Oxytocin, Vasotocin and Analogs

What is oxytocin?

A neuropeptide, oxytocin has nine amino acids. Parturition, nursing, and pair bonding are all facilitated by this hormone, neurotransmitter, and neuromodulator. An early and influential figure in the study of neurotransmitters, Sir Henry H. Dale, discovered oxytocin in 1906. Using pituitary extracts, Dale (1906) described oxytocin, which induced a strong uterine contraction in pregnant cats. The term "quick birth" comes from oxytocin's physiological properties, which were first discovered. In addition to its role in enhancing interpersonal trust, oxytocin modulates memory and information processing, alleviates stress and anxiety, and decreases pain and inflammatory and immunological responses. Oxytocin enters the periphery through the posterior pituitary after being produced in the hypothalamic paraventricular and supraoptic nuclei. Oxytocin is able to exert its effects all across the central nervous system (CNS) since it is released from synapses and axons. Oxytocin is efficiently transported to many brain regions by cells that originate in the paraventricular nucleus of the hypothalamus (PVN). These regions include the amygdala, BNST, lateral septum, hippocampus, and nucleus accumbens (NAc). According to Neumann and Landgraf (2012), the oxytocin receptor (OTR) is present in different parts of the brain and body depending on the species and gender. The endogenous oxytocin system's activity can vary from one person to another due to factors such as dynamic variations in OTR expression and distinct downstream pathways in specific locations following activation.

Oxytocin peptide

A disulfide bridge connects Cys residues 1 and 6, making all neurohypophysial hormones nonapeptides. The end product is a peptide with a cyclic portion of six amino acids and a three-residue tail that is α-amidated at the COOH end. The amino acid at position 8 determines whether a peptide belongs to the vasopressin or oxytocin family. Peptides in the former include basic amino acids (Lys, Arg), whereas those in the latter have a neutral amino acid. Stimulating oxytocin receptors requires isoleucine at position 3, while acting on vasopressin receptors requires Arg or Lys at position 8. Many think that the polarity difference between these amino acid residues is what allows the vasopressin and oxytocin peptides to bind to their respective receptors. Two peptides, one similar to oxytocin and the other to vasopressin, are present in almost every vertebrate species. Osteichthyes, the ancestors of all vertebrates, have isotocin and vasotocin in their hormone repertoire. As a result, scientists have postulated two distinct evolutionary lines: one for reproductive activities (the isotocin-mesotocin-oxytocin line) and another for water homeostasis (the vasotocin-vasopressin line). The presence of vasotocin in the earliest cyclostomes suggests that vasopressin and oxytocin may have originated from a common ancestor gene that was duplicated during cyclostome radiation. Precursor gene encoding the precursor protein should be about 500 million years old, according to estimations based on oxytocin and vasopressin gene nucleotide levels. A significant selection pressure, maybe through coevolution with specialized processing enzymes or the appropriate receptors, may have contributed to the remarkable structural stability of nonapeptides throughout evolution. Chondrichthyes, a kind of cartilaginous fish, have a very wide variety of oxytocin -like peptides. Rather than salts, urea is used for osmoregulation by these marine fishes. Because they are no longer subject to the regulation of ionic homeostasis, the oxytocin -like hormones in Chondrichthyes may have acquired their remarkable variety. One interesting finding is that the Pacific ratfish, a type of Chondrichthyes, really produces oxytocin, the hormone often seen in placental mammals. All nonmammalian tetrapods, including birds, reptiles, and amphibians, produce mesotocin, an oxytocin -like hormone. This includes lungfishes and marsupials. While every marsupial has mesotocin, just two in South America express oxytocin entirely. The North American opossum (Didelphis virginiana) and the Northern brown bandicoot (Isoodon macrourus) both have oxytocin in addition to mesotocin. After isotocin, which is present in bony fishes, and vasotocin, which is present in all nonmammalian vertebrates, mesotocin has the greatest distribution among vertebrates. Regardless of its constancy, the exact physiological function of this peptide remains unknown. Whether marsupial animals with both oxytocin and mesotocin have two separate receptors is an open question. Annetocin, an oxytocin -related peptide, was first isolated from the most basic species of earthworm, Eisenia foetida. Earthworms and leech larvae can be induced to produce eggs by injecting them with the hormone annetocin.

Oxytocin structure

Oxytocin consists of nine amino acids: Cysteine, Tyrosine, Isoleucine, Glutamine, Asparagine, Cysteine, Proline, Leucine, and Glycine. The first and sixth cysteine residues are linked by a disulfide bond. This link depicts the structure of oxytocin in a circular configuration. The makeup of oxytocin resembles that of vasopressin, another neuropeptide hormone produced in the posterior pituitary. The sole distinction between these two neurohypophyseal hormones is in the third and eighth amino acids.

Oxytocin benefits

Some have referred to oxytocin as a stress hormone, while others have said it helps the body deal with stress. When faced with adversity, oxytocin plays a key role. Oxytocin has several interactions with the immunological, autonomic, and hypothalamic-pituitary-adrenal (HPA) systems; it also regulates stress response and helps the body recover from difficult times. Understanding this part of oxytocin's actions also requires consideration of time. Sodium challenge, great physical exertion, intense pain, pair bond development, ejaculation, or sexual climax are all examples of situations that trigger the release of vasopressin and oxytocin. Oxytocin and social ties may have a function in calming the organism and reducing inflammation in all of these situations. This would aid in the restoration of systems to homeostasis and the prediction of future allostatic demands.

The fact that oxytocin may enhance its own production and release helps to explain why it is used so frequently to aid the process of giving birth. Increasing the future production of endogenous oxytocin can be achieved even in nonpregnant animals by stimulating the release of oxytocin or by providing exogenous oxytocin. Coping with chronic problems, particularly in a social environment, may depend on oxytocin's capacity to feed forward and boost its own synthesis. The ability of vasopressin to feed forward can be amplified by androgens. In contrast to oxytocin, vasopressin often has distinct and, in many cases, opposing long-term consequences.

Oxytocin function

(1) Regulate Uterus

As a long-standing target of oxytocin, the pregnant uterus is only one of several. When administered in a clinical setting, oxytocin induces labor and is among the most powerful uterotonic drugs. As a result, regulating dysmenorrhea and preventing premature labor could benefit from the creation of highly selective oxytocin antagonists. At term, the rat uterine epithelium was seen to express the oxytocin gene. After only three days, estrogen caused a seventy-fold increase in oxytocin mRNA levels, which were higher than hypothalamic oxytocin mRNA levels. The oxytocin gene was shown to be expressed in the amnion and placenta of rats, as well as in the amnion, chorion, and decidua of humans. Most investigations have failed to find any evidence of substantial elevations of oxytocin in maternal plasma or intrauterine tissues prior to the start of labor. However, there is some evidence that the pattern of oxytocin production is related to the progress of pregnancy. Nocturnal uterine activity was positively associated with maternal, but not foetal, oxytocin concentrations in rhesus monkeys, and these concentrations rose steadily during the latter stages of pregnancy and delivery.

(2) Promote milk ejection

Traditional medicine has long held that oxytocin is responsible for the release of milk from the breast gland. Babies start sucking on their nipples at around the same time as their mammary glands start secreting milk. When the touch receptors at that location are stimulated, a cascade of sensory impulses is initiated, starting in the nipples and ending in the hypothalamus's secretory oxytocinergic neurons. Every 5–15 minutes, these neurons engage in a coordinated burst of high-frequency activity, which is characterized by a short (3–4 s) burst of action potential discharge. The lactating breasts get oxytocin via the bloodstream, which receives a tremendous discharge of oxytocin with each burst. In the lactiferous ducts, sinuses, and alveoli of the breast tissue, it stimulates myoepithelial cells to contract. Human breast milk production starts 30 seconds to 1 minute after suctioning starts. This mechanism, which lasts until weaning, is known as milk ejection or the milk let-down reflex.

(3) Regulate Kidney function

Neurohypophysial hormones regulate hydromineral excretion and have the kidney as one of their peripheral target tissues. When the oxytocin and AVP neurons are activated, the blood is flooded with hormones in response to stimuli like hypovolemia or hyperosmolarity. Both hormone levels rise exponentially with increasing plasma sodium concentration after it surpasses 130 mM. oxytocin is a natriuretic that does not cause hypertension. Unlike the volume regulatory components of Na⁺ homeostasis, it is engaged in normal osmolar control. The glomerular filtration rate and effective filtration percentage were somewhat elevated in rats who were given oxytocin acutely and were aware. One of the key mechanisms by which oxytocin produces its natriuretic action is by decreasing tubular Na⁺ reabsorption, most likely in the collecting duct or the terminal distal tubule.

Oxytocin mechanism of action

oxytocin is an oligopeptide hormone composed of nine amino acyl residues, or a nonapeptide hormone. It is one of two hormones that are stored and released by the posterior pituitary gland but produced in the hypothalamus. It is released from the hypothalamic paraventricular nucleus into the posterior pituitary gland to be used later. The pars nervosa, also known as the neural or posterior lobe, is the particular region of the posterior pituitary gland that stores oxytocin. Most hormones cause negative feedback loops after they are produced, but oxytocin is one of the few that exhibits positive feedback loops, which means that the release of oxytocin stimulates the creation of even more oxytocin. This feedback contrasts with antidiuretic hormone (ADH), also known as vasopressin (the second and only other hormone stored and released by the posterior pituitary), which has a negative feedback loop after release. After this hormone has had an effect on the body, less of it is secreted.

The effect on the female reproductive system of exogenous oxytocin is identical to that of endogenous oxytocin. Both forms of oxytocin work by increasing intracellular calcium in uterine myofibrils through G-protein coupled receptors, which in turn promote uterine contractions in the myometrium. When the oxytocin receptor is activated, it sends out a cascade of signals that, through positive feedback, raise intracellular calcium levels, which in turn induce uterine contraction. An increase in the frequency and strength of contractions, made possible by the feedback loop of oxytocin stimulation and subsequent uterine contractions, allows a woman to give birth entirely vaginally. Nerve impulses sent to the mother's brain by the fetus's head pressing on the cervix trigger the posterior pituitary to release oxytocin. The oxytocin is subsequently transported to the uterus via the bloodstream, where it intensifies uterine contractions. This cycle repeats again until the baby is born. The myoepithelial cells in a woman's breasts contract in response to oxytocin, which also stimulates contractions in the uterus. It is in the alveolar ducts that this process takes place. Contractions like this move milk out of the ducts and into the bigger sinuses that allow for milk ejection. This milk-ejection response is similarly affected by positive feedback. In the same way that uterine contractions indicate oxytocin release into the blood after vaginal birth, a baby's effort to latch on to his mother's breast promotes the production of milk from the breast. Concurrently, oxytocin travels to the brain, where it stimulates the release of even more of the hormone.

Therapeutic use of oxytocin

Trust, social recognition, communicative behavior, and attachment were among the many human social behaviors that were found to be improved after intranasal treatment of oxytocin in healthy participants. Additionally, anxiety and cortisol reactions can be reduced with the use of synthetic oxytocin. Clinical investigations have shown promising results in treating social behavior issues (empathy, facial recognition, verbal memory, etc.) using occupational therapy with this non-invasive approach in individuals with autism, schizophrenia, or social anxiety. Patients with Fragile X who also have symptoms of social anxiety showed improvements in eye gazing and lower cortisol responses to a social challenge after receiving intranasal occupational therapy. Research on a variety of mental illnesses, particularly those marked by emotional and/or social dysfunctions, has consistently highlighted occupational therapy as an intriguing adjunctive treatment option.

Synthetic oxytocin

Du Vigneaud's group created an artificial oxytocin in the 1950s; it had the ability to regulate hormone levels when administered. Nevertheless, the Institute for Safe Medication Practices has classified twelve medications, including synthetic oxytocin (SynOT), as "high-alert medications." The FDA has issued a "black box" warning on SynOT, meaning that it should not be used for inducing labor without proper medical grounds. Being the current first-line drug for induced labor and labor augmentation, SynOT can facilitate cervical softening, maturation, and uterine contractions. Doses and concentrations needed may vary depending on factors including cervical maturity and medication susceptibility. On the other hand, harm to mothers and infants might be worsened by synOT use in large quantities.

The negative impacts of synOT on both mothers and infants have been the subject of an increasing amount of research. An even more extreme case of uterine tissue lactate generation might result, for instance, from synOT's enhanced stimulation of uterine contractions. Lactate levels in amniotic fluid increased with increasing synOT dose, suggesting that the contracting uterine muscle was exposed to a more anaerobic environment. This, in turn, reduced the pH of the umbilical artery and raised the likelihood of newborn acidemia and hypoxia. The endogenous oxytocin system, the mother's stress reactivity, mood, and mothering behaviors (including nursing and lactation) may be impacted by synOT exposure during delivery. A negative association between synOT exposure and prefeeding organization at one hour postpartum has been observed, and correlational data imply that synOT during perinatal period may influence the maturation of children's behavioral systems. Particularly rhythmic reflexes like sucking, jaw jerking, and swallowing—which are primordial reflexes that promote the onset of breastfeeding—may be inhibited by SynOT. If oxytocin has the potential to influence other newborn behaviors, more study is required to confirm it.

Oxytocin vs dopamine

Despite their structural differences, oxytocin is a peptide and dopamine is a monoamine; both are released in reaction to social contact, food, sex, and massage, and are classified as reward, feel-good, and love hormones. Dopamine influences CNS function in a broad variety of ways. Autism and depression are among the neuropsychiatric behavioral diseases that have been linked to disruptions in dopaminergic neurotransmission, which can have far-reaching implications on mood and behavior. Uncertainty still surrounds the long-term consequences of dysregulated dopamine function in other brain circuits. It is becoming clear that altered dopamine levels contributing to neuropathologic-related behavioral disorders may impact the neuropeptide oxytocin, which is associated with significant social abnormalities in mental patients. When it comes to sexual behavior, social connection, and affiliation, oxytocin plays a major role. Some individuals with dopamine-dependent illnesses have lately shown abnormalities in peripheral and central oxytocin levels. We conclude that oxytocin interacts with central dopamine systems and is thus a critical substrate in the nervous system. Recent research has linked oxytocin to modulating mesolimbic dopamine pathways in drug addiction and withdrawal, in addition to its effects on psychosocial functioning. Some aspects of sexual behavior have also been linked to this two-way function of dopamine.

Oxytocin vs serotonin

Serotonin (5-HT) and oxytocin are significant neuromodulators involved in the regulation and manifestation of various behaviors, including human emotions and social interactions. Both systems play a role in managing stress, anxiety, and social cooperation. Additionally, their dysfunction is linked to major psychiatric disorders such as depression and autism. Recent animal studies have revealed specific anatomical connections between these two molecules. Serotonergic fibers from the dorsal and medial raphe nuclei of the brainstem project to magnocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus, where oxytocin is released. In this area, 5-HT fibers coincide with the distribution of oxytocin cells. Recent findings indicate that the treatment of oxytocin during the postnatal period enhances the length of serotonergic axons in both the hypothalamus and the amygdala. In exchange, 5-HT can regulate oxytocin secretion via interacting with several 5-HT receptors in the hypothalamus.

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