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") 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.

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.

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.

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) 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.

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.

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). 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, and in the enteric nervous system

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.

• 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.

• Uterine contraction – important for cervical dilation before birth and causes contractions during the second and third stages of labor.

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 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.
• 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 , and may also be involved in regulating the secretion of atrial natriuretic peptide.

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

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 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.

• 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.

• 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 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.
• 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.
• 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)

• Stress'. Oxytocin has various anti-stress functions; it reduces blood pressure and cortisol levels, increasing tolerance to pain, and reducing anxiety. Oxytocin may play a role in encouraging "tend and befriend", as opposed to "fight or flight", behavior, in response to stress.

• 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 Nasally-administered oxytocin 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 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.

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. 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).