Oxytocin

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

oxytocin receptor
Identifiers
Symbol(s)	OXTR
Entrez	5021
OMIM	167055
RefSeq	NM_000916
UniProt	P30559
Other data
Locus	Chr. 3 p25

Oxytocin should not be confused with oxycodone hydrochloride whose trade name is OxyContin.

Oxytocin (Greek: "quick birth")(OXT) is a mammalian hormone that also acts as a neurotransmitter in the brain. In women, it is released mainly after distention of the cervix and vagina during labor, and after stimulation of the nipples, facilitating birth and breastfeeding, respectively. OXT is released during orgasm in both sexes. In the brain, OXT is involved in social recognition and bonding, and might be involved in the formation of trust between people.

Synthesis, storage and release

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

Secretion of OXT from the neurosecretory nerve endings is regulated by the electrical activity of the OXT 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 OXT-containing vesicles, which are released by exocytosis when the nerve terminals are depolarised.

Structure and relation to vasopressin

Oxytocin structure. Inset shows OXT bound to neurophysin

OXT 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. OXT has a molecular mass of 1007 daltons. One international unit (IU) of OXT is the equivalent of about 2 micrograms of pure peptide.

The structure of OXT 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 OXT by 2 amino acids. 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). (Gimpl 2001). A table showing the sequences of members of the vasopressin/OXT superfamily and the species expressing them is present in the vasopressin article. OXT 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.

OXT and vasopressin are the only known hormones released by the human posterior pituitary gland to act at a distance. However, OXT neurons make other peptides, including corticotropin-releasing hormone (Crh) and dynorphin, for example, that act locally. The magnocellular neurons that make OXT are adjacent to magnocellular neurons that make vasopressin, and are similar in many respects.

Actions

OXT has peripheral (hormonal) actions, and also has actions in the brain. The actions of OXT are mediated by specific, high affinity OXT receptors. The OXT receptor (OXTR) 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.

Peripheral (hormonal) actions

The peripheral actions of OXT mainly reflect secretion from the pituitary gland. OXT 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, OXT receptors are also found in the kidney and heart.

• Letdown reflex – in lactating (breastfeeding) mothers, OXT 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 hypothalamus. The stimulation causes neurons that make OXT to fire action potentials in intermittent bursts; these bursts result in the secretion of pulses of OXT from the neurosecretory nerve terminals of the pituary gland.
• Uterine contraction – important for cervical dilation before birth and causes contractions during the second and third stages of labor. OXT 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 OXT receptor, reproductive behavior and parturition is normal. (Takayanagi 2005)
• OXT is secreted into the blood at orgasm – in both males and females (Carmichael et al 1987). In males, OXT may facilitate sperm transport in ejaculation.
• Due to its similarity to vasopressin, it can reduce the excretion of urine slightly. More important, in several species, OXT can stimulate sodium excretion from the kidneys (natriuresis), and in humans, high doses of OXT can result in hyponatremia.
• OXT and OXT 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. (Paquin & Danalache 2002, Jankowski 2004). However, the absence of either OXT or its receptor in knockout mice has not been reported to produce cardiac insufficiencies. (Takayanagi 2005)

Actions of oxytocin within the brain

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

• Sexual arousal. OXT injected into the cerebrospinal fluid causes spontaneous erections in rats (Gimpl 2001), reflecting actions in the hypothalamus and spinal cord.
• Bonding. In the Prairie Vole, OXT 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 [1]. In people, plasma concentrations of OXT have been reported to be higher amongst people who claim to be falling in love. OXT 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 OXT pathways in the brain might be a feature of autism.
• Maternal behavior. Sheep and rat females given OXT antagonists after giving birth do not exhibit typical maternal behavior. By contrast, virgin sheep females show maternal behavior towards foreign lambs upon cerebrospinal fluid infusion of OXT, which they would not do otherwise. [2]
• Various anti-stress functions. OXT reduces blood pressure and cortisol levels, increasing tolerance to pain, and reducing anxiety. OXT may play a role in encouraging "tend and befriend", as opposed to "fight or flight", behavior, in response to stress.
• Increasing trust and reducing fear. In a risky investment game, experimental subjects given nasally administered OXT 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 OXT was not merely affecting risk-aversion (Kosfeld 2005). Nasally-administered OXT has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses) (Kirsch 2005). There is no conclusive evidence for access of OXT to the brain through intranasal administration, however. To be determined is whether or not the OXT administered is actually triggering the measured responses through peripheral actions or at certain brain regions where the blood-brain barrier is absent (e.g., the area postrema).
• According to some studies in animals, OXT inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol) and reduces withdrawal symptoms. (Kovacs 1998)
• Certain learning and memory functions are impaired by centrally-administered OXT. (Gimpl 2001)

Uses

Template:Drugbox Synthetic OXT is sold as medication under the trade names Pitocin and Syntocinon and also as generic Oxytocin. OXT is destroyed in the gastrointestinal tract, and therefore must be administered by injection or as nasal spray. OXT has a half-life of typically about three minutes in the blood. OXT given intravenously does not enter the brain in significant quantities - it is excluded from the brain by the blood-brain barrier. Drugs administered by nasal spray are thought to have better access to the CNS. An OXT nasal spray has been used to stimulate breastfeeding.

Injected OXT analogues are used to induce labour and support labour in case of non-progression of parturition. It has largely replaced ergotamine as the principal agent to increase uterine tone in acute postpartum haemorrhage. OXT is also used in veterinary medicine to facilitate birth and to increase milk production. The tocolytic agent atosiban (Tractocile®) acts as an antagonist of OXT 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 OXT might help those who suffer from social anxieties, while others have noted the potential for abuse with confidence tricks.

References

• 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
• 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
• Froböse G, Froböse R. (2006) Lust and Love: Is It More Than Chemistry? (translated by M. Gross). Royal Society of Chemistry. ISBN 0-85404-867-7.
• Gimpl G, Fahrenholz F. (2001) The oxytocin receptor system: structure, function, and regulation. Physiological Reviews 81: full text PMID 11274341
• Jankowski et al. (2004) Oxytocin in cardiac ontogeny. Proc Natl Acad Sci USA 101:13074-9 online PMID 15316117
• Kirsch P et al. (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25:11489-93 PMID 16339042
• Kosfeld M et al. (2005) Oxytocin increases trust in humans. Nature 435:673-676. PDF PMID 15931222
• Kovacs GL, Sarnyai Z, Szabo G. (1998) Oxytocin and addiction: a review. Psychoneuroendocrinology 23:945-62 PMID 9924746
• 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
• 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

External links

• ColoState.edu - 'Oxytocin in a nine amino acid peptide that is synthesized in hypothalamic neurons and transported down axons of the posterior pituitary for secretion into blood' (from on-line textbook, Pathophysiology of the Endocrine System), R.A. Bowen
• Economist.com - 'Paying through the nose: A person's level of trust can be changed with a chemical spray', The Economist (June 2, 2005)
• Metroactive.com - 'Love Is a Drug: Once the realm of poets, artists and philosophers, love has been exposed as biochemistry, Dan Pulcrano, Metro Silicon Valley (February 9, 2005)
• NewScientist.com - 'Trust me, I’m spraying you with hormones' (report on trust study), Andy Coghlan, New Scientist (June 1, 2005
• NewScientist.com - 'Release of Oxytocin due to penetrative sex reduces stress and neurotic tendencies', New Scientist (January 26, 2006)
• NIH.gov - 'Oxytocin (Systemic)' (drug information), National Institute of Medicine
• Oxytocin.org - 'I get a kick out of you: Scientists are finding that, after all, love really is down to a chemical addiction between people', The Economist (February 12, 2004)
• SMH.com.au - 'To sniff at danger: Inhalable oxytocin could become a cure for social fears', Boston Globe (January 12, 2006)

• UTMem.edu - 'Posterior Pituitary (Neurohypophysis)' (lecture notes), Samuel Dagogo-Jack, University of Tennessee (January 17, 2003)

• verolabs.com - Company producing the first commercially-available body spray claimed to contain oxytocin. Its potential effectiveness has been questioned, given the relatively minuscule amount that would be absorbed by the wearer and the even smaller amount that would be absorbed by others. Verolabs does not provide information about the amount of oxytocin contained in the product.

• Hug the Monkey - A weblog devoted entirely to oxytocin