Oxytocin
oxytocin, prepro- (neurophysin I)
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| Identifiers | |
| Symbol(s) | OXT OT |
| Entrez | 5020 |
| OMIM | 167050 |
| RefSeq | NM_000915 |
| UniProt | P01178 |
| Other data | |
| Locus | Chr. 20 p13 |
oxytocin receptor
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| 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 blood, but which is also released into the brain. In women, it is secreted into the blood after distention of the cervix and vagina during labor, facilitating childbirth, and after stimulation of the nipples, facilitating breastfeeding. Oxytocin is also released during orgasm in both men and women. In the brain, oxytocin is involved in sexual behavior, regulating food intake, social recognition and bonding, and, as suggested by some recent research, it might be involved in the formation of "trust" between people.
Synthesis, storage and release
Oxytocin is made by a population of unusually large neurons in the hypothalamus - specifically, in the magnocellular neurosecretory cells of the supraoptic nucleus and paraventricular nucleus. It is released into the blood from the neorosecretory nerve endings of these neurons, which are found in the posterior lobe of the pituitary gland. Oxytocin is also made by some smaller ("parvocellular") neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.
In the pituitary gland, oxytocin 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 oxytocin is derived by enzymatic cleavage. Typically one oxytocin neuron has just a single axon that projects to the posterior pituitary, but this axon gives rise to about 10,000 nerve terminals, each of which may contain many thousands of vesicles. Each vesicle contains about 10,000 molecules of oxytocin.
Oxytocin secretion 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.
Structure and relation to vasopressin
Oxytocin is a nonapeptide (i.e. it has nine amino acids), with a molecular mass of 1007 daltons: cysteine-tyrosine-isoleucine-glutamine-asparagine-cysteine-proline-leucine-glycine
The cysteine residues form a sulfur bridge. One international unit (IU) of oxytocin is equivalent to about 2 micrograms of peptide. The structure of oxytocin is very like that of vasopressin, which is also a nonapeptide with a sulfur bridge, whose sequence differs from oxytocin by two amino acids:
cysteine-tyrosine-phenylalanine-glutamine-asparagine-cysteine-proline- arginine-glycine
Sequences of other members of the vasopressin/oxytocin superfamily and the species expressing them are given in the vasopressin article. Oxytocin and vasopressin were discovered, isolated and synthesized by Vincent du Vigneaud in 1953, work for which he won the Nobel Prize in Chemistry in 1955.
Oxytocin and vasopressin are the only true hormones secreted from the human posterior pituitary gland. However, oxytocin neurons make several other peptides, including cholecystokinin and dynorphin that act either within the hypothalamus or within the posterior pituitary gland, rather than at distant targets. The magnocellular neurons that make oxytocin are amongst other magnocellular neurons that make vasopressin; these are, in many respects, very similar to the oxytocin neurons.
Actions
Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. The actions of oxytocin are mediated by a specific, high affinity oxytocin receptor; this molecule is a G-protein-coupled receptor, present in cell membranes. G[1] It belongs to the rhodopsin-type (class I) group of G-protein-coupled receptors.
Peripheral (hormonal) actions
The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland; there is some evidence that some oxytocin is also produced in the uterus. There are receptors for oxytocin receptors in 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.
- Letdown reflex – in 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. When an infant sucks at the nipple, sensory receptors are activated, and this information is relayed by spinal nerves to the hypothalamus, and ultimately causes the neurons that make oxytocin to fire action potentials in intermittent bursts. These bursts result in the secretion of large pulses of oxytocin secretion from the neurosecretory nerve terminals in the pituary gland.
- Uterine contraction – oxytocin is an important hormone for cervical dilation before birth and it causes uterine contractions during the second and third stages of labor. Oxytocin secretion during breastfeeding causes mild can continue to cause uterine contractions during the first few weeks of lactation; these are usually mild but sometimes can be painful. The actions of oxytocin upon the uterus are part of the physiological mechanisms for expelling the fetus and placenta, and they also assist the uterus in "clotting" the placental attachment after birth. Oxytocin seems to play a role in parturition in all mammalian species; it is secreted at high levels during labor, and uterine sensitivity to oxytocin as at its maximum just before birth begins. However, although important, the role of oxytocin is not essential for normal parturition; for example in transgenic mice that cannot make any oxytocin, or mice that cannot make any receptors for oxytocin (so-called "gene knockout" mice), parturition is normal, although the mice are unable to feed their young.[2]
- Oxytocin is secreted into the blood at orgasm in both males and females [3] In males, oxytocin may facilitate sperm transport in ejaculation.
- Because of its similarity to vasopressin, high doses of oxytocin can affect the excretion of urine slightly (it is a weak agonist at vasopressin receptors). More important, 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 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. [4]. 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 of the blood-brain barrier. Nevertheless, injections of very small amounts of oxytocin into the brain have several recognised effects on behavior, and as injections of oxytocin antagonists impair these same behaviors, it seems likely that these are behaviors that are normally regulated by oxytocin released within the brain.
The behavioral effects of oxytocin might reflect either release from centrally-projecting oxytocin neurons, (these are small neurons, separate from the large neurons that project to the pituitary gland), or release of oxytocin from the dendrites of the magnocellular oxytocin neurons. Oxytocin receptors are found on neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus and septum and the nucleus of the solitary tract.
- Sexual arousal Oxytocin injected into the cerebrospinal fluid causes erections in rats, reflecting actions both 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 [1]). 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 might have 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 show maternal behavior towards foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise. [2]
- Anti-stress functions Oxytocin injected into the brain reduces blood pressure and cortisol secretion, increases tolerance to pain, and reduces anxiety. Oxytocin might 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, volunteers who were given given nasally administered oxytocin displayed "the highest level of trust" twice as often as a 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[5]. Nasally-administered oxytocin has also been reported to reduce fear, possibly by inhibiting the amygdala, which is thought to be responsible for fear responses. [6]
- According to some studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol) and reduces withdrawal symptoms. [7]
Uses
Template:Drugbox Synthetic oxytocin is sold as medication under the names Pitocin and Syntocinon and also as generic Oxytocin. Oxytocin is destroyed in the gastrointestinal tract, and so must be administered by injection into the blood stream (for effects on peripheral organs) or by nasal spray (to reach brain areas). Oxytocin 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 central nervous system. An oxytocin nasal spray has been used to stimulate breastfeeding; oxytocin acts in the brain to facilitate the activity of the oxytocin neurons.Oxytocin has a half-life of about three minutes in the blood.
Oxytocin analogues are used in obstetrics to induce labour and support labour in case of non-progression of parturition, and 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®) is an antagonist of oxytocin receptors; it is registered in many countries to suppress premature labour between 24 and 33 weeks of gestation, and is reported to have fewer side-effects than drugs previously used for this (ritodrine, salbutamol and terbutaline).
Evolution
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).
References
- ↑ Gimpl G, Fahrenholz F (2001) The oxytocin receptor system: structure, function, and regulation. Physiological Reviews 81: full text PMID 11274341
- ↑ 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
- ↑ Carmichael MSet al (1987) Plasma oxytocin increases in the human sexual response. J Clin Endocrinol Metab 64:27-31 PMID 3782434
- ↑ Jankowski et al (2004) Oxytocin in cardiac ontogeny. Proc Natl Acad Sci USA 101:13074-9 online PMID 15316117
- ↑ Kosfeld M et al (2005) Oxytocin increases trust in humans. Nature 435:673-676
- ↑ Kirsch P et al (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans J Neurosci 25:11489-93 PMID 16339042 PDF PMID 15931222
- ↑ Kovacs GL et al (1998) Oxytocin and addiction: a review. Psychoneuroendocrinology 23:945-62 PMID 9924746
- 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 320kb PDF
News stories
- Economist.com - 'Paying through the nose: A person's level of trust can be changed with a chemical spray', The Economist (June 2, 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)