Oxytocin
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|
| Systematic (IUPAC) name |
| 1-({(4R,7S,10S,13S,16S,19R)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-16-(4-hydroxybenzoyl)-13-[(1S)-1-methylpropyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-4-yl}carbonyl)-L-prolyl-L-leucylglycinamide |
| Clinical data |
| Trade names |
Pitocin |
| AHFS/Drugs.com |
monograph |
| Pregnancy cat. |
A (AU) |
| Legal status |
POM (UK) OTC (US) |
| Routes |
Intranasal, IV, IM |
| Pharmacokinetic data |
| Bioavailability |
nil |
| Protein binding |
30% |
| Metabolism |
hepatic oxytocinases |
| Half-life |
1–6 min |
| Excretion |
Biliary and renal |
| Identifiers |
| CAS number |
50-56-6 Y |
| ATC code |
H01BB02 |
| PubChem |
CID 439302 |
| IUPHAR ligand |
2174 |
| DrugBank |
DB00107 |
| ChemSpider |
388434 Y |
| UNII |
1JQS135EYN Y |
| KEGG |
D00089 Y |
| ChEBI |
CHEBI:7872 Y |
| ChEMBL |
CHEMBL395429 N |
| Chemical data |
| Formula |
C43H66N12O12S2 |
| Mol. mass |
1007.19 g/mol |
SMILES
- CC[C@H](C)[C@@H]1NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H](N)CSSC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC1=O)C(=O)N3CCC[C@H]3C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O
|
InChI
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InChI=1S/C43H66N12O12S2/c1-5-22(4)35-42(66)49-26(12-13-32(45)57)38(62)51-29(17-33(46)58)39(63)53-30(20-69-68-19-25(44)36(60)50-28(40(64)54-35)16-23-8-10-24(56)11-9-23)43(67)55-14-6-7-31(55)41(65)52-27(15-21(2)3)37(61)48-18-34(47)59/h8-11,21-22,25-31,35,56H,5-7,12-20,44H2,1-4H3,(H2,45,57)(H2,46,58)(H2,47,59)(H,48,61)(H,49,66)(H,50,60)(H,51,62)(H,52,65)(H,53,63)(H,54,64)/t22-,25-,26-,27-,28-,29-,30-,31-,35-/m0/s1 Y
Key:XNOPRXBHLZRZKH-DSZYJQQASA-N Y
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| N (what is this?) (verify) |
Oxytocin (//; Oxt) is a mammalian neurohypophysial hormone. Produced by the hypothalamus and stored and secreted by the posterior pituitary gland, oxytocin acts primarily as a neuromodulator in the brain.
Oxytocin plays an important role in the neuroanatomy of intimacy, specifically in sexual reproduction of both sexes, in particular during and after childbirth; its name, meaning "swift childbirth", comes from Greek ὀξύς, oksys "swift" and τόκος, tokos "birth." It is released in large amounts after distension of the cervix and uterus during labor, facilitating birth, maternal bonding, and, after stimulation of the nipples, lactation. Both childbirth and milk ejection result from positive feedback mechanisms.[1]
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 "bonding hormone". There is some evidence that oxytocin promotes ethnocentric behavior, incorporating the trust and empathy of in-groups with their suspicion and rejection of outsiders.[3] Furthermore, genetic differences in the oxytocin receptor gene (OXTR) have been associated with maladaptive social traits such as aggressive behaviour.[4]
It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[5]
Contents
- 1 Medical uses
- 2 Side effects
- 3 Structure and relation to vasopressin
- 4 Actions
- 5 Synthesis, storage, and release
- 5.1 Neural sources
- 5.2 Non-neural sources
- 6 Evolution
- 7 Fear and anxiety response
- 8 History
- 9 References
- 10 Further reading
- 11 External links
Medical uses
Injected oxytocin analogues are used for labor induction and to support labor in case of difficult parturition. It has largely replaced ergometrine as the principal agent to increase uterine tone in acute postpartum hemorrhage. Oxytocin is also used in veterinary medicine to facilitate birth and to stimulate milk release. The tocolyticagent 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).
Synthetic oxytocin is sold as proprietary medication under the trade names Pitocin and Syntocinon, and as generic oxytocin. Oxytocin is destroyed in the gastrointestinal tract, so it must be administered by injection or as nasal spray. It has a half-life of typically about three minutes in the blood when given intravenously. When administered intranasally via a nasal spray, oxytocin crosses the blood–brain barrier and exhibits psychoactive effects in humans.[6] Oxytocin nasal sprays have been used to stimulate breastfeeding, but the efficacy of this approach is doubtful.[7]
The trust-inducing property of oxytocin might help those who suffer from social anxieties and mood disorders,[8] but with the potential for abuse with confidence tricks[9][10] and military applications.[11]
Side effects
Oxytocin is relatively safe when used at recommended doses, and side effects are uncommon.[12] The following maternal events have been reported:[12]
- 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
- Birth
- Increase fetal blood flow
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:[12]
- Decreased heart rate or heart rate decelerations
- Cardiac arrhythmia
- Brain damage
- Seizures
- Death
Structure and relation to vasopressin
Oxytocin is a peptide of nine amino acids (a nonapeptide). Its systematic name is cysteine-tyrosine-isoleucine-glutamine-asparagine-cysteine-proline-leucine-glycine-amide (cys – tyr – ile – gln – asn – cys – pro – leu – gly – NH2, or CYIQNCPLG-NH2). Oxytocin has a molecular mass of 1007 daltons. One international unit (IU) of oxytocin is the equivalent of about 2 micrograms of pure peptide. While the structure of oxytocin is highly conserved in placental mammals, a novel structure of oxytocin was recently reported in marmosets, tamarins, and other new world primates. Genomic sequencing of the gene for oxytocin revealed a single in-frame mutation (thymine for cytosine) which results in a single amino acid substitution at the 8-position (proline for leucine).[13]
The biologically active form of oxytocin, commonly measured by RIA and/or HPLC techniques, is also known as the octapeptide "oxytocin disulfide" (oxidized form), but oxytocin also exists as a reduced dithiol nonapeptide called oxytoceine.[14] It has been theorized that open chain oxytoceine (the reduced form of oxytocin) may also act as a free radical scavenger (by donating an electron to a free radical); oxytoceine may then be oxidized back to oxytocin via the redox potential of dehydroascorbate <---> ascorbate.[15]
Oxytocin (ball-and-stick) bound to its carrier protein neurophysin (ribbons)
The structure of oxytocin is very similar to that of vasopressin (cys – tyr – phe – gln – asn – cys – pro – arg – gly – NH2), also a nonapeptide with a sulfur bridge, whose sequence differs from oxytocin by two 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 and dynorphin, for example, that act locally. The magnocellular neurosecretory cells that make oxytocin are adjacent to magnocellular neurosecretory cells that make vasopressin. These are large neuroendocrine neurons which are excitable and can generate action potentials.
Actions
Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. Its actions are mediated by specific, high-affinity oxytocin receptors. The oxytocin receptor is a G-protein-coupled receptor that requires Mg2+ and cholesterol. It belongs to the rhodopsin-type (class I) group of G-protein-coupled receptors.
The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. (See oxytocin receptor for more detail on its action.) 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 that are collaterals from them.[16] 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.
- 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.[17] Suckling 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, oxytocin 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.[18]
- Social behavior[3][19] and wound healing: Oxytocin is also thought to modulate inflammation by decreasing certain cytokines. Thus, the increased release in oxytocin following positive social interactions has the potential to improve wound healing. A study by Marazziti and colleagues used heterosexual couples to address this possibility. They found increases in plasma oxytocin following a social interaction were correlated with faster wound healing. They hypothesized this was due to oxytocin reducing inflammation, thus allowing the wound to heal faster. This study provides preliminary evidence that positive social interactions may directly impact aspects of health.[20]
- The relationship between oxytocin and human sexual response is unclear. At least two uncontrolled studies have found increases in plasma oxytocin at orgasm – in both men and women.[21][22] Plasma oxytocin levels are notably increased around the time of self-stimulated orgasm and are still higher than baseline when measured five minutes after self arousal.[21] The authors of one of these studies speculated that oxytocin's effects on muscle contractibility may facilitate sperm and egg transport.[21]
- In a study measuring oxytocin serum levels in women before and after sexual stimulation, the author suggests it serves an important role in sexual arousal. This study found genital tract stimulation resulted in increased oxytocin immediately after orgasm.[23] Another study reported increases of oxytocin during sexual arousal could be in response to nipple/areola, genital, and/or genital tract stimulation as confirmed in other mammals.[24] Murphy et al. (1987), studying men, found oxytocin levels were raised throughout sexual arousal with no acute increase at orgasm.[25] 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 these changes "may simply reflect contractile properties on reproductive tissue".[26]
- Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and security around the mate.[27] This suggests oxytocin may be important for the inhibition of the brain regions associated with behavioral control, fear, and anxiety, thus allowing orgasm to occur. Research has also demonstrated that oxytocin can decrease anxiety and protect against stress, particularly in combination with social support.[28]
- 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 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.[29][30] However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.[18]
- 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 an antagonist of vasopressin.[31]
- Autism: Oxytocin may play a role in autism and may be an effective treatment for autism's repetitive and affiliative behaviors.[32] Oxytocin treatments also resulted in an increased retention of affective speech in adults with autism.[33] Two related studies in adults, in 2003 and 2007, found 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.[34] Oxytocin has also been implicated in the etiology of autism, with one report suggesting 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.[33][35] Autism may also be associated with an aberrant methylation of OXTR.[33] After treatment with inhaled oxytocin, autistic patients exhibit more appropriate social behavior.[36] 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.[37]
- 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 they were interacting with a computer showed no such reaction, leading to the conclusion that oxytocin was not merely affecting risk aversion.[38] Nasally administered oxytocin has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses).[39] Indeed, studies in rodents have shown oxytocin can efficiently inhibit fear responses by activating an inhibitory circuit within the amygdala.[40][41] Some researchers have argued oxytocin has a general enhancing effect on all social emotions, since intranasal administration of oxytocin also increases envy and Schadenfreude.[42]
- Trust is increased by oxytocin.[43][44][45] Disclosure of emotional events is a sign of trust in humans. When recanting a negative event, humans that receive intranasal oxytocin share more emotional details and stories with more emotional significance.[44] Humans also find faces more trustworthy after receiving intranasal oxytocin. In a study, participants that received intranasal oxytocin viewed photographs of human faces with neutral expressions and found them to be more trustworthy than those who did not receive oxytocin.[43] This may be because oxytocin reduces the fear of social betrayal in humans.[46] Even after experiencing social alienation by being excluded from a conversation, humans that received oxytocin scored higher in trust on the Revised NEO Personality Inventory.[45]
- While Oxytocin increases trust,[43][44][45] it does so only to a certain degree. In a study, participants played a variation of the trust game and acted as an “investor,” deciding how much money to allocate to a “trustee.”[47] The trustee was described as trustworthy, untrustworthy, or neutral. Participants that received intranasal oxytocin gave more money to the trustworthy and neutral trustees. Participants that received oxytocin did not give more money to the untrustworthy trustee, implying that oxytocin only increases trust when there is no reason to be distrustful.[45] When there is a reason to be distrustful, such as experiencing betrayal, differing reactions are associated with oxytocin receptor gene (OXTR) differences. Those with the CT haplotype experience a stronger reaction, in the form of anger, to betrayal.[48]
- Oxytocin affects social distance between adult males and females, and may be responsible at least in part for romantic attraction and subsequent monogamous pair bonding. An oxytocin nasal spray caused men in a monogamous relationship, but not single men, to increase the distance between themselves and an attractive woman during a first encounter by 10 to 15 centimeters. The researchers suggested that oxytocin may help promote fidelity within monogamous relationships.[49]
- Affecting generosity by increasing empathy during perspective taking: In a neuroeconomics experiment, intranasal oxytocin increased generosity in the Ultimatum Game by 80%, but had 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 into which role they would be placed.[50] Serious methodological questions have arisen, however, with regard to the role of oxytocin in trust and generosity.[51]
- Empathy in healthy males has been shown to be increased after intranasal oxytocin[8][52] This is most likely due to the effect of oxytocin in enhancing eye gaze.[53] There is some discussion about which aspect of empathy oxytocin might alter – for example, cognitive vs. emotional empathy.[54]
- Cognitive function: Certain learning and memory functions are impaired by centrally administered oxytocin.[55] Also, systemic oxytocin administration can impair memory retrieval in certain aversive memory tasks.[56] Interestingly, oxytocin does seem to facilitate learning and memory specifically for social information. Healthy males administered intranasal oxytocin show improved memory for human faces, in particular happy faces.[57][58] They also show improved recognition for positive social cues over threatening social cues [59][60] and improved recognition of fear.[61]
- Sexual arousal: Oxytocin injected into the cerebrospinal fluid causes spontaneous erections in rats,[55] reflecting actions in the hypothalamus and spinal cord. Centrally administrated oxytocin receptor antagonists can prevent noncontact 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.[62]
- 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.[63] Oxytocin has a role in social behaviors in many species, so it likely also does in humans. In a 2003 study, both humans and dog oxytocin levels in the blood rose after five to 24 minutes of a petting session. This possibly plays a role in the emotional bonding between humans and dogs.[64]
- Maternal behavior: Female rats given oxytocin antagonists after giving birth do not exhibit typical maternal behavior.[65] By contrast, virgin female sheep show maternal behavior toward foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise.[66] 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.[67]
- Drug interactions: According to some studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol), and reduces withdrawal symptoms.[68] MDMA (ecstasy) may increase feelings of love, empathy, and connection to others by stimulating oxytocin activity primarily via activation of serotonin 5-HT1A receptors, if initial studies in animals apply to humans.[69] The anxiolytic Buspar (buspirone) may produce some of its effects via 5-HT1A receptor-induced oxytocin stimulation as well.[70][71]
- 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.[72]
- Romantic attachment: In some studies, high levels of plasma oxytocin have been correlated with romantic attachment. For example, if a couple is separated for a long period of time, anxiety can increase due to the lack of physical affection. Oxytocin may aid romantically attached couples by decreasing their feelings of anxiety when they are separated.[27]
Synthesis, storage, and release
| Oxytocin/neurophysin I prepropeptide |
| Identifiers |
| Symbols |
OXT ; OT; OT-NPI; OXT-NPI |
| External IDs |
OMIM: 167050 MGI: 97453 HomoloGene: 55494 GeneCards: OXT Gene |
| Gene ontology |
| Molecular function |
• neurohypophyseal hormone activity
• oxytocin receptor binding
|
| Cellular component |
• extracellular region
• extracellular space
• secretory granule
• terminal bouton
|
| Biological process |
• response to amphetamine
• regulation of heart rate
• maternal aggressive behavior
• signal transduction
• elevation of cytosolic calcium ion concentration
• heart development
• female pregnancy
• memory
• grooming behavior
• response to sucrose stimulus
• positive regulation of norepinephrine secretion
• response to activity
• sleep
• positive regulation of prostaglandin secretion
• response to estradiol stimulus
• response to retinoic acid
• response to progesterone stimulus
• response to prostaglandin E stimulus
• social behavior
• negative regulation of urine volume
• positive regulation of renal sodium excretion
• response to cocaine
• hyperosmotic salinity response
• maternal behavior
• sperm ejaculation
• eating behavior
• drinking behavior
• response to peptide hormone stimulus
• response to ether
• negative regulation of blood pressure
• positive regulation of blood pressure
• positive regulation of ossification
• positive regulation of female receptivity
• positive regulation of synaptic transmission
• response to glucocorticoid stimulus
• response to cAMP
• response to electrical stimulus
• regulation of sensory perception of pain
• positive regulation of synapse assembly
• male mating behavior
• positive regulation of penile erection
• positive regulation of hindgut contraction
• negative regulation of gastric acid secretion
• positive regulation of uterine smooth muscle contraction
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| Sources: Amigo / QuickGO |
|
| Orthologs |
| Species |
Human |
Mouse |
|
| Entrez |
5020 |
18429 |
|
| Ensembl |
ENSG00000101405 |
ENSMUSG00000027301 |
|
| UniProt |
P01178 |
P35454 |
|
| RefSeq (mRNA) |
NM_000915 |
NM_011025 |
|
| RefSeq (protein) |
NP_000906 |
NP_035155 |
|
| Location (UCSC) |
Chr 20:
3.05 – 3.05 Mb |
Chr 2:
130.58 – 130.58 Mb |
|
| PubMed search |
[1] |
[2] |
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The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene.[73][74][75] This precursor protein also includes the oxytocin carrier protein neurophysin I.[76] The inactive precursor protein is progressively hydrolyzed into smaller fragments (one of which is neurophysin I) via a series of enzymes. The last hydrolysis that releases the active oxytocin nonapeptide is catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM).[77]
The activity of the PAM enzyme system is dependent upon vitamin C (ascorbate), which is a necessary vitamin cofactor. By chance, sodium ascorbate by itself was found to stimulate the production of oxytocin from ovarian tissue over a range of concentrations in a dose-dependent manner.[78] 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.[79]
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.[16] The peripheral hormonal and behavioral brain effects of oxytocin are thought to be coordinated through its common release through these collaterals.[16] Oxytocin is also made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.[80] 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.
Non-neural sources
Outside the brain, oxytocin-containing cells have been identified in several diverse tissues, including in females in the corpus luteum [81][82] and the placenta,[83] in males in the testicles'interstitial cells of Leydig,[84] the retina,[85] the adrenal medulla,[86] the thymus[87] and the pancreas.[88] 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.
Male
The Leydig cells in some species have been shown to possess the biosynthetic machinery to manufacture testicular oxytocin de novo, to be specific, in rats (which can synthesize vitamin C endogenously), and in guinea pigs, which, like humans, require an exogenous source of vitamin C (ascorbate) in their diets.[89]
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 F2α to cause regression of the corpus luteum.
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,[90] the homologs are further apart and transcribed in the same direction).
The two genes are believed to result 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).[55]
Fear and anxiety response
Oxytocin is typically remembered for the effect it has on prosocial behaviors, such as its role in facilitating trust and attachment between individuals. Consequently, oxytocin is often referred to as the “love hormone".[91] However, oxytocin has a more complex role than solely enhancing prosocial behaviors. There is consensus that oxytocin modulates fear and anxiety; that is, it does not directly elicit fear or anxiety.[92] Two dominant theories explain the role of oxytocin in fear and anxiety. One theory states that oxytocin increases approach/avoidance to certain social stimuli and the second theory states that oxytocin increases the salience of certain social stimuli, causing the animal or human to pay closer attention to socially relevant stimuli.[93]
Individuals who receive an intranasal dose of oxytocin identify facial expressions of disgust faster than individuals who do not receive oxytocin.[93] Facial expressions of disgust are evolutionarily linked to the idea of contagion. Thus, oxytocin increases the salience of cues that imply contamination, which leads to a faster response because these cues are especially relevant for survival. In another study, after administration of oxytocin, individuals displayed an enhanced ability to recognize expressions of fear compared to the individuals who received the placebo.[94] Oxytocin modulates fear responses by enhancing the maintenance of social memories. Rats that are genetically modified to have a surplus of oxytocin receptors display a greater fear response to a previously conditioned stressor. Oxytocin enhances the aversive social memory, leading the rat to display a greater fear response when the aversive stimulus is encountered again.[92]
- Gender differences
To make the role of oxytocin even more complex, it has been shown that oxytocin differentially affects males and females. Females who are administered oxytocin are overall faster in responding to socially relevant stimuli than males who received oxytocin.[95][96] Additionally, after the administration of oxytocin, females show increased amygdala activity in response to threatening scenes; however, males do not show increased amygdala activation. This phenomenon can be explained by looking at the role of gonadal hormones, specifically estrogen, which modulate the enhanced threat processing seen in females. Estrogen has been shown to stimulate the release of oxytocin from the hypothalamus and promote receptor binding in the amygdala.[96]
- Effect in predictable and unpredictable stimuli
Oxytocin increases defensive responding to unpredictable stimuli, but not to predictable stimuli. This result leads to the assumption that oxytocin’s effect is context-dependent. Thus, oxytocin may reinforce prosocial behaviors after an initial bond is formed, but may enhance defensive behaviors to unfamiliar individuals.[91]
Oxytocin is beneficial because it can either enhance social bonding or promote defensive behaviors depending on the situation.[91] It would not be adaptive if oxytocin consistently enhanced social approach and other prosocial behaviors, especially in uncertain and potentially dangerous social contexts. Fear and anxiety are typically thought to be maladaptive, as these traits often underlie various psychological disorders. However, it is important to note that both fear and anxiety responses help to protect an individual. These emotions render environmental cues more important, leading to a greater likelihood the individual or animal will acknowledge the potential threat. Ultimately this process leads to a greater chance of survival.
History
The word oxytocin was coined from the term oxytocic (used at least in the 1800s to refer to agents such as ergots that would cause uterine stimulation; Greekὀξύς, oxys, and τόκος, tokos, meaning "quick birth") by chemists at Parke, Davis, and Company around 1927,[97] two decades after its uterine-contracting properties were discovered by British pharmacologist Sir Henry Hallett Dale in 1906.[98] The milk ejection property of oxytocin was described by Ott and Scott in 1910[99] and by Schafer and Mackenzie in 1911.[100]
The nine amino acid sequence of oxytocin was elucidated by Vincent du Vigneaud et al.and by Tuppy in 1953[101] and synthesized biochemically soon after by du Vigneaud et al. in 1953.[102][103] Oxytocin was the first polypeptide hormone to be sequenced and synthesized.[104] Vigneaud was awarded the Nobel Prize in 1955 for his work.[105]
References
- ^ Marieb Human Anatomy & Physiology 9th edition, chapter:16, page:599
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- ^ du Vigneaud V, Ressler C, Swan JM, Roberts CW, Katsoyannis PG (June 1954). "The synthesis of oxytocin". J. Am. Chem. Soc. 76 (12): 3115–3121. doi:10.1021/ja01641a004.
- ^ du Vigneaud V, Ressler C, Swan JM, Roberts CW, Katsoyannis PG (1954). "The Synthesis of Oxytocin1". Journal of the American Chemical Society 76 (12): 3115–3121. doi:10.1021/ja01641a004.
- ^ du Vigneaud V (1956). "Trail of sulfur research: from insulin to oxytocin". Science 123 (3205): 967–74. doi:10.1126/science.123.3205.967. PMID 13324123.
Further reading
- Lee HJ, Macbeth AH, Pagani JH, Young WS (June 2009). "Oxytocin: the Great Facilitator of Life". Progress in Neurobiology 88 (2): 127–51. doi:10.1016/j.pneurobio.2009.04.001. PMC 2689929. PMID 19482229.
- Caldwell HK, Young WS III (2006). "Oxytocin and Vasopressin: Genetics and Behavioral Implications". In Abel L, Lim R. Handbook of neurochemistry and molecular neurobiology. Berlin: Springer. pp. 573–607. ISBN 0-387-30348-0.
External links
- Trust, Morality and Oxytocin, a TED talk by Paul J. Zak (July 2011)
- Molecular neurobiology of social bonding: Implications for autism spectrum disorders, a National Institutes of Health lecture by Larry Young (January 4, 2010)
- The science of love: I get a kick out of you from The Economist (February 12, 2004)
- Endocrine system:
- hormones
- Peptide hormones
- Steroid hormones
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Endocrine
glands |
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Hypothalamic-
pituitary
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Hypothalamus
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- GnRH
- TRH
- Dopamine
- CRH
- GHRH/Somatostatin
- Melanin concentrating hormone
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Posterior pituitary
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Anterior pituitary
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- α
- FSH
- FSHB
- LH
- LHB
- TSH
- TSHB
- CGA
- Prolactin
- POMC
- CLIP
- ACTH
- MSH
- Endorphins
- Lipotropin
- GH
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Adrenal axis
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Adrenal cortex:
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- aldosterone
- cortisol
- DHEA
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Adrenal medulla:
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- epinephrine
- norepinephrine
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Thyroid axis
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Thyroid:
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- thyroid hormone
- calcitonin
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Parathyroid:
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Gonadal axis
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Testis::
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Ovary:
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- estradiol
- progesterone
- activin and inhibin
- relaxin (pregnancy)
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Placenta:
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- hCG
- HPL
- estrogen
- progesterone
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Islet-Acinar
Axis
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Pancreas:
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- glucagon
- insulin
- amylin
- somatostatin
- pancreatic polypeptide
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Pineal gland
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Other
glands |
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Thymus:
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- Thymosins
- Thymosin α1
- Beta thymosins
- Thymopoietin
- Thymulin
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Digestive system:
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Stomach:
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Duodenum:
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- CCK
- Incretins
- secretin
- motilin
- VIP
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Ileum:
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- enteroglucagon
- peptide YY
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Liver/other
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- Insulin-like growth factor
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Adipose tissue:
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- leptin
- adiponectin
- resistin
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Skeleton::
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Kidney:
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- JGA (renin)
- peritubular cells
- calcitriol
- prostaglandin
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Heart:
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noco (d)/cong/tumr, sysi/epon
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proc, drug (A10/H1/H2/H3/H5)
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Hypothalamic-pituitary hormones and analogues (H01)
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| Hypothalamic |
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GNRH
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- Agonists: Gonadorelin
- Nafarelin
- Histrelin
Antagonists: Cetrorelix
- Ganirelix
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Somatostatin
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- Agonists: Lanreotide
- Octreotide
- Pasireotide
- Vapreotide
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| Anterior pituitary |
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ACTH
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- Agonists: Corticotropin
- Cosyntropin
- Tetracosactide
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GH
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- Agonists: IGF-1 (Mecasermin/Mecasermin rinfabate)
- Sermorelin
- Somatrem
- Tesamorelin
Antagonists: Pegvisomant
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TSH
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| Posterior pituitary |
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Oxytocin
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- Agonists: Argiprestocin
- Aspartocin
- Carbetocin
- Cargutocin
- Demoxytocin
- Nacartocin
Antagonists: Atosiban
- Barusiban
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Vasopressin
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- Agonists: Argipressin
- Desmopressin
- Felypressin
- Lypressin
- Ornipressin
- Terlipressin
Antagonists: Conivaptan
- Demeclocycline
- Lixivaptan
- Mozavaptan
- Nelivaptan
- Relcovaptan
- Satavaptan
- Tolvaptan
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noco (d)/cong/tumr, sysi/epon
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proc, drug (A10/H1/H2/H3/H5)
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Uterotonics/labor inducers/oxytocics (G02A)
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| Cervical ripening |
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Ergot alkaloids
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- Ergometrine# (+oxytocin)
- Methylergometrine
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Prostaglandins and
analogues
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- E: Misoprostol/E1#
- Gemeprost/E1
- Dinoprostone/E2
- Sulprostone/E2
- F: Dinoprost/F2α
- Carboprost/F2α
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| Contraction induction |
- Oxytocin#
- Carbetocin
- Demoxytocin
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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Neuropeptidergics
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| Cholecystokinin |
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CCKA
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- Agonists: Cholecystokinin
- CCK-4
Antagonists: Amiglumide
- Asperlicin
- Devazepide
- Dexloxiglumide
- Lintitript
- Lorglumide
- Loxiglumide
- Pranazepide
- Proglumide
- Tarazepide
- Tomoglumide
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CCKB
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- Agonists: Cholecystokinin
- CCK-4
- Gastrin
Antagonists: CI-988 (PD-134,308)
- Itriglumide
- L-365,360
- Netazepide
- Proglumide
- Spiroglumide
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| CRH |
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CRF1
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- Agonists: Corticorelin
- Corticotropin releasing hormone
- Sauvagine
- Stressin I
- Urocortin
Antagonists: Antalarmin
- Astressin-B
- CP-154,526
- LWH-234
- NBI-27914
- Pexacerfont
- R-121,919
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CRF2
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- Agonists: Corticorelin
- Corticotropin releasing hormone
- Sauvagine
- Urocortin
Antagonists: Astressin-B
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| Galanin |
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GAL1
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- Agonists: Galanin
- Galanin-like peptide
- Galmic
- Galnon
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GAL2
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- Agonists: Galanin
- Galanin-like peptide
- Galmic
- Galnon
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GAL3
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- Agonists: Galanin
- Galmic
- Galnon
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| MCH |
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MCH1
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- Agonists: Melanin concentrating hormone
Antagonists: ATC-0175
- GW-803,430
- NGD-4715
- SNAP-7941
- SNAP-94847
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MCH2
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- Agonists: Melanin concentrating hormone
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| Melanocortin |
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MC1
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- Agonists: alpha-MSH
- Afamelanotide
- BMS-470,539
- Bremelanotide
- Melanotan II
Antagonists: Agouti signalling peptide
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MC2
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- Agonists: ACTH
- Cosyntropin
- Tetracosactide
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MC3
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- Agonists: alpha-MSH
- Bremelanotide
- Melanotan II
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MC4
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- Agonists: alpha-MSH
- Bremelanotide
- Melanotan II
- PF-00446687
- THIQ
Antagonists: Agouti-related peptide
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MC5
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- Agonists: alpha-MSH
- Melanotan II
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Unsorted
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- Agonists: Alsactide
- Codactide
- Giractide
- Norleusactide
- Seractide
- Tosactide
- Tricosactide
- Tridecactide
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| Neuropeptide S |
- Agonists: Neuropeptide S
Antagonists: SHA-68
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| Neuropeptide Y |
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Y1
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- Agonists: Neuropeptide Y
- Peptide YY
Antagonists: BIBP-3226
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Y2
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- Agonists: Neuropeptide Y
- Peptide YY
Antagonists: BIIE-0246
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Y4
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- Agonists: Neuropeptide Y
- Pancreatic polypeptide
- Peptide YY
Antagonists: UR-AK49
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Y5
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- Agonists: Neuropeptide Y
- Peptide YY
Antagonists: Lu AA-33810
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| Neurotensin |
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NTS1
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- Agonists: Neurotensin
- Neuromedin N
Antagonists: Meclinertant
- SR-142,948
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NTS2
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- Agonists: Neurotensin
Antagonists: Levocabastine
- SR-142,948
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| Opioid |
See Template:Opioidergics instead.
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| Orexin |
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OX1
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- Agonists: Orexin-A
Antagonists: Almorexant
- Filorexant
- SB-334,867
- SB-408,124
- SB-649,868
- Suvorexant
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OX2
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- Agonists: Orexin-A
Antagonists: Almorexant
- Filorexant
- SB-649,868
- Suvorexant
- TCS-OX2-29
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| Oxytocin |
- Agonists: Aspartocin
- Carbetocin
- Cargutocin
- Demoxytocin
- Nacartocin
- Oxytocin
- TC OT 39
- TGOT
- Vasotocin (argiprestocin)
- WAY-267,464
Antagonists: Atosiban
- Barusiban
- Epelsiban
- L-368,899
- L-371,257
- L-372,662
- Retosiban
- SSR-126,768
- Tocinoic acid
- WAY-162,720
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| Tachykinin |
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NK1
|
- Agonists: Substance P
Antagonists: Aprepitant
- Befetupitant
- Burapitant
- Casopitant
- CI-1021
- CP-96,345
- CP-99,994
- CP-122,721
- Dapitant
- Ezlopitant
- Figopitant
- FK-888
- Fosaprepitant
- GR-203,040
- GW-597,599
- HSP-117
- L-733,060
- L-741,671
- L-743,310
- L-758,298
- Lanepitant
- LY-306,740
- Maropitant
- Netupitant
- NKP-608
- Nolpitantium besilate
- Orvepitant
- Rolapitant
- RP-67,580
- SDZ NKT 343
- Serlopitant
- Telmapitant
- Vestipitant
- Vofopitant
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NK2
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- Agonists: Neurokinin A
Antagonists: GR-159,897
- Ibodutant
- Nepadutant
- Saredutant
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NK3
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- Agonists: Neurokinin B
Antagonists: Osanetant
- Talnetant
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| Vasopressin |
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V1A
|
- Agonists: Felypressin
- Lypressin
- Ornipressin
- Selepressin
- Terlipressin
- Vasopressin (argipressin)
- Vasotocin (argiprestocin)
Antagonists: Atosiban
- Conivaptan
- Demeclocycline
- PF-184563
- Relcovaptan
- RG7314
- TC OT 39
- WAY-267,464
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V1B
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- Agonists: Desmopressin
- Felypressin
- Lypressin
- Ornipressin
- Terlipressin
- Vasopressin (argipressin)
- Vasotocin (argiprestocin)
Antagonists: Demeclocycline
- Nelivaptan
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V2
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- Agonists: Desmopressin
- Felypressin
- Lypressin
- Ornipressin
- TC OT 39
- Terlipressin
- Vasopressin (argipressin)
- Vasotocin (argiprestocin)
Antagonists: Conivaptan
- Demeclocycline
- Lixivaptan
- Mozavaptan
- Satavaptan
- Tolvaptan
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