Oxytocin

Oxytocin is a mammalian hormone that in women is released mainly after stimulation of the nipples or distention of the vagina and that facilitates birth and breastfeeding. It is also released during orgasm in both sexes. In the brain, it acts as a neurotransmitter and is involved in bonding and the formation of trust between people.

Synthetic oxytocin is sold as medication under the trade names Pitocin and Syntocinon and also as generic Oxytocin.

Synthesis, storage and release
Oxytocin 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 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.

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 neurosecretory nerve endings in the pituitary; the endings contain large numbers of oxytocin-containing vesicles, which are released by exocytosis when the terminals are depolarised.

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.

The structure of oxytocin is very similar to that of vasopressin, which is also a nonapeptide with a sulfur bridge. Oxytocin and vasopressin are the only known hormones released by the human posterior pituitary gland to act at a distance. However, oxytocin neurons can make corticotropin-releasing hormone (CRH) and vasopressin neurons 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.

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.

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.

Actions
Oxytocin has peripheral (hormonal) actions, and also has actions in the brain.

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.


 * 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 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 in the pituary 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. (Takayanagi 2005)
 * Oxytocin is secreted into the blood at orgasm – in both males and females (Carmichael et al 1987). In males, oxytocin may facilitate sperm transport in ejaculation.
 * 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. (Paquin & Danalache 2002, Jankowski 2004). However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies. (Takayanagi 2005)

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 (Gimpl 2001), 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 . 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 show maternal behavior towards foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise.
 * Various anti-stress functions. Oxytocin 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.
 * 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 (Kosfeld 2005). Nasally-administered oxytocin has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses). (Kirsch 2005)
 * According to some studies in animals, oxytocin 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 oxytocin. (Gimpl 2001)

Uses
Oxytocin is destroyed in the gastrointestinal tract, and is therefore 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. Drugs administered by nasal spray are thought to have better access to the CNS.

Injected oxytocin analogues (Pitocin, Syntocinon) 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.

The tocolytic agent atosiban (Tractocile&reg;) 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).

An oxytocin nasal spray (trade name: Syntocinon nasal spray) has been used to stimulate breastfeeding.

Some have suggested that the trust-inducing property of oxytocin might help those who suffer from social anxieties and autism, while others have noted the potential for abuse with confidence tricks.

Oxytocin is used in veterinary medicine to facilitate birth and to increase milk production.

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 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 can be found in cyclostomes (modern members of the Agnatha). (Gimpl 2001)