Oxytocin

Oxytocin
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
  • AU: A
Intranasal, IV, IM
Pharmacokinetic data
Protein binding 30%
Metabolism hepatic oxytocinases
Half-life 1–6 min (IV)
~2 h (intranasal)[1][2]
Excretion Biliary and renal
Identifiers
50-56-6 Yes
H01BB02
PubChem CID 439302
IUPHAR ligand 2174
DrugBank DB00107 Yes
ChemSpider 388434 Yes
UNII 1JQS135EYN Yes
KEGG D00089 Yes
ChEBI CHEBI:7872 Yes
ChEMBL CHEMBL395429 
Chemical data
Formula C43H66N12O12S2
1007.19 g/mol
  (what is this?)  (verify)
For the narcotic painkiller OxyContin, see Oxycodone.

Oxytocin (/ˌɒksɨˈtoʊsɪn/; Oxt) is a mammalian neurohypophysial hormone. Produced in the supraoptic and paraventricular nuclei of the hypothalamus by nerve axons, and stored in 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. 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.[3]

Recent studies have begun to investigate oxytocin's role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, and maternal behaviors.[4] 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.[5] Furthermore, genetic differences in the oxytocin receptor gene (OXTR) have been associated with maladaptive social traits such as aggressive behaviour.[6]

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.[7]

Structure and relation to vasopressin

Oxytocin (ball-and-stick) bound to its carrier protein neurophysin (ribbons)

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).[8]

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.[9] 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 dehydroascorbate <---> ascorbate redox couple.[10]

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.

Physiological effects

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.[11] 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.

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.[19] 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.[20] Murphy et al. (1987), studying men, found oxytocin levels were raised throughout sexual arousal with no acute increase at orgasm.[21] 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".[22]
Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and security when in the company of the mate.[23] 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.[24]
Empathy in healthy males has been shown to be increased after intranasal oxytocin[48][49] This is most likely due to the effect of oxytocin in enhancing eye gaze.[50] There is some discussion about which aspect of empathy oxytocin might alter – for example, cognitive vs. emotional empathy.[51]

Synthesis, storage, and release

Oxytocin/neurophysin I prepropeptide
Identifiers
SymbolsOXT ; OT; OT-NPI; OXT-NPI
External IDsOMIM: 167050 MGI: 97453 HomoloGene: 55494 GeneCards: OXT Gene
Orthologs
SpeciesHumanMouse
Entrez502018429
EnsemblENSG00000101405ENSMUSG00000027301
UniProtP01178P35454
RefSeq (mRNA)NM_000915NM_011025
RefSeq (protein)NP_000906NP_035155
Location (UCSC)Chr 20:
3.05 – 3.05 Mb		Chr 2:
130.58 – 130.58 Mb
PubMed search

The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene.[78][79][80] This precursor protein also includes the oxytocin carrier protein neurophysin I.[81] 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).[82]

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.[83] 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.[84]

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.[11] The peripheral hormonal and behavioral brain effects of oxytocin are thought to be coordinated through its common release through these collaterals.[11] Oxytocin is also made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.[85] 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 [86][87] and the placenta,[88] in males in the testicles' interstitial cells of Leydig,[89] the retina,[90] the adrenal medulla,[91] the thymus[92] and the pancreas.[93] 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.[94]

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,[95] 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).[52]

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".[96] 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.[97] 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.[98]

Individuals who receive an intranasal dose of oxytocin identify facial expressions of disgust faster than individuals who do not receive oxytocin.[98] 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.[99] 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.[97]

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.[98][100] 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.[100]

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.[96]

Oxytocin is beneficial because it can either enhance social bonding or promote defensive behaviors depending on the situation.[96] 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.

Medical uses

An intravenous infusion of oxytocin is used to induce labor and to support labor in case of difficult parturition. It is unclear whether a high dose is better than a standard dose for labor induction. 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 tocolytic agent 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). [101]

Side effects

Oxytocin is relatively safe when used at recommended doses, and side effects are uncommon.[102] The following maternal events have been reported:[102]

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.

During pregnancy, increased uterine motility has led to decreased heart rate, cardiac arrhythmia, seizures, brain damage, death in the fetus/neonate:[102]

Mechanism of action

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.[103][104] Unlike the case of intravenous administration, intranasal oxytocin has a duration of at least 2.25 hours and as long as 4 hours.[1][2]

Brand names

Synthetic oxytocin is sold as proprietary medication under the trade names Pitocin and Syntocinon, and as generic oxytocin.

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,[105] two decades after its uterine-contracting properties were discovered by British pharmacologist Sir Henry Hallett Dale in 1906.[106] The milk ejection property of oxytocin was described by Ott and Scott in 1910[107] and by Schafer and Mackenzie in 1911.[108]

The nine amino acid sequence of oxytocin was elucidated by Vincent du Vigneaud et al. and by Tuppy in 1953[109] and synthesized biochemically soon after by du Vigneaud et al. in 1953.[110][111] Oxytocin was the first polypeptide hormone to be sequenced and synthesized.[112] Vigneaud was awarded the Nobel Prize in 1955 for his work.[113]

Research

Oxytocin nasal sprays have been used to stimulate breastfeeding, but the efficacy of this approach is doubtful.[114]

The trust-inducing property of oxytocin might help those with social anxiety and depression,[48] but with the potential for abuse with confidence tricks[115][116] and military applications.[117] The use of oxytocin in relationship counseling is being investigated, as research has shown the hormone could both enhance trust and improve people's ability to interpret the emotions of others correctly.[118]

A nasal spray formulation of oxytocin branded Syntocinon is under development by Retrophin for the treatment of lactation deficiency and as a novel treatment for autism and schizophrenia.[119] As of October 2014, it has reached phase III, phase II, and phase II clinical trials for these indications, respectively.[120] In October 2014, Retrophin divested Syntocinon to Turing Pharmaceuticals.[121]

References

  1. ↑ 1.0 1.1 Weisman O, Zagoory-Sharon O, Feldman R (September 2012). "Intranasal oxytocin administration is reflected in human saliva". Psychoneuroendocrinology 37 (9): 1582–6. doi:10.1016/j.psyneuen.2012.02.014. PMID 22436536.
  2. ↑ 2.0 2.1 Huffmeijer R, Alink LR, Tops M et al. (2012). "Salivary levels of oxytocin remain elevated for more than two hours after intranasal oxytocin administration". Neuro Endocrinol. Lett. 33 (1): 21–5. PMID 22467107.
  3. ↑ Marieb Human Anatomy & Physiology 9th edition, chapter:16, p. 599
  4. ↑ Lee HJ, Macbeth AH, Pagani JH, Young WS (June 2009). "Oxytocin: the great facilitator of life". Prog. Neurobiol. 88 (2): 127–51. doi:10.1016/j.pneurobio.2009.04.001. PMC 2689929. PMID 19482229.
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  7. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  8. ↑ Lee AG, Cool DR, Grunwald WC, Neal DE, Buckmaster CL, Cheng MY, Hyde SA, Lyons DM, Parker KJ (August 2011). "A novel form of oxytocin in New World monkeys". Biol. Lett. 7 (4): 584–7. doi:10.1098/rsbl.2011.0107. PMC 3130245. PMID 21411453.
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  36. ↑ Huber D, Veinante P and Stoop R (April 2005). "Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala". Science 308 (5719): 245–8. doi:10.1126/SCIENCE.1105636. PMID 15821089.
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  38. ↑ Shamay-Tsoory SG, Fischer M, Dvash J, Harari H, Perach-Bloom N, Levkovitz Y (November 2009). "Intranasal administration of oxytocin increases envy and schadenfreude (delight in the misfortunes of others)". Biological Psychiatry 66 (9): 864–70. doi:10.1016/j.biopsych.2009.06.009. PMID 19640508.
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