Oxytocin

Overview
Oxytocin is a mammalian hormone that acts primarily as a neurotransmitter in the brain. Also known as alpha-hypophamine (α–hypophamine), oxytocin has the distinction of being the very first polypeptide hormone to be sequenced and synthesized biochemically by Vincent du Vigneaud et al. in 1953.

Oxytocin is best known for its roles in female reproduction: 1) it is released in large amounts after distension of the cervix and uterus during labor, and 2) after stimulation of the nipples, facilitating birth and breastfeeding. Recent studies have begun to investigate oxytocin's role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, and maternal behaviors. For this reason, it is sometimes referred to as the "love hormone."

Actions
Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. The actions of oxytocin are mediated by specific, high affinity oxytocin receptors. 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.

Peripheral (hormonal) actions
The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. (See oxytocin receptor for more detail on its action.)


 * Letdown reflex – in lactating (breastfeeding) mothers, oxytocin acts at the mammary glands, causing milk to be 'let down' into subareolar sinuses, from where it can be excreted via 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 of the pituitary 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 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.

It is also important to note that more studies have been done to examine sexual arousal in women compared to men. Women experience longer orgasms compared to men and have a more complex reproductive endocrine system with clearly identified cycles such as, menstruation, lactation, menopause, and pregnancy. This allows more opportunities to measure and examine the hormones related to sexual arousal.
 * The relationship between oxytocin and human sexual response is unclear. At least two non-controlled studies have found increases in plasma oxytocin at orgasm – in both men and women. Plasma oxytocin levels are notably increased around the time of self stimulated orgasm and are still higher than baseline when measured 5 minutes after self arousal. The authors of one of these studies speculated that oxytocin's effects on muscle contractibility may facilitate sperm and egg transport. In a study that measured oxytocin serum levels in women before and after sexual stimulation the author suggests that oxytocin serves an important role in sexual arousal. This study found that genital tract stimulation resulted in increased oxytocin immediately after orgasm. Another study that reports increases of oxytocin during sexual arousal states that it could be in response to nipple/areola, genital, and/or genital tract stimulation as confirmed in other mammals. Murphy et al. (1987), studying men, found that oxytocin levels were raised throughout sexual arousal and there was no acute increase at orgasm. A more recent study of men found an increase in plasma oxytocin immediately after orgasm, but only in a portion of their sample that did not reach statistical significance. The authors noted that these changes "may simply reflect contractile properties on reproductive tissue."

Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and security around the mate. In order to reach full orgasm, it is necessary that brain regions associated with behavioral control, fear and anxiety are deactivated; which allows individuals to let go of fear and anxiety during sexual arousal. Many studies have already shown a correlation of oxytocin with human bonding, increases in trust, and decreases in fear. One study confirmed that there was a positive correlation between oxytocin plasma levels and an anxiety scale measuring the adult romantic attachment. This suggests that oxytocin may be important for the inhibition of brain regions that are associated with behavioral control, fear, and anxiety, thus allowing orgasm to occur.


 * Due to its similarity to vasopressin, it can reduce the excretion of urine slightly. 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. However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.


 * Modulation of hypothalamic-pituitary-adrenal axis activity. Oxytocin, under certain circumstances, indirectly inhibits release of adrenocorticotropic hormone and cortisol and, in those situations, may be considered and antagonist of vasopressin.


 * Autism. Oxytocin may play a role in autism and may be an effective treatment for autism's repetitive and affiliative behaviors. Oxytocin treatments also resulted in an increased retention of affective speech in adults with autism. Two related studies in adults, in 2003 and 2007, found that oxytocin decreased repetitive behaviors and improved interpretation of emotions. More recently, intranasal administration of oxytocin was found to increase emotion recognition in children as young as 12 who are diagnosed with autism spectrum disorders Oxytocin has also been implicated in the etiology of autism with one report suggesting that autism is correlated with genomic deletion of the gene containing the oxytocin receptor gene (OXTR). Studies involving Caucasian and Finnish samples and Chinese Han families provide support for the relationship of OXTR with autism. Autism may also be associated by an aberrant methylation of OXTR, as reported by Gregory and colleagues.  After treatment with inhaled oxytocin, autistic patients exhibit more appropriate social behavior. While this research suggests some promise, further clinical trials of oxytocin are required to demonstrate potential benefit and side effects in the treatment of autism. As such, researchers do not recommend use of oxytocin as a treatment for autism outside of clinical trials.


 * 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. Nasally administered oxytocin has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses). Some researchers have argued that oxytocin has a general enhancing effect on all social emotions since intranasal administration of oxytocin also increases envy and schadenfreude.


 * Affecting generosity by increasing empathy during perspective taking. In a neuroeconomics experiment, intranasal oxytocin increased generosity in the Ultimatum Game by 80% but has no effect in the Dictator Game that measures altruism.  Perspective-taking is not required in the Dictator Game, but the researchers in this experiment explicitly induced perspective-taking in the Ultimatum Game by not identifying to participants which role they would be in.


 * Certain learning and memory functions are impaired by centrally administered oxytocin. Also, systemic oxytocin administration can impair memory retrieval in certain aversive memory tasks. Interestingly, oxytocin does seem to facilitate learning and memory specifically for social information. Healthy males administered intranasal oxytocin show improved memory for human faces, particularly happy faces. They also show improved recognition for positive social cues over threatening social cues


 * Empathy in healthy males has been shown to be increased after intranasal oxytocin This is most likely due to the effect of oxytocin in enhancing eye gaze. There is some discussion about which aspect of empathy oxytocin might alter, for example cognitive vs emotional empathy.

Actions 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, or which are collaterals from them. Oxytocin receptors are expressed by neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus, septum, nucleus accumbens and brainstem.


 * Sexual arousal. Oxytocin injected into the cerebrospinal fluid causes spontaneous erections in rats, reflecting actions in the hypothalamus and spinal cord. Centrally administrated oxytocin receptor antagonists can prevent non contact erections, which is a measure of sexual arousal. Studies using oxytocin antagonists in female rats provide data that oxytocin increases lordosis, indicating an increase in sexual receptivity.


 * 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. Oxytocin has a role in social behaviors in many species, and so it seems likely that it also does in humans.


 * Maternal behavior. Female rats given oxytocin antagonists after giving birth do not exhibit typical maternal behavior. By contrast, virgin female sheep show maternal behavior towards foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise. Oxytocin is involved in the initiation of maternal behavior not its maintenance, for example, it is higher in mothers after they interact with unfamiliar children rather than their own.


 * According to some studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol) and reduces withdrawal symptoms.


 * Preparing fetal neurons for delivery. Crossing the placenta, maternal oxytocin reaches the fetal brain and induces a switch in the action of neurotransmitter GABA from excitatory to inhibitory on fetal cortical neurons. This silences the fetal brain for the period of delivery and reduces its vulnerability to hypoxic damage.


 * MDMA (ecstasy) may increase feelings of love, empathy and connection to others by stimulating oxytocin activity via activation of serotonin 5-HT1A receptors, if initial studies in animals apply to humans. The anxiolytic Buspar (buspirone) also appears to produce some or all of its effect via 5-HT1A receptor-induced oxytocin stimulation.

Drug forms
Synthetic oxytocin is sold as proprietary medication under the trade names Pitocin and Syntocinon and also as generic oxytocin. Oxytocin is destroyed in the gastrointestinal tract, and therefore must be 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. There is no evidence for significant central nervous system entry of oxytocin by nasal spray. Oxytocin nasal sprays have been used to stimulate breastfeeding but the efficacy of this approach is doubtful.

Injected oxytocin analogues are used for labor induction and to support labor in case of non-progression of parturition. It has largely replaced ergometrine as the principal agent to increase uterine tone in acute postpartum haemorrhage. Oxytocin is also used in veterinary medicine to facilitate birth and to stimulate milk release. The tocolytic agent atosiban (Tractocile) acts as an antagonist of oxytocin receptors; this drug is registered in many countries to suppress premature labor 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 oxytocin might help those who suffer from social anxieties and mood disorders, while others have noted the potential for abuse with confidence tricks and military applications.

Potential adverse reactions
Oxytocin is relatively safe when used at recommended doses, and side effects are uncommon. The following maternal events have been reported:


 * Subarachnoid hemorrhage
 * Increased heart rate
 * Decreased blood pressure
 * Cardiac arrhythmia and premature ventricular contraction
 * Impaired uterine blood flow
 * Pelvic hematoma
 * Afibrinogenonemia, which can lead to hemorrhage and death
 * Anaphylaxis
 * Nausea and vomiting

Excessive dosage or long term administration (over a period of 24 hours or longer) have been known to result in tetanic uterine contractions, uterine rupture, postpartum hemorrhage, and water intoxication, sometimes fatal.

Increased uterine motility has led to the following complications in the fetus/neonate:


 * Decreased heart rate or heart rate decelerations
 * Cardiac arrhythmia
 * Brain damage
 * Seizures
 * Death

In addition, use of pitocin in the mother has been associated with neonatal jaundice, retinal hemorrhage, and low five-minute Apgar score.

Synthesis, storage, and release
The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene. This precursor protein also includes the oxytocin carrier protein neurophysin I. The inactive precursor protein is progressively hydrolyzed into smaller fragments (one of which is neurophysin I) via a series of enzymes. The last hydrolysis which releases the active oxytocin nonapeptide is catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM).

The activity of the PAM enzyme system is dependent upon ascorbate which is a necessary vitamin cofactor. By chance, it was discovered that sodium ascorbate by itself stimulated the production of oxytocin from ovarian tissue over a range of concentrations in a dose-dependent manner. Many of the same tissues (e.g. ovaries, testes, eyes, adrenals, placenta, thymus, pancreas) where PAM (and oxytocin by default) is found are also known to store higher concentrations of vitamin C.

Neural sources
In the hypothalamus, oxytocin is made in magnocellular neurosecretory cells of the supraoptic and paraventricular nuclei and is stored in Herring bodies at the axon terminals in the posterior pituitary. It is then released into the blood from the posterior lobe (neurohypophysis) of the pituitary gland. These axons (likely, but dendrites have not been ruled out) have collaterals that innervate oxytocin receptors in the nucleus accumbens. The peripheral hormonal and behavioral brain effects of oxytocin it has been suggested are coordinated through its common release through these collaterals. Oxytocin is also made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord. Depending on the species, oxytocin-receptor expressing cells are located in other areas, including the amygdala and bed nucleus of the stria terminalis.

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

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.

Non-neural sources
Outside the brain, oxytocin-containing cells have been identified in several diverse tissues including the corpus luteum, the  interstitial cells of Leydig, the retina, the adrenal medulla, the placenta, the thymus and the pancreas. The finding of significant amounts of this classically "neurohypophysial" hormone outside the central nervous system raises many questions regarding its possible importance in these different tissues.

Female
Oxytocin is synthesized by corpora lutea of several species, including ruminants and primates. Along with estrogen, it is involved in inducing the endometrial synthesis of prostaglandin F2α to cause regression of the corpus luteum.

Male
The Leydig cells in some species have also been shown to possess the biosynthetic machinery to manufacture testicular oxytocin de novo, specifically, in rats (who can synthesize Vitamin C endogenously), and in guinea pigs who (like humans) require an exogenous source of vitamin C (ascorbate) in their diets.

Structure and relation to vasopressin
Oxytocin is a peptide of nine amino acids (a nonapeptide). The sequence is cys – tyr – ile – gln – asn – cys – pro – leu – gly - NH2 (CYIQNCPLG-NH2). 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 biologically active form of oxytocin, commonly measured by RIA and/or HPLC techniques, is also known as the octapeptide "oxytocin disulfide" (oxidized form), but oxytocin also exists as a reduced dithiol nonapeptide called oxytoceine. It has been theorized that open chain oxytoceine (the reduced form of oxytocin) may also act as a free radical scavenger (by donating an electron to a free radical); oxytoceine may then be oxidized back to oxytocin via the redox potential of dehydroascorbate <---> ascorbate.

The structure of oxytocin is very similar to that of vasopressin (cysteine – tyrosine – phe – gln – asn – cys – pro – arg – gly-NH2), also a nonapeptide with a sulfur bridge, whose sequence differs from oxytocin by 2 amino acids. 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 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 corticotropin-releasing hormone (CRH) and 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 receptor polymorphism
The oxytocin receptor in humans has several alleles, which differ in their effectiveness. Individuals homozygous for the "G" allele, when compared to carriers of the "A" allele, show higher empathy, lower stress response, as well as lower prevalence of autism and of poor parenting skills.

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 usually located close to each other (less than 15,000 bases apart) on the same chromosome and are transcribed in opposite directions (however, in fugu, the homologs are further apart and transcribed in the same 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).

Industrial use of drug
Oxytocin can be administered to bovine animals in order to increase the production of dairy milk.

Misuse of drug
Reports exist of hundreds of girls being kidnapped from across India and brought to Sodhawas and Geerwar villages in Alwar district of Rajasthan, where they are given oxytocin injections to hasten their puberty and pushed into prostitution. The kidnapped girls have reportedly been as young as six-month-old babies. They are raised by the villagers as their own daughters.