Oxytocin

Oxytocin (ŏk'sĭ-tō'sĭn) (Greek: "quick birth") is a mammalian hormone that also acts as a neurotransmitter in the brain. In females, it is released in large amounts after distension of the cervix and vagina during labor, and after stimulation of the nipples, facilitating birth and breastfeeding, respectively. It is occasionally misspelled as oxytoxin. Synthetic oxytocin is sold as medication under the trade names Pitocin and Syntocinon as well as generic oxytocin.

In humans, oxytocin is released during orgasm in both sexes. In the brain, oxytocin is involved in social recognition and bonding, and may be involved in the formation of trust between people ^[1] and generosity ^[2]

Additional recommended knowledge

How to ensure accurate weighing results every day?

Guide to balance cleaning: 8 simple steps

How to quickly check pipettes?

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 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.

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 (cysteine - tyrosine - phenylalanine - glutamine - asparagine - cysteine - proline - arginine - glycine), 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.

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 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 – 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.^[3]
• Oxytocin is secreted into the blood at orgasm – in both males and females.^[4] In males, oxytocin may facilitate sperm transport during their development.
• Due to its similarity to vasopressin, it 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.
• 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. ^[5][6] However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.^[3]

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,^[7] 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.^[8] 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.
• Autism. A 1998 study found significantly lower levels of oxytocin in blood plasma of autistic children.^[9] A 2003 study found a decrease in autism spectrum repetitive behaviors when oxytocin was administered intravenously.^[10] A 2007 study reported that oxytocin helped autistic adults retain the ability to evaluate the emotional significance of speech intonation.^[11]
• 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. ^[12]
• 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.^[13] Nasally administered oxytocin has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses).^[14] There is no conclusive evidence for access of oxytocin to the brain through intranasal administration, however.
• 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 experimental explicitly induced perspective-taking in the Ultimatum Game by not identifying to participants which role they would be in.^[15]
• According to some studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol) and reduces withdrawal symptoms.^[16]
• 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.^[17]
• Certain learning and memory functions are impaired by centrally administered oxytocin.^[7]
• 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.^[18]

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. There is no evidence for significant CNS entry of oxytocin by nasal spray. Oxytocin nasal sprays have been used to stimulate breastfeeding but the efficacy of this approach is doubtful^[19].

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.

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 (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).^[7]

References

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