytocin secreted from the pituitary gland cannot re-enter the brain because of the blood-brain barrier. Instead, the behavioral effects of oxytocin are thought to reflect release from centrally projecting oxytocin neurons, different from those that project to the pituitary gland. Oxytocin receptors are expressed by neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus, septum and brainstem.

  • Sexual arousal. Oxytocin injected into the cerebrospinal fluid causes spontaneous erections in rats,[9] reflecting actions in the hypothalamus and spinal cord.
  • 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.[10] Oxytocin has a role in social behaviors in many species, and so it seems likely that it has similar roles in humans.
  • Autism. Oxytocin may play a role in autism and may be an effective treatment for autism's repetitive and affiliative behaviors.[11] Two related studies in adults, in 2003 and 2007, found that oxytocin decreased repetitive behaviors and improved interpretation of emotions, but these preliminary results do not necessarily apply to children.[12]
  • Maternal behavior. Rat females given oxytocin antagonists after giving birth do not exhibit typical maternal behavior.[13] By contrast, virgin female sheep show maternal behavior towards foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise. [14]
  • Increasing trust and reducing fear. 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.[15] Nasally administered oxytocin has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses).[16] There is no conclusive evidence for access of oxytocin to the brain through intranasal administration, however.
  • Affecting generosity by increasing empathy during perspective taking. In a neuroeconomics experiment, intranasal oxytocin increased generosity in the Ultimatum Game by 80% but has no effect in the Dictator Game that measures altruism. Perspective-taking is not required in the Dictator Game, but the researchers in this experiment explicitly induced perspective-taking in the Ultimatum Game by not identifying to participants which role they would be in.[17]
  • According to some studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol) and reduces withdrawal symptoms.[18]
  • Preparing fetal neurons for delivery. Crossing the placenta, maternal oxytocin reaches the fetal brain and induces a switch in the action of neurotransmitter GABA from excitatory to inhibitory on fetal cortical neurons. This silences the fetal brain for the period of delivery and reduces its vulnerability to hypoxic damage.[19]
  • Certain learning and memory functions are impaired by centrally administered oxytocin.[9]. Also, systemic oxytocin administration can impair memory retrieval in certain aversive memory tasks. [20]
  • MDMA (ecstasy) may increase feelings of love, empathy and connection to others by stimulating oxytocin activity via activation of serotonin 5-HT1A receptors, if initial studies in animals apply to humans.[21]

[edit] Drug forms

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 therefore must be administered by injection or as nasal spray. Oxytocin has a half-life of typically about three minutes in the blood. Oxytocin given intravenously does not enter the brain in significant quantities - it is excluded from the brain by the blood-brain barrier. There is no evidence for significant CNS entry of oxytocin by nasal spray. Oxytocin nasal sprays have been used to stimulate breastfeeding but the efficacy of this approach is doubtful.[22]

Injected oxytocin analogues are used to induce labor and support labor in case of non-progression of parturition. It has 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; this drug is registered in many countries to suppress premature labour between 24 and 33 weeks of gestation. It has fewer side-effects than drugs previously used for this purpose (ritodrine, salbutamol and terbutaline). Some have suggested that the trust-inducing property of oxytocin might help those who suffer from social anxieties and mood disorders, while others have noted the potential for abuse with confidence tricks.[23][24]

[edit] Potential adverse reactions

Oxytocin is relatively safe when used at recommended doses. Potential side effects include:[citation needed]

[edit] Evolution

Virtually all vertebrates have an oxytocin-like nonapeptide hormone that supports reproductive functions and a vasopressin-like nonapeptide hormone involved in water regulation. The two genes are always located close to each other (less than 15,000 bases apart) on the same chromosome and are transcribed in opposite directions. 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]

[edit] References

  1. ^ a b 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
  2. ^ a b Carmichael MS, Humbert R, Dixen J, Palmisano G, Greenleaf W, Davidson JM (1987). "Plasma oxytocin increases in the human sexual response," J Clin Endocrinol Metab 64:27-31 PMID 3782434
  3. ^ Carmichael MS, Warburton VL, Dixen J & Davidson JM (1994). "Relationship among cardiovascular, muscular, and oxytocin responses during human sexual activity," Archives of Sexual Behavior 23 59–79.
  4. ^ Murphy ME, Seckl JR, Burton S, Checkley SA & Lightman SL (1987). "Changes in oxytocin and vasopressin secretion during sexual activity in men," Journal of Clinical Endocrinology and Metabolism 65:738–741.
  5. ^ Kruger THC, Haake P, Chereath D, Knapp W, Janssen OE, Exton MS, Schedlowski M & Hartmann U (2003). "Specificity of the neuroendocrine response to orgasm during sexual arousal in men," Journal of Endocrinology 177:57–64
  6. ^ 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
  7. ^ Jankowski et al. (2004) Oxytocin in cardiac ontogeny. Proc Natl Acad Sci USA 101:13074-9 online PMID 15316117
  8. ^ Walenty Hartwig - Practical Endocrinology, ISBN 83-200-1415-8
  9. ^ a b c Gimpl G, Fahrenholz F. (2001) The oxytocin receptor system: structure, function, and regulation. Physiological Reviews 81: full text PMID 11274341
  10. ^ Vacek M, High on Fidelity. What can voles teach us about monogamy?
  11. ^ Bartz JA, Hollander E (2008). "Oxytocin and experimental therapeutics in autism spectrum disorders". Prog Brain Res 170 (451–62): 451. doi:10.1016/S0079-6123(08)00435-4. PMID 18655901. 
  12. ^ Opar A (2008). "Search for potential autism treatments turns to 'trust hormone'". Nat Med 14 (4): 353. doi:10.1038/nm0408-353. PMID 18391923. 
  13. ^ Van Leengoed E, Kerker E, Swanson HH (1987). "Inhibition of post-partum maternal behaviour in the rat by injecting an oxytocin antagonist into the cerebral ventricles". Journal of Endocrinology 112 (2): 275–282. doi:10.1677/joe.0.1120275. PMID 3819639. http://joe.endocrinology-journals.org/cgi/content/abstract/112/2/275. 
  14. ^ Kendrick KM, The Neurobiology of Social Bonds
  15. ^ Kosfeld M et al. (2005) Oxytocin increases trust in humans. Nature 435:673-676. PDF PMID 15931222
  16. ^ Kirsch P et al. (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25:11489-93 PMID 16339042
  17. ^ Zak, P.J. Stanton, A.A., Ahmadi, A. 2007. Oxytocin increases generosity in humans. PLoS ONE 2(11): e1128. [1]
  18. ^ Kovacs GL, Sarnyai Z, Szabo G. (1998) Oxytocin and addiction: a review. Psychoneuroendocrinology 23:945-62 PMID 9924746
  19. ^ Tyzio R et al.(2006) Maternal Oxytocin Triggers a Transient Inhibitory Switch in GABA Signaling in the Fetal Brain During Delivery. Science 314: 1788-1792 PMID 17170309
  20. ^ de Oliveira LF, Camboim C, Diehl F, Consiglio AR, Quillfeldt JA. Glucocorticoid-mediated effects of systemic oxytocin upon memory retrieval. Neurobiology of Learning and Memory. 87(1):67-71, 2007. PMID 16997585
  21. ^ Thompson MR, Callaghan PD, Hunt GE, Cornish JL, McGregor IS. A role for oxytocin and 5-HT(1A) receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine ("ecstasy"). Neuroscience. 146:509-14, 2007. PMID 17383105
  22. ^ Fewtrell MS, Loh KL, Blake A, Ridout DA, Hawdon J. Randomised, double blind trial of oxytocin nasal spray in mothers expressing breast milk for preterm infants. Arch Dis Child Fetal Neonatal Ed. 2006 May;91(3):F169-74. PMID 16223754
  23. ^ Predrag Petrovic, Raffael Kalisch, Tania Singer and Raymond J Dolan,Oxytocin Attenuates Affective Evaluations of Conditioned Faces and Amygdala Activity, Journal of Neuroscience, online June 25, 2008.
  24. ^ Boston Globe, January 12, 2006 [2]

[edit] External links

v • d • e
Endocrine system: hormones (Peptide hormones · Steroid hormones)
Endocrine
glands
Vasopressin · Oxytocin
Other end.
glands
Non-end.
glands
Target-derived
NGF · BDNF · NT-3
Retrieved from "http://en.wikipedia.org/wiki/Oxytocin"
Personal tools