Oxytocin

The oxytocin (from the Greek ὀξύς oxys "quick" and τόκος tokos "birth", known for this reason as the hormone of childbirth and lactation), is produced by the supraoptic and paraventricular nuclei of the hypothalamus and is released into the circulation through the neurohypophysis. It functions as a neuromodulator in the central nervous system, modulating social and sentimental behaviors, sexual patterns, and parental behavior. It occurs mostly when the individual experiences highly pleasant sensations.

In women, oxytocin is similarly released in large amounts upon distension of the cervix and vagina during childbirth, as well as ejection of breast milk in response to nipple stimulation by suckling. of the baby, thus facilitating childbirth and lactation and after orgasm, which is why it is associated with sexual pleasure and the formation of emotional bonds.

In the brain it seems to be involved in the recognition and establishment of social relationships and could be involved in the formation of relationships of trust and generosity between people.

Synthesis and secretion

Neuronsmagnocellular PVN oxytocin secretaries. PaLM side magnocellular part.

Oxytocin is a hormone and neuropeptide, synthesized by magnocellular neurosecretory nerve cells in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus, from where it is transported by its transport protein, neurophysin, along the axons of hypothalamic neurons to their terminations in the posterior pituitary (neurohypophysis), where it is stored and from where it is secreted into the bloodstream.
The secretion of this substance in the neurosecretory endings is regulated by the electrical activity of the oxytocin cells of the hypothalamus. These cells generate action potentials, which propagate along their axons to the neurohypophysis. These axonal fibers contain large numbers of oxytocin-rich vesicles, which are released by exocytosis when their neurosecretory terminals depolarize.

In the rat, oxytocin is produced in about 9,000 hypothalamic magnocellular neurons, each of which sends an axon to the neurohypophysis, where it presents about 2,000 neurosecretory varicosities.

Structure and relationship with vasopressin

Oxytocin is a peptide of nine amino acids (a nonapeptide). Its sequence is:

cysteine-thyrosine-isoleucine-glutamine-asparagine-cysteine-prolina-leucina-glycin

Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (in the three-letter system),

CYIQNCPLG (in the form of notation of a letter).

Cysteine residues form a disulfide bridge. Oxytocin has a molecular mass of 1007 daltons. One international unit (IU) of oxytocin is equivalent to 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 also with a disulfide bridge, whose sequence differs from that oxytocin in just two amino acids. A table showing the sequences of members of the vasopressin/oxytocin superfamily and the species that express them is available in the Vasopressin article. Oxytocin and vasopressin were isolated 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 posterior pituitary gland in humans that act at a distance. However, oxytocic 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 the magnocellular neurons that make vasopressin and are similar in many respects.

Releasing oxytocin

The main stimuli that cause the release of oxytocin into the bloodstream are nipple sucking, stimulation of the genitals and distension of the cervix, known as the Ferguson reflex.

Effects of oxytocin

Oxytocin (OXT) has peripheral (hormonal) and central (neurotransmitter) effects on the brain.
The effects of OXT are mediated by high-affinity specific receptors (OXT-R). The oxytocin receptor is a G protein-coupled receptor that requires Mg⁺⁺ and cholesterol. It belongs to the rhodopsin-like (class I) Gαq group of G protein-coupled receptors.

Peripheral (hormonal) actions

The peripheral actions of oxytocin are primarily due to secretion from the pituitary gland (see oxytocin receptor for details).

• Breastfeeding – in mothers who breast-feed their children, oxytocin acts in the breast glands causing the secretion of milk to a collective chamber, from which it can be extracted by nipple suction. The sensation of baby suction in the nipple is transmitted by spinal nerves to hypothalamus. The stimulation of the same induces the producing neurons to produce oxytocin by shooting the action potentials in intermittent bursts; these bursts result in the secretion of oxytocin pulses from the neurosecretary nerve terminals of the pituitary gland (activating the secretion of milk and closing the positive feedback circle).

• Uterin contraction – important for cervical dilation prior to delivery, as well as contractions during the secondary and tertiary stages of childbirth. The release of oxytocin during breastfeeding also causes moderate and often annoying contractions during the first weeks of breastfeeding, which helps the recovery of the uterus and the coagulation of the placenta binding area after delivery. However, in studies with mice lacking the specific oxytocin receptor, reproductive and childbirth behaviour was normal.

• The relationship between oxytocin and human sexual response is uncertain. At least two unchecked studies have found increased blood levels of oxytocin during orgasm - both in men and in women. Authors of one of these studies speculate that the effects of oxytocin on genital muscle contraction capacity can facilitate the transport of sperm and egg. Murphy et al. (1987), in a study conducted in men, found that the levels of oxytocin rose during sexual stimulation, and that there was no sharp increase at the time of orgasm. A more recent male study found an increase in blood plasma oxytocin immediately after orgasm, but only in a portion of the sample that did not reach statistical significance. The authors noted that these changes "can simply reflect contactial properties of reproductive tissue."

• Due to its similarity with vasopressin, it can slightly reduce urine excretion. More importantly, in some species, oxytocin can stimulate sodium excretion by the kidneys (natriuresis), and in humans, high doses of oxytocin can lead to hyponatremia.

• Oxytocin and its receptors are also found in the heart, and the hormone may have an important role in the development of the feeling of love, which happens to the human being when in love, behaviors such as palpitations, activation of the sweat glands (sudoration), joy, among other behaviors promoting the differentiation of cardiomyocytes. However, it has not been reported that the absence of oxytocin or its receptor in mice knockout It results in heart failure.
• Modulation of the activity of the hypothalamic-pituitary-adrenal axis. Oxytocin, under certain circumstances, indirectly inhibits the release of adrenocorticotropa and cortisol hormone and, in these situations, may be considered antagonist of vasopressin.

Actions on the brain and effects on behavior

Oxytocin, secreted by the neurohypophysis into the blood, cannot re-enter the brain due to the blood-brain barrier. Therefore, it is thought that the behavioral effects of oxytocin reflect its release by central oxytocic neurons, different from those that secrete it in the pituitary. Oxytocin receptors are expressed on neurons in many parts of the brain and spinal cord, including the amygdala, nucleus accumbens, medial preoptic hypothalamus, ventromedial hypothalamus, bed nucleus of the stria terminalis, septum, central gray matter, and brain stem.

• Sexual excition. Oxytocin injected into the brain spinal fluid causes spontaneous erections in rats, reflecting effects on hypothalamus and spina dorsal.

• In the Microtus ochrogaster rodents, oxytocin released into the female's brain during sexual activity is important for the establishment of monogamic couple ties with their sexual partner. vasopressin seems to have a similar effect on males. In humans, a concentration of oxytocin in higher plasma has been reported among people who claim to be falling in love. Oxytocin has a role in behavior in multiple species and therefore it seems likely to have similar human roles.

• Decrease in autism. A 1998 study found significantly lower levels of oxytocin in blood plasma of autistic children. A 2003 study found a decline in the spectrum of autistic repetitive behaviors when intravenous oxytocin was administered.
  

A 2007 study reported that oxytocin helped autistic adults retain the ability to assess the emotive meaning of intonation when speaking.
An example of this is that research has discovered that the absence of the hormone oxytocin could play a relevant role in the appearance of autism. It is also thought that its function is associated with contact and orgasm.

• Motherly ties. Girls of sheep and rats who receive oxytocin antagonists after giving birth do not exhibit typical maternal behavior. In contrast, virgin female sheep show maternal behavior towards strange lambs by receiving an oxytocin brainspinal infusion, which they would not do otherwise. Studies performed with sheep that are not in gestation period show that the supply of oxytocin in the brain produces artificially maternal reflexes. The administration of estrogen and progesterone, as well as cervical (sexual) vaginal stimulation, produce that same effect. On the contrary, if the sheep is under the effects of epidural anesthesia, the previous effect is neutralized. Babies recognize the vocalizations that mothers direct towards them, which induces complex hormonal processes that exert a particular influence on attachment between mother and child and on the behavior of the baby. In a child suffering from stress, the consolation from her mother's voice activates a hormonal process very similar to that of a child receiving a physical stimulus. The voice activates the production of oxytocin in the human being, while in the case of rats, a physical contact is necessary to produce that effect.

• Building confidence and reducing social fear. In a risky investment game, experimental subjects who received nasally administered oxytocin showed "the highest level of confidence" twice as often as the control group. The subjects to whom they were told that they were interacting with a computer did not show this reaction, leading to the conclusion that oxytocin was not affecting only the perception of risk-aversion. It has also been reported that oxytocin administered nasally reduces fear, possibly inhibiting amygdala (which is thought to be responsible for responses to fear). However, there is no conclusive evidence that oxytocin gains access to the brain by nasal administration. Therefore, this hormone is becoming increasingly important in neuroeconomy, a science that studies the brain mechanisms involved in making financial decisions.

• Action on generosity by increasing empathy during perspective-taking. In a neuroeconomic experiment, intranasal oxytocin increased generosity in the ultimatum Game by 80% but had no effect on the dictator's Game that measures altruism. Perspective taking is not necessary in the Dictator's Game, but the researchers of this experiment explicitly induced the taking of perspective in the Ultimatum Game by not indicating the players on which role they would participate.

• According to some animal studies, oxytocin inhibits the development of tolerance to several addictive drugs (opiates, cocaine, alcohol) and reduces withdrawal symptoms.

• Preparation of fetal neurons for childbirth. Crossing the placenta, maternal oxytocin reaches the fetal brain and induces a change in the action of the GABA neurotransmitter to inhibitor in fetal cortical neurons. This silences the fetal brain during the birth process and reduces its vulnerability to hypoxia.

• Some learning and memory functions are diminished by the central administration of oxytocin.

• MDMA drug (extasy) can increase loving, empathetic and connection feelings to others by stimulating the activity of oxytocin by activating serotonin 5-HT1A receptors, if initial animal studies are extrapolated to humans.

Oxytocin in the sexual act

The hormones oxytocin and vasopressin are involved in the regulation of both male and female sexual motivation. Oxytocin is released at orgasm and is associated with sexual pleasure and the formation of emotional attachments. Based on the pleasure model of sexual motivation, the increase in pleasure from intercourse that occurs after the release of oxytocin it can encourage motivation to engage in future sexual reproductive activities. Emotional closeness may be an especially strong predictor of sexual motivation in women, and insufficient oxytocin release may subsequently decrease sexual reproductive arousal and motivation in women.

High levels of vasopressin can lead to a decrease in sexual motivation for females. A link between vasopressin release and aggression has been observed in females, which can affect sexual arousal and motivation leading to feelings of abandonment and hostility towards a sexual partner. In males, vasopressin It is involved in the arousal phase. Vasopressin levels have been shown to increase during the erectile response upon arousal, and decrease from baseline after ejaculation. The increase in vasopressin during the erectile response may be directly associated with increased motivation to engage in behavior sexual.

Oxytocin and older adults

The generation of oxytocin has positive effects in older adults. Among them are being a rejuvenating agent helping to maintain muscle regeneration. In addition, it helps prevent senile dementia, even, in some cases, alleviating its symptoms.

Pharmaceutical forms

Oxytocin is marketed as Oxytocin (medication). Oxytocin is destroyed in the gastrointestinal tract, and therefore must be administered as an injection or as a nasal spray. It has a typical half-life of three minutes in blood. Given intravenously, it cannot enter the brain in significant amounts because it cannot cross the blood-brain barrier. There is no evidence of significant oxytocin input to the central nervous system when administered as a nasal spray. Oxytocin nasal sprays have been used to stimulate lactation, but the efficiency of this application is questionable.

Injected oxytocin analogues are used to induce and promote labor in arrested labor. It has generally replaced ergotamine and ergonovine or ergometrine as the main agent for increasing uterine tone in postpartum hemorrhage. Oxytocin is also used in veterinary medicine to facilitate parturition and help let-down of milk.
The tocolytic agent atosiban acts as an oxytocin receptor antagonist; This drug is registered in many countries to suppress premature births between weeks 24 and 31 of gestation. It has fewer side effects than other drugs previously used for this purpose (ritodrine, salbutamol, and terbutaline).

Potential Adverse Reactions

Oxytocin is relatively safe when used at recommended doses. Possible side effects include:

• Central Nervous System: subaracnoid bleeding, epileptic crisis.

• Cardiovascular system: tachycardia, arterial hypertension, increased systemic venous return, increased heart load and arrhythmias.

• Genitourinary: problems of uterine blood flow, pelvic hematoma, tetanus uterine contractions, uterin rupture, postpartum bleeding.

• Direct intravenous administration without professional supervision of oxytocin is associated with uterina hypertony, uterina breakage, placental retention.

Evolution

Virtually all vertebrates have an oxytocin-like nonapeptide hormone that facilitates reproductive functions and a vasopressin-like nonapeptide hormone involved in water regulation. The two genes are always close to each other (separated by less than 15,000 base pairs) on the same chromosome and are transcribed in opposite directions. Both genes are thought to have 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).

History of the discovery of oxytocin

In 1953 it was discovered that oxytocin was a short peptide containing 9 amino acid residues, with a disulfide bridge between two cystine moieties in position 1 and 6. For the synthesis of this hormone Du Vigneaud received the Nobel Prize in 1955 and since then, highly purified synthetic oxytocin has been available in obstetrics.

Complementary bibliography

• Paul J. Zak, “Neurobiology of trust”, Mind and Brain40, 2010, pp. 12-17.