Oxytocin

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", OXT) is a mammalian hormone that is secreted into the bloodsteam from the posterior pituitary gland, and which is also released into the brain where it has effects on social behaviors. In pregnant women, OXT 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. OXT is also secreted during orgasm in both sexes; in men it facilitates movement of sperm. In the brain, OXT is involved in social recognition, bonding, sexual arousal and reproductive behaviors, and might be involved in the formation of trust between people. In some species, including rats, OXT also promotes sodium excretion (natriuresis), and it can have this pharmacological effect when given in high doses to humans also.

Synthesis, storage and release

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

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. OXT is produced by enzymatic cleavage of a large precursor protein molecule, which is the product of oxytocin mRNA.

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 precursor molecule from which OXT is derived. The folding of the neurophysin molecule is believed to be important for packaging OXT into the neurosecretory vesicles.

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.

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 by action potentials.

Structure and relation to vasopressin

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 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) 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 cholecystokinin (CCK) 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.

All eutherian mammals 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 OXT 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.

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 caudal brainstem, and from there 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 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 OXT receptors in both the myometrium (the muscles of the uterus) and endometrium towards the end of pregnancy. The actions of OXT on the myometrium directly induce uterine contractions; the actions on the endometrium result in the profdubction of prostaglandins, which also act on the myometrium to stimulate uterine contractions. OXT 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 OXT and in mice lacking the OXT 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 OXT is absolutely essential for this reflex.
• OXT is secreted into the blood at orgasm – in both males and females In males, OXT may facilitate sperm transport in ejaculation. At ejaculation, OXT secretion stimulates contractions of the male reproductive tract (the seminiferous tubules, epididymis and the prostate gland). OXT 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. OXT also modulate androgen levels in these tissues by stimulating the conversion of testosterone to dihydrotestostone (DHT) by 5-alpha-reductase.
• 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, and may also be involved in regulating the secretion of atrial natriuretic peptide. . However, the absence of either OXT or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.

Actions of oxytocin within the brain

OXT secreted from the pituitary gland cannot re-enter the brain because it cannot cross 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, and/or release from the cell bodies and dendrites of the magnocellular neurons 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, olfactory bulb, septum and areas of the caudal brainstem including the nucleus of the solitary tract Some of these sites (the nucleus of the solitary tract and spinal cord) recieve a very dense innervation from parvocellular oxytocin neurons, but others (amygdala and ventromedial 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.

• Sexual arousal. OXT injected into the cerebrospinal fluid causes erections in male rats, reflecting actions in the hypothalamus and spinal cord. OXT also facilitates sexual behavior in female rats.
• 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 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 that have been treated with estrogen show maternal behavior towards foreign lambs upon cerebrospinal fluid infusion of OXT, which they would not do otherwise.

• 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.
• In males, oxytocin can facilitate penile erection by stimulating sexual arousal. These actions are partly at the level of the spinal cord and partly at the level of the hypothalamus (especially the ventromedial hypothalamus)
• 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 Nasally-administered OXT has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses) . 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.
• There have been reports that certain learning and memory functions are impaired by centrally-administered OXT. The interpretation of these findings is controversial.

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 but, as noted above, there is no good evidence that it reaches the CNSin significant quantities.

Injected OXT analogues are used to induce labor and support labor in case of non-progression of parturition. These have 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.

Further Reading

• 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
• 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.

External links

• ColoState.edu - 'Oxytocin is 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
• NIH.gov - 'Oxytocin (Systemic)' (drug information), National Institute of Medicine