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2068/02/25
Oxytocin
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Oxytocin ( /kstosn/) is a mammalian hormone that acts primarily as a neuromodulator

in the brain. Also known as alpha-hypophamine (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.[1]
Oxytocin is best known for its roles in female reproduction. It is released in large amounts 1)
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.[2] For this reason, it is sometimes referred to as the "love hormone".[3]

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 Gprotein-coupled receptor which requires Mg2+ and cholesterol. It belongs to the rhodopsin-type
(class I) group of G-protein-coupled receptors.
[edit] 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.[6] 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 are
normal.[7]

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. [8][9] 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. [8] The authors of one of
these studies speculated that oxytocin's effects on muscle contractibility may
facilitate sperm and egg transport. [8] 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.[10] 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. [11] Murphy et al.
(1987), studying men, found that oxytocin levels were raised throughout
sexual arousal and there was no acute increase at orgasm. [12] 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."[13]

More studies have been done to examine sexual arousal in women than in men. Some scientists
believe that women experience longer orgasms than men and have a more complex reproductive
endocrine system with clearly identified cycles such as, menstruation, lactation, menopause, and
pregnancy.[14] This allows more opportunities to measure and examine the hormones related to
sexual arousal. However, notable sex researchers have gathered data indicating no difference in
duration and mechanism between male and female orgasms, [15] an idea first alluded to by Kinsey
and others.[16] Thus, perhaps the disproportionate number of studies on sexual arousal in women
reflects an implicit cultural view of female arousal and orgasm as particularly mysterious or
'exceptional.'[17]
Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and
security around the mate.[18] 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.[19] 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.[20][21] However, the absence of
either oxytocin or its receptor in knockout mice has not been reported to
produce cardiac insufficiencies.[7]

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.[22]

Autism. Oxytocin may play a role in autism and may be an effective

treatment for autism's repetitive and affiliative behaviors.[23] Oxytocin
treatments also resulted in an increased retention of affective speech in
adults with autism.[24] 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 [25] 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. [24][26] Autism may
also be associated by an aberrant methylation of OXTR, as reported by
Gregory and colleagues.[24] After treatment with inhaled oxytocin, autistic
patients exhibit more appropriate social behavior. [27] 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.[28] Nasally
administered oxytocin has also been reported to reduce fear, possibly by
inhibiting the amygdala (which is thought to be responsible for fear
responses).[29] 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.[30]

Reducing trust of strangers, and increasing cultural and racial bias. [31]

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.[32]

Certain learning and memory functions are impaired by centrally

administered oxytocin.[33] Also, systemic oxytocin administration can impair
memory retrieval in certain aversive memory tasks. [34] 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. [35][36] They also show
improved recognition for positive social cues over threatening social cues [37]
[38]
and improved recognition of fear[39]

Empathy in healthy males has been shown to be increased after intranasal

oxytocin[40][41] This is most likely due to the effect of oxytocin in enhancing eye
gaze.[42] There is some discussion about which aspect of empathy oxytocin
might alter, for example cognitive vs emotional empathy. [43]

[edit] 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.[44] 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,[33] 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 behavior, indicating an increase in sexual receptivity. [14]

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. [45]
Oxytocin has a role in social behaviors in many species, and so it seems likely
that it also does in humans. In 2003, a study showed that in both humans and
dogs oxytocin levels in the blood rose after five to twenty four minutes of a
petting session. It is possible that this plays a role in the emotional bonding
between humans and dogs. [46]

Maternal behavior. Female rats given oxytocin antagonists after giving birth
do not exhibit typical maternal behavior. [47] By contrast, virgin female sheep
show maternal behavior towards foreign lambs upon cerebrospinal fluid
infusion of oxytocin, which they would not do otherwise. [48] 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.[49]

According to some studies in animals, oxytocin inhibits the development of

tolerance to various addictive drugs (opiates, cocaine, alcohol) and reduces
withdrawal symptoms.[50]

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.[51]

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. [52] The anxiolytic
Buspar (buspirone) also appears to produce some or all of its effect via 5HT1A receptor-induced oxytocin stimulation.[53][54]

[edit] 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.[55]
Injected oxytocin analogues are used for labor induction and to support labor in case of nonprogression 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[41], while others have noted the potential for abuse with
confidence tricks[56][57] and military applications.[58]
The Center of Cognitive Neuroscience in Lyon, France concluded that oxytocin may help reduce
the negative symptoms of autism.[59]
[edit] Potential adverse reactions

Oxytocin is relatively safe when used at recommended doses, and side effects are uncommon.[60]
The following maternal events have been reported:[60]

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:[60]

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.
[edit] Industrial use

Oxytocin can be administered to bovine animals in order to increase the production of dairy
milk.[citation needed]

[edit] Synthesis, storage, and release

The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene.[61][62][63]
This precursor protein also includes the oxytocin carrier protein neurophysin I.[64] 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).[65]
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.[66] 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.[67]
[edit] 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.[44] The peripheral hormonal and
behavioral brain effects of oxytocin it has been suggested are coordinated through its common
release through these collaterals.[44] Oxytocin is also made by some neurons in the
paraventricular nucleus that project to other parts of the brain and to the spinal cord.[68]
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.
[edit] Non-neural sources

Outside the brain, oxytocin-containing cells have been identified in several diverse tissues
including the corpus luteum,[69][70] the interstitial cells of Leydig,[71] the retina,[72] the adrenal
medulla,[73] the placenta,[74] the thymus[75] and the pancreas.[76] 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.

[edit] 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 F2 to
cause regression of the corpus luteum.
[edit] 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.[77]

[edit] 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,[78] as well as lower prevalence of autism and of poor
parenting skills.[79]

[edit] 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,[80] 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 cyclostomata (modern members of
the Agnatha).[33]

[edit] See also