Oxytocin

Oxytocin
Systematic name
IUPAC name  ?
Identifiers
CAS number	50-56-6
ATC code	H01BB02
PubChem	439302
DrugBank	BTD00016
Chemical data
Formula	C43H66N12O12S2
Mol. weight	1007.19 g/mol
Pharmacokinetic data
Bioavailability	nil
Protein binding	30%
Metabolism	hepatic oxytocinases
Half life	1-6 min
Excretion	Biliary and renal
Therapeutic considerations
Pregnancy cat.	?
Legal status	?
Routes	Intranasal, IV, IM

oxytocin, prepro- (neurophysin I)
Identifiers
Symbol	OXT
Alt. Symbols	OT
Entrez	5020
HUGO	8528
OMIM	167050
RefSeq	NM_000915
UniProt	P01178
Other data
Locus	Chr. 20 p13

Oxytocin (ŏk'sĭ-tō'sĭn) is a relatively small polypeptide hormone released from the posterior lobe of the pituitary gland in mammals and that plays an important role in birth and ejection of milk from the female breast. It also also acts as a neurotransmitter in the brain. Along with the antidiuretic hormone vassopressin, oxytocin is one of the two major hormones secreted from this part of the pituitary gland (Blakemore and Jennett 2001).

Ocytocin, which means "quick birth," in Greek, is released in large amounts in females after distension of the cervix and vagina during labor, stimulating smooth muscle contractions iof the uterus, facilitating childbirth. It is also released after stimulation of the nipples, stimulating muscular contractions around the alveoli and milk ducts in the breasts, facilitating breastfeeding.

In humans, oxytocin is released during orgasm in both sexes. In the brain, oxytocin is involved in social recognition and bonding, and might be involved in the formation of trust between people (Kosfeld 2005). Also, oxytocin has been known to affect the brain by regulating circadian homeostasis, such as a person's body temperature, activity level, and wakefulness (Kraft 2007).

Oxytocin involves harmonious interaction between neural and hormonal systems, being made in nerve rather than in glandular cells (where most hormones are made) and which is released following sensory nerve stimulation of the nerve cells (Blakemore and Jennett 2001). For examle, the suckling, sight and sound of an infant and other stimuli associated with breast feeding stimulated communcation with hypothalamic nerve celsl and and the actios are raid. (Blakemore and Jennett 2001).

Structure

Ocytocin is a hormone, meaning it is a chemical messenger secreted by cells (including tissues and organs) in one part of a multicellular organism to travel to and coordinate the activities of different cells, providing a value to the whole organism. An enormous range of chemicals are used for this type of cell-to-cell communication, including peptides (chains of amino acids) and steroids (a type of fat-soluble organic compound). Oxytocin is a peptide hormone.

Oxytocin has the chemical formula C₄₃H₆₆N₁₂O₁₂S₂. It is a relatively short polypeptide, being composed of only 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, an antidiuretic hormone that is also a nonapeptide: cysteine - tyrosine - phenylalanine - glutamine - asparagine - cysteine - proline - arginine - glycine). Vassopressin, whose residues also form a sulfur bridge, has a sequence that differs from oxytocin by 2 amino acids.

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 was the first hormone in which its structure was identified and which was synthesized in the laboratory. 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.

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.

The posterior pituitary essentially contains the endings of nerves whose cell bodies lie in the the hypothalamus (Blakemore and Jennett 2001). The hormone is manufactured in the cell bodies in the hypothalamus in the form of a larger, precursor molecule. It is then transported down the nerve fibers to the posterior lobe, where the active hormone is cleaved from the precursor molecule and then is secreted directly into the blood capillaries from the nerve endings of the posterior pituitary (Blakemore and Jennett 2001). Oxytocin also is made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.

Oxytocin structure. Inset shows oxytocin bound to neurophysin

In the pituitary gland, oxytocin is packaged in large, dense-core vesicles, where it is bound to neurophysin I; neurophysin is a large peptide fragment of the giant 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 depolarized.

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 (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) (Gimpl and Fahrenholz 2001).

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.

• Letdown reflect. 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 of the pituitary gland.
• Uterine contraction. Uterine contraction is important for cervical dilation before birth and causes contractions during the second and third stages of labor. Also, 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).
• Orgasm and sperm transport. 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.
• Urine and sodium excretion. Due to its similarity to vasopressin, oxytocin can reduce the excretion of urine slightly. 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.
• Possible embryonal development in rodents. 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 et al. 2002; Jankowski et al. 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 and Fahrenholz 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 (Vacek 2002). In people, plasma concentrations of oxytocin have been reported to be higher among 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.
• Autism. A 1998 report on a research study noted significantly lower levels of oxytocin in blood plasma of autistic children (Modahl et al. 1998). In 2003, a research team reported a decrease in autism spectrum repetitive behaviors when oxytocin was administered intravenously (Hallander et al. 2003). A 2007 study reported that oxytocin helped autistic adults retain the ability to evaluate the emotional significance of speech intonation (Hollander et al. 2007).
• Maternal behavior. Sheep and rat females 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 (Kendrick 2007).
• 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 et al. 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 et al. 2005). There is no conclusive evidence for access of oxytocin to the brain through intranasal administration, however.

• 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.
• Certain learning and memory functions are impaired by centrally administered oxytocin.
• The illicit party drug MDMA (ecstasy) may increase feelings of love, empathy and connection to others by stimulating oxytocin activity via activation of serotonin 5HT1A receptors, if initial studies in animals apply to humans.

Drug forms

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 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. Drugs administered by nasal spray are thought to have better access to the CNS. Oxytocin nasal sprays have been used to stimulate breastfeeding.

Injected oxytocin analogues 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. 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; 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).

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

Potential adverse reactions

Oxytocin is relatively safe when used at recommended doses. Potential side effects include:^{[citation needed]}

• Central nervous system: Subarachnoid hemorrhage, seizures.
• Cardiovascular: Increased heart rate, blood pressure, systemic venous return, cardiac output, and arrhythmias.
• Genitourinary: Impaired uterine blood flow, pelvic hematoma, tetanic uterine contractions, uterine rupture, postpartum hemorrhage.

References

ISBN links support NWE through referral fees

Gimpl G, Fahrenholz F. (2001) The oxytocin receptor system: structure, function, and regulation. Physiological Reviews 81: full text PMID 11274341</ref>

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External links

• Caldwell, H.K. and Young, W.S., III. Oxytocin and Vasopressin: Genetics and Behavioral Implications in Lim, R. (ed.) Handbook of Neurochemistry and Molecular Neurobiology, 3rd edition, Springer, New York, pp. 573-607, 2006. 320kb PDF
• NewScientist.com - 'Release of Oxytocin due to penetrative sex reduces stress and neurotic tendencies', New Scientist (January 26, 2006)
• 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)

• Hug the Monkey - A weblog devoted entirely to oxytocin
• Oxytocin and understanding other minds

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