Endogenous Metabolite
- The primary target of Oxytocin is the oxytocin receptor (OTR) [1]
- The primary target of Oxytocin is the oxytocin receptor (OTR) [2]

Oxytocin is a pleiotropic, peptide hormone with broad implications for general health, adaptation, development, reproduction, and social behavior. Endogenous oxytocin and stimulation of the oxytocin receptor support patterns of growth, resilience, and healing. Oxytocin can function as a stress-coping molecule, an anti-inflammatory, and an antioxidant, with protective effects especially in the face of adversity or trauma. Oxytocin influences the autonomic nervous system and the immune system. These properties of oxytocin may help explain the benefits of positive social experiences and have drawn attention to this molecule as a possible therapeutic in a host of disorders. However, as detailed here, the unique chemical properties of oxytocin, including active disulfide bonds, and its capacity to shift chemical forms and bind to other molecules make this molecule difficult to work with and to measure. The effects of oxytocin also are context-dependent, sexually dimorphic, and altered by experience. In part, this is because many of the actions of oxytocin rely on its capacity to interact with the more ancient peptide molecule, vasopressin, and the vasopressin receptors. In addition, oxytocin receptor(s) are epigenetically tuned by experience, especially in early life. Stimulation of G-protein-coupled receptors triggers subcellular cascades allowing these neuropeptides to have multiple functions. The adaptive properties of oxytocin make this ancient molecule of special importance to human evolution as well as modern medicine and health; these same characteristics also present challenges to the use of oxytocin-like molecules as drugs that are only now being recognized. SIGNIFICANCE STATEMENT: Oxytocin is an ancient molecule with a major role in mammalian behavior and health. Although oxytocin has the capacity to act as a "natural medicine" protecting against stress and illness, the unique characteristics of the oxytocin molecule and its receptors and its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug [2].

The pituitary neuropeptide oxytocin promotes social behavior, and is a potential adjunct therapy for social deficits in schizophrenia and autism. Oxytocin may mediate pro-social effects by modulating monoamine release in limbic and cortical areas, which was investigated herein using in vivo microdialysis, after establishing a dose that did not produce accompanying sedative or thermoregulatory effects that could concomitantly influence behavior. The effects of oxytocin (0.03-0.3 mg/kg subcutaneous) on locomotor activity, core body temperature, and social behavior (social interaction and ultrasonic vocalizations) were examined in adult male Lister-hooded rats, using selective antagonists to determine the role of oxytocin and vasopressin V1a receptors. Dopamine and serotonin efflux in the prefrontal cortex and nucleus accumbens of conscious rats were assessed using microdialysis. 0.3 mg/kg oxytocin modestly reduced activity and caused hypothermia but only the latter was attenuated by the V1a receptor antagonist, SR49059 (1 mg/kg intraperitoneal). Oxytocin at 0.1 mg/kg, which did not alter activity and had little effect on temperature, significantly attenuated phencyclidine-induced hyperactivity and increased social interaction between unfamiliar rats without altering the number or pattern of ultrasonic vocalizations. In the same rats, oxytocin (0.1 mg/kg) selectively elevated dopamine overflow in the nucleus accumbens, but not prefrontal cortex, without influencing serotonin efflux. Systemic oxytocin administration attenuated phencyclidine-induced hyperactivity and increased pro-social behavior without decreasing core body temperature and selectively enhanced nucleus accumbens dopamine release, consistent with activation of mesocorticolimbic circuits regulating associative/reward behavior being involved. This highlights the therapeutic potential of oxytocin to treat social behavioral deficits seen in psychiatric disorders such as schizophrenia [1].

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- In rats, administration of Oxytocin attenuated phencyclidine (PCP)-induced hyperactivity, increased social interaction behavior, and enhanced dopamine release in the nucleus accumbens [1]

Analysis of monoamines[1]
Microdialysis samples were analyzed using High Performance Liquid Chromatography with electrochemical detection as described previously. Defrosted samples were kept on ice before injection (15 µl) into a Targa C18 3 µM column (100 × 1.0 m) using a Perkin Elmer Series 200 autosampler. Dopamine, 5-HT and their major metabolites; 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were detected using a mobile phase (20 mM potassium dihydrogen phosphate, 20 mM sodium acetate, 0.1 mM ethylenediaminetetraacetic acid, 0.15 mM octanesulfonic acid, and 10% methanol, pH 3.9) at 0.4 ml/min (Dionex P680 pump), and measured against standards with a DECADE II SDC Detector I and Clarity software using a potential of + 0.75 V. The percentage change from baseline for every microdialysate molecule was calculated for each individual rat. PFC samples were excluded from one rat due to incorrect probe placement and two others because of flow disruption. In one rat NAc dopamine was below the detection limit; n = 6/7 per group in the PFC, and n = 7/8 in the NAc.

Dose–response and antagonist studies with oxytocin on core body temperature and locomotor activity[1]
To establish a suitable dose of oxytocin, which would not suppress locomotor activity (LMA) or produce hypothermia during microdialysis studies, rats (n = 12) were tested using a within-subjects design on four occasions at weekly intervals following injection of vehicle and each dose of oxytocin (0.03, 0.1, or 0.3 mg/kg s.c.) in a pseudo-random order to serve as their own control. This range was selected from previous reports showing that oxytocin doses above 0.3 mg/kg s.c. or i.p. suppress spontaneous locomotion in other rat strains so we included lower doses to identify those devoid of this unwanted effect. To establish the relative contribution of oxytocin and vasopressin V1a receptors to hypothermia produced by the highest dose, a further 12 rats received vehicle or oxytocin (0.3 mg/kg s.c.) in the presence and absence of the non-peptide selective V1a receptor antagonist SR49059 (1 mg/kg i.p.) or the selective oxytocin antagonist L-368,899 (2 mg/kg i.p.), on six occasions at weekly intervals (within-subjects design). Although original peptide antagonists for these receptors showed poor stability and selectivity the development of non-peptide antagonists greatly improved pharmacokinetic properties. The current non-peptide antagonists (SR49059 and L-368,889) were selected because they possess the best overall profile of commercially available oxytocin and V1a antagonists; having high affinity, relative selectivity, good BBB penetration, and plasma half-life and are devoid of partial agonist activity. Doses of these brain penetrant antagonists were selected from previous studies showing < 15 min onset and 2–4 h duration in rodents. SR49059 prevented oxytocin-induced pro-social behavior and hypothermia, whereas L-368,899 (which has brain penetration demonstrated by PET studies), prevented anxiolytic effects of oxytocin in the open field, reduced conditioned disgust behavior during social interaction and attenuated sexual motivation in male rats]. The cross-over repeat within-subject design for dose–response and antagonist studies greatly reduced the number of rats required and the inter-individual variation of measurements made in line with the 3 R’s principle.

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Doses and routes of administration:
Compounds were dissolved in 0.154 M saline (vehicle also containing 5% dimethyl sulfoxide for the antagonists) and administered at volume of 1 ml/kg subcutaneous (s.c.) (oxytocin)

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Effect of oxytocin on PCP-induced hyperactivity, social interaction, and PFC and NAc dopamine and 5-HT efflux[1]
Oxytocin at 0.03 and 0.1 mg/kg were selected for further investigation, as these doses did not produce confounding effects on ambulation and body temperature in dose–response studies described above. A separate group of rats (n = 32, Figure S1) was used to examine the effect of these two doses on PCP-induced hyperactivity, and on the basis of these findings 0.1 mg/kg oxytocin was administered 7 days later, prior to assessment of social interaction and USVs. The following week rats underwent stereotaxic surgery to implant microdialysis probes into the PFC and NAc and after 7 days recovery the effects of oxytocin on dopamine efflux from these brain regions was assessed. One week was left between each of the three protocols (Figure S1) to ensure complete drug wash-out and minimize any carry over effects from the previous procedure.

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Locomotor activity[1]
LMA was assessed on a single occasion as described above. Animals received oxytocin or vehicle after 30 min arena habituation, and vehicle or PCP (5.6 mg/kg i.p.; an established dose to examine “antipsychotic-like” activity) 30 min later, resulting in four treatment combinations: vehicle + vehicle, PCP + vehicle, PCP + 0.03 mg/kg oxytocin, PCP + 0.1 mg/kg (n = 8/group; between-subjects design).

Absorption, Distribution and Excretion
Oxytocin is fully bioavailable when administered via the parenteral route. After parenteral administration, it takes approximately 40 minutes for oxytocin to reach steady-state concentrations in plasma. Oxytocinase is primarily responsible for the metabolism and regulation of oxytocin levels during pregnancy; only a small fraction of the neurohormone is excreted unchanged in the urine. In a study of 10 women who underwent oxytocin-induced labor, the mean metabolic clearance was 7.87 mL/min. Oxytocin is destroyed by chymotrypsin in the gastrointestinal tract. Following intravenous injection of oxytocin, the uterine response appears almost immediately and subsides within 1 hour. Following intramuscular injection, the uterine response appears within 3–5 minutes and lasts for 2–3 hours. After intranasal instillation of 10-20 units of oxytocin (nasal preparations are no longer sold in the US), the myoepithelial tissue surrounding the alveoli of the mammary glands begins to contract within minutes and lasts for 20 minutes; intravenous injection of 100-200 mIU of oxytocin produces the same effect. Similar to vasopressin, oxytocin is distributed in the extracellular fluid. A small amount of oxytocin may enter the fetal circulation. It is currently unknown whether this drug is secreted into human breast milk. Its rapid clearance from the plasma is primarily accomplished by the kidneys and liver. Only a small amount of oxytocin is excreted unchanged in the urine. For more complete data on the absorption, distribution, and excretion of oxytocin (7 types), please visit the HSDB record page. Metabolism/Metabolites Oxytocin is primarily cleared from the plasma via the liver and kidneys. Oxytocin is mainly responsible for the metabolism and regulation of oxytocin levels during pregnancy; only a small amount of the neurohormone is excreted unchanged in the urine. Oxytocinase gradually increases throughout pregnancy, peaking in plasma, placenta, and uterus near term. Oxytocinase activity: The placenta is the primary source of oxytocinase during pregnancy, producing more and more of the enzyme as maternal oxytocin levels increase. Oxytocinase is also expressed in the mammary glands, heart, kidneys, and small intestine. Oxytocin is present in the brain, spleen, liver, skeletal muscle, testes, and colon, with lower activity. Degradation of oxytocin in non-pregnant women, men, and umbilical cord blood is negligible. Oxytocinase is a circulating enzyme produced in early pregnancy that can also inactivate the polypeptide. During pregnancy, oxytocinase inactivates oxytocin by cleaving the peptide bond between 1-cysteine and 2-tyrosine. Biological half-life: The plasma half-life of oxytocin is 1–6 minutes. The half-life shortens in late pregnancy and during lactation.
The plasma half-life of oxytocin is approximately 3 to 5 minutes.

Interactions


It has been reported that administration of oxytocin 3-4 hours after prophylactic use of vasoconstrictors combined with tail block anesthesia can cause severe hypertension.

It may alter the cardiovascular effects of oxytocin, causing milder tachycardia but more severe hypotension compared to oxytocin alone; sinus bradycardia with atrioventricular rhythm abnormalities have been observed in pregnant women when oxytocin is used concurrently with cyclopropane anesthesia.

Oxytocin can cause venous spasm, leading to peripheral accumulation of thiopental sodium, thereby delaying the induction of thiopental sodium anesthesia; however, this interaction has not been definitively confirmed. Oxytocin has been reported to...

[1]. Oxytocin attenuates phencyclidine hyperactivity and increases social interaction and nucleus accumben dopamine release in rats. Neuropsychopharmacology. 2019 Jan;44(2):295-305.

[2]. Is Oxytocin "Nature's Medicine"? Pharmacol Rev. 2020 Oct;72(4):829-861.

Therapeutic Uses
This product is intended for medical use, not for selective induction of labor. Oxytocin. Current information is insufficient to determine the benefit-risk ratio of this product for selective induction of labor. This product is defined as: for the convenience of initiating labor in women with full-term pregnancies without medical indications. Selective Induction of Labor. /US Product Label Includes/
This product is indicated for initiating or enhancing uterine contractions to achieve early vaginal delivery when necessary and deemed appropriate for the health of the fetus or mother. Oxytocin. Indicated for patients with medical indications for induction of labor, such as Rh incompatibility, gestational diabetes, preeclampsia in late or near pregnancy, and in cases where delivery is in the best interests of the mother and child or premature rupture of membranes necessitates delivery. /US Product Label Includes/
Indicated for stimulating or strengthening uterine contractions, such as in cases of uterine atony. Oxytocin…/US Product Label Includes/
Indicated as adjunctive therapy for the treatment of incomplete or unavoidable miscarriage. In early pregnancy, curettage is generally considered the preferred treatment. In mid-trimester miscarriage, oxytocin infusion usually empties the uterus successfully. However, in these cases, other treatments may be necessary. /Included in US product label/
For more complete data on the therapeutic uses of oxytocin (11 types), please visit the HSDB record page.

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Drug Warnings
When oxytocin is used in excess, in combination with abortion pills, or in sensitive patients, uterine hyperstimulation may occur, manifested as strong (hypertonic) and/or persistent (tetanic) uterine contractions, or uterine resting tension of 15–20 mm H2O between contractions, which may lead to uterine rupture, cervical and vaginal tears, postpartum hemorrhage, placental abruption, impaired uterine blood flow, amniotic fluid embolism, and fetal trauma (including intracranial hemorrhage).
Adverse effects on the fetus may include sinus bradycardia, tachycardia, premature ventricular contractions and other arrhythmias, as well as permanent damage. Central nervous system or brain injury, and death due to asphyxia. Increased uterine mobility. Alternatively, use of this drug in sensitive women may lead to uteroplacental insufficiency and fetal heart rate variability deceleration, fetal hypoxia, perinatal liver necrosis, and fetal hypercapnia. Maternal overdose. Pelvic hematoma has been reported, but these may also be associated with higher rates of assisted vaginal delivery in primiparous women, pelvic venous congestion and fragility (especially in cases of varicose veins), and inadequate episiotomy repair. Rare events. When using large doses of oxytocin, severe decreases in maternal systolic and diastolic blood pressure, increased heart rate, increased systemic venous return and cardiac output, and arrhythmias may occur; these side effects may be particularly dangerous in patients with valvular heart disease and those undergoing spinal and epidural anesthesia. Oxytocin use may enhance these side effects; this may be associated with reports of oxytocin-induced thrombocytopenia, afibrinogenemia, and hypoprothrombinemia. Postpartum hemorrhage. The incidence of postpartum hemorrhage can be minimized through strict control of delivery.
For more drug warnings (complete) data on oxytocin (22 in total), please visit the HSDB record page.

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Pharmacodynamics
Oxytocin is a nonapeptide pleiotropic hormone with important physiological functions. Its most well-known function is to stimulate labor and lactation, but it also has important physiological effects on metabolic and cardiovascular function, sexual and maternal behavior, mating relationships, social cognition and fear conditioning. Notably, oxytocin receptors are not limited to the reproductive system, but are also present in many peripheral tissues and central nervous system structures, including the brainstem and amygdala.

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- It is involved in regulating PCP-induced behavioral abnormalities and dopaminergic transmission in the rat brain, which may be related to its potential role in the treatment of neuropsychiatric disorders. Oxytocin[1]
- This review explores whether oxytocin is a "natural medicine" and summarizes its role in physiological and pathological processes (e.g., social behavior, mood regulation) and its potential therapeutic applications in neuropsychiatric disorders. This review [2]

C43H66N12O12S2

1007.1873

1006.436

50-56-6

6233-83-6 (acetate)

439302

L-Cysteinyl-L-tyrosyl-L-isoleucyl-L-glutaminyl-L-asparaginyl-L-cysteinyl-L-prolyl-L-leucylglycinamide cyclic (1®6)-disulfide; or Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 (Disulfide bridge:Cys1-Cys6)

CYIQNCPLG-NH2 (Disulfide bridge:Cys1-Cys6)

White to off-white solid powder

1.3±0.1 g/cm3

1533.3±65.0 °C at 760 mmHg

192-194°C

881.1±34.3 °C

0.0±0.3 mmHg at 25°C

1.554

Endogenous Metabolite

-4.26

12

15

17

69

1870

9

S1C([H])([H])[C@@]([H])(C(N2C([H])([H])C([H])([H])C([H])([H])[C@@]2([H])C(N([H])[C@]([H])(C(N([H])C([H])([H])C(N([H])[H])=O)=O)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)=O)N([H])C([C@]([H])(C([H])([H])C(N([H])[H])=O)N([H])C([C@]([H])(C([H])([H])C([H])([H])C(N([H])[H])=O)N([H])C([C@]([H])([C@@]([H])(C([H])([H])[H])C([H])([H])C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])C2C([H])=C([H])C(=C([H])C=2[H])O[H])N([H])C([C@]([H])(C([H])([H])S1)N([H])[H])=O)=O)=O)=O)=O

XNOPRXBHLZRZKH-DSZYJQQASA-N

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

(2S)-1-({(4R,7S,10S,13S,16S,19R)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-16-(4-hydroxybenzyl)-13-[(1S)-1-methylpropyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-4-yl}carbonyl)-N-{(1S)-1-[(2-amino-2-oxoethyl)carbamoyl]-3-methylbutyl}pyrrolidine-2-carboxamide

α-Hypophamine; Oxytocic hormone; Uteracon; Syntocinone; Pitocin; Synpitan

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (99.3 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)