Oxytocin is made in the brain and released into the blood and directly into brain circuits. It's best known as the hormone behind childbirth contractions and breastfeeding, and synthetic oxytocin (brand name Pitocin) is a real, widely used hospital drug for those exact jobs. Because it also affects brain circuits tied to bonding, stress, and trust, researchers have spent 20+ years testing nasal oxytocin sprays for autism, anxiety, addiction, and appetite — but those results have been inconsistent, and none of that is an approved use. This page covers both sides: the solid medical use and the much shakier experimental one.
How strong is the evidence?
For its actual approved job — starting or speeding up labor and controlling bleeding after birth — oxytocin is backed by decades of clinical use and solid trial data; that part of the evidence is as strong as it gets. For the uses people usually get excited about (bonding, mood, autism, weight loss, cutting cravings), the picture is much weaker: mostly small human trials and animal studies with inconsistent, sometimes contradictory, results. Of the 40 papers reviewed, most are reviews, mechanism papers, or animal studies; only a handful are controlled human trials, and several of those failed to replicate earlier promising findings.
Uses
What people use it for
Starting or speeding up labor
Human trialsGiven through an IV drip in the hospital to kick off contractions or make a slow labor progress faster. This is its main, FDA-approved job.
Controlling bleeding after delivery
Human trialsA shot or IV dose given right after birth to help the uterus clamp down, which controls bleeding and helps deliver the placenta.
Helping breast milk flow when it isn't letting down well
Some human dataNasal, under-the-tongue, or cheek (buccal) oxytocin has been tried in mothers struggling to breastfeed, to help trigger the milk-ejection reflex.
Research on autism and social difficulties
Some human dataNasal oxytocin sprays have been tested in people with autism spectrum disorder and Prader-Willi syndrome to see if they improve social engagement. Results across studies have been inconsistent.
Research on cravings, mood, and appetite
Some human dataScientists are testing oxytocin for alcohol cravings, anxiety, and overeating. Animal studies look encouraging; human trials have been mixed, and some early promising results didn't hold up in later, better-designed studies.
Potential benefits
What it may help with
Starts and strengthens labor contractions
Human trialsThis is oxytocin's proven job. Given by IV drip, it reliably triggers uterine contractions and can shorten labor by up to about 2 hours compared with no drip — though it doesn't lower the chance of needing a C-section.
Controls bleeding after childbirth
Human trialsA dose right after delivery is the standard way doctors help the uterus contract down and prevent dangerous postpartum bleeding — a routine, well-established use.
Can help milk let-down during breastfeeding
Some human dataA review of trials in 639 women found that oxytocin given under the tongue or in the cheek increased milk production in mothers having trouble breastfeeding, without causing more breast pain. The higher dose tested (100 IU) worked slightly better than the lower one (10 IU). Real breastfeeding support and skin-to-skin contact usually reduce the need for this in the first place.
May ease social difficulties in autism — but results are inconsistent
Some human dataPeople with autism sometimes have lower natural oxytocin activity, and giving it as a nasal spray has helped social engagement in some clinical trials and animal studies. But other trials have shown no clear benefit, so this isn't a reliable, proven treatment yet — researchers now think dosing it only when needed, alongside social therapy, may work better than daily dosing.
May reduce alcohol cravings — promising in animals, weaker in people
Some human dataIn animal studies, oxytocin reliably cuts down drinking. Early human studies found it reduced craving and heavy drinking too, but more recent, better-controlled human trials couldn't repeat those results, so this remains unproven in people.
May reduce appetite and support weight loss in people who are obese
Some human dataSmall human studies in people with obesity or binge eating found that oxytocin reduced calorie intake and appeared to help with weight loss, mainly by cutting fat mass. It seems to work better in people with higher body weight or leptin resistance, and barely at all in people at a normal weight — so it isn't a general weight-loss shortcut.
May calm anxiety and low mood — mostly shown in animals so far
Animal / labIn mice, oxytocin injected directly into the brain reduced anxiety- and depression-like behavior in both sexes, though the effect was stronger in males and varied with female hormone levels. This hasn't been confirmed as a treatment in people; a human study on postpartum depression found the relationship unclear, and in some psychiatric patients oxytocin has actually increased distrust or envy toward others.
May support bone strength — animal evidence, hints in people
Animal / labIn animal studies, oxytocin builds new bone and can reverse the bone loss that comes with low estrogen. In people, women with anorexia or missed periods who have lower oxytocin tend to have weaker bone structure, and postmenopausal women with higher oxytocin levels tend to have denser bones — but no human trial has tested giving oxytocin to actually treat bone loss.
Studies:34445256Low oxytocin is linked to worse period pain
Some human dataWomen with a history of painful periods had lower oxytocin levels during menstruation than women without period pain, and lower levels tracked with worse pain. This is just an association from blood samples, not proof that taking oxytocin would relieve cramps.
Studies:32046441
What to watch for
Side effects & risks
- Serious
Contractions that come too hard or too often (uterine overstimulation)
Too much oxytocin during labor can cause the uterus to contract too strongly or too frequently, which can stress the baby and mother. This is exactly why hospitals dose it carefully and monitor continuously.
- Moderate
Blood pressure drops and heart rate changes with fast IV doses
Giving a large dose of oxytocin quickly (like a 10 IU bolus during a C-section) can cause the heart and blood vessels to react — dropping blood pressure or speeding up heart rate. This is riskier in people who've lost a lot of blood or have a weak heart.
- Mild
Reduced effectiveness with prolonged high doses
Giving high doses of oxytocin for a long stretch can make the uterus's oxytocin receptors stop responding as well, meaning the drug works less as labor goes on.
- Moderate
Possible link to postpartum mood problems
One review noted that oxytocin given during labor has been associated with postpartum depression in some data, but it's unclear whether the oxytocin causes this, is just a marker of a harder birth, or is unrelated.
- Mild
Can increase distrust or envy in some people
In some psychiatric research, oxytocin didn't just make people friendlier — it sometimes increased suspicion of outsiders or envy toward others, especially in people who already have biased social thinking. It's not a simple 'niceness' hormone.
Dosing
Dosing — what studies used
For its real medical use, oxytocin dosing is well established: hospitals use a carefully controlled IV drip during labor and a standard shot or IV dose right after delivery. For every other use people search for — social behavior, mood, weight loss, cravings — there is no agreed-upon dose. Human trials have used wildly different amounts, routes, and schedules, which is a big part of why results have been so inconsistent. Treat any dosing outside the labor/delivery context as unproven and experimental, not a protocol to follow on your own.
Inducing or speeding up labor
Approved labelStarted at 1-3 mIU/min, increased in steps up to a maximum of about 36 mIU/min
Rate increased every 15-40 minutes as needed · Throughout active labor, under continuous monitoring · IV infusion
This is a hospital protocol run by trained staff with continuous monitoring, not a self-administered dose.
Preventing bleeding after delivery (postpartum hemorrhage)
Approved label5-10 IU
Single dose right after delivery · One-time, sometimes followed by a low-dose infusion · IV or intramuscular injection
Routine standard of care immediately after birth.
Bolus dosing during C-section
Human trialDoses around 10 IU used historically, though there's no agreed-upon 'best' dose
Single bolus at delivery · One-time · IV bolus
Higher bolus doses raise the risk of blood pressure and heart rate side effects, especially if the mother has low blood volume or a weak heart; many anesthesiologists now favor smaller, slower doses.
Supporting breastfeeding/milk let-down
Human trial10 IU or 100 IU compared head-to-head; the 100 IU dose worked slightly better
Before nursing or pumping sessions · As needed while breastfeeding was being established · Sublingual or buccal
From a Cochrane review of 4 older trials (639 women) with real risk of bias; not routinely used today given better breastfeeding support options.
Nasal oxytocin sprays used in social/mood/weight research come in many different doses and schedules across studies (commonly in the 20-40 IU per spray range in published trials), with no dose ever proven best. Don't treat any of this as a home protocol — the injectable form is a prescription drug used under medical supervision, and the nasal form is a research tool, not an approved treatment.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Oxytocin is made by a small part of the brain (the hypothalamus) and released two ways: straight into the bloodstream, where it acts like a hormone on the body, and directly onto brain circuits, where it acts like a signal between brain cells. Touch, breastfeeding, and the stretching of the cervix during labor all trigger its release. In the body, it locks onto receptors in the uterus and breast, making the uterine muscle contract and the milk ducts squeeze — that's the well-proven mechanical effect. In the brain, it acts on circuits involved in bonding, fear, and stress, generally turning down the body's stress response and making social cues feel more important — which is the theory behind its use for anxiety, autism, and addiction, even though translating that into a reliable drug effect in people has been much harder than the animal data suggested.
Who should avoid it
- Should never be used to induce or speed up labor outside a monitored medical setting — it needs continuous monitoring for contraction strength and the baby's heart rate.
- Caution in anyone with a weak heart, very low blood volume, or unstable blood pressure, since rapid doses can cause a sudden drop in blood pressure.
- Not a self-directed 'biohack' for bonding, mood, or weight loss — nasal oxytocin can have unpredictable or even negative social effects (more suspicion, more envy) in some people, particularly those with existing psychiatric conditions.
- People with a history of postpartum mood problems should discuss labor oxytocin use with their care team given the unresolved link noted in research.
Interactions to know
- Estrogen makes oxytocin receptors more sensitive, which is part of why its effects differ between pregnancy, sex, and hormonal stages of the menstrual cycle.
- Epidural anesthesia and emergency C-section during birth blunt the body's own natural oxytocin release and its calming effects on the mother.
- Oxytocin's appetite-suppressing effect works downstream of leptin (the body's fullness hormone) and appears stronger in people with leptin resistance or higher body weight, weaker in normal-weight people.
- Oxytocin and the related hormone vasopressin share overlapping receptors, so oxytocin's effects can partly depend on the vasopressin system too.
The papers that matter most
Key studies
The definitive rundown of how oxytocin is actually dosed and used in real childbirth care, including doses, risks, and limits.
The physiology and pharmacology of oxytocin in labor and in the peripartum period
The main human-trial evidence for using oxytocin to help breastfeeding, including a head-to-head dose comparison.
Oxytocin for promoting successful lactation
A comprehensive look at oxytocin's broader roles in stress, healing, and the immune system, and why it's hard to turn into a reliable drug.
Is Oxytocin "Nature's Medicine"?
The most current summary of why oxytocin nasal spray trials for autism have had mixed results, and where the field is heading.
Oxytocin and autism: Insights from clinical trials and animal models
Honest accounting of how promising animal results for alcohol cravings didn't hold up when re-tested in later human trials.
Barriers and Breakthroughs in Targeting the Oxytocin System to Treat Alcohol Use Disorder
Summarizes early human data suggesting oxytocin can reduce calorie intake and support weight loss in people who are obese.
Oxytocin: A Potential Therapeutic for Obesity
Bottom line
As a childbirth drug, oxytocin is proven, standard medicine — it starts labor and stops dangerous bleeding, under a doctor's care. As a bonding, mood, weight-loss, or anti-craving supplement, it's still an open research question with inconsistent results, not something to self-administer expecting reliable effects.
Research papers
Studies we have on file for Oxytocin. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
40 papers
The physiology and pharmacology of oxytocin in labor and in the peripartum period.
Oxytocin is a reproductive hormone implicated in the process of parturition and widely used during labor. Oxytocin is produced within the supraoptic nucleus and paraventricular nucleus of the hypothalamus and released from the posterior pituitary lobe into the circulation. Oxytocin is released in pulses with increasing frequency and amplitude in the first and second stages of labor, with a few pulses released in the third stage of labor. During labor, the fetus exerts pressure on the cervix of the uterus, which activates a feedforward reflex-the Ferguson reflex-which releases oxytocin. When myometrial contractions activate sympathetic nerves, it decreases oxytocin release. When oxytocin binds to specific myometrial oxytocin receptors, it induces myometrial contractions. High levels of circulating estrogen at term make the receptors more sensitive. In addition, oxytocin stimulates prostaglandin synthesis and release in the decidua and chorioamniotic membranes by activating a specific type of oxytocin receptor. Prostaglandins contribute to cervical ripening and uterine contractility in labor. The oxytocin system in the brain has been implicated in decreasing maternal levels of fear, pain, and stress, and oxytocin release and function during labor are stimulated by a social support. Moreover, studies suggest, but have not yet proven, that labor may be associated with long-term, behavioral and physiological adaptations in the mother and infant, possibly involving epigenetic modulation of oxytocin production and release and the oxytocin receptor. In addition, infusions of synthetic oxytocin are used to induce and augment labor. Oxytocin may be administered according to different dose regimens at increasing rates from 1 to 3 mIU/min to a maximal rate of 36 mIU/min at 15- to 40-minute intervals. The total amount of synthetic oxytocin given during labor can be 5 to 10 IU, but lower and higher amounts of oxytocin may also be given. High-dose infusions of oxytocin may shorten the duration of labor by up to 2 hours compared with no infusion of oxytocin; however, it does not lower the frequency of cesarean delivery. When synthetic oxytocin is administered, the plasma concentration of oxytocin increases in a dose-dependent way: at infusion rates of 20 to 30 mIU/min, plasma oxytocin concentration increases approximately 2- to 3-fold above the basal level. Synthetic oxytocin administered at recommended dose levels is not likely to cross the placenta or maternal blood-brain barrier. Synthetic oxytocin should be administered with caution as high levels may induce tachystole and uterine overstimulation, with potentially negative consequences for the fetus and possibly the mother. Of note, 5 to 10 IU of synthetic oxytocin is often routinely given as an intravenous or intramuscular bolus administration after delivery to induce uterine contractility, which, in turn, induces uterine separation of the placenta and prevents postpartum hemorrhage. Furthermore, it promotes the expulsion of the placenta.
Is Oxytocin "Nature's Medicine"?
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.
Maternal plasma levels of oxytocin during breastfeeding-A systematic review.
Oxytocin is a key hormone in breastfeeding. No recent review on plasma levels of oxytocin in response to breastfeeding is available. Systematic literature searches on breastfeeding induced oxytocin levels were conducted 2017 and 2019 in PubMed, Scopus, CINAHL, and PsycINFO. Data on oxytocin linked effects and effects of medical interventions were included if available. We found 29 articles that met the inclusion criteria. All studies had an exploratory design and included 601 women. Data were extracted from the articles and summarised in tables. Breastfeeding induced an immediate and short lasting (20 minutes) release of oxytocin. The release was pulsatile early postpartum (5 pulses/10 minutes) and coalesced into a more protracted rise as lactation proceeded. Oxytocin levels were higher in multiparous versus primiparous women. The number of oxytocin pulses during early breastfeeding was associated with greater milk yield and longer duration of lactation and was reduced by stress. Breastfeeding-induced oxytocin release was associated with elevated prolactin levels; lowered ACTH and cortisol (stress hormones) and somatostatin (a gastrointestinal hormone) levels; enhanced sociability; and reduced anxiety, suggesting that oxytocin induces physiological and psychological adaptations in the mother. Mechanical breast pumping, but not bottle-feeding was associated with oxytocin and prolactin release and decreased stress levels. Emergency caesarean section reduced oxytocin and prolactin release in response to breastfeeding and also maternal mental adaptations. Epidural analgesia reduced prolactin and mental adaptation, whereas infusions of synthetic oxytocin increased prolactin and mental adaptation. Oxytocin infusion also restored negative effects induced by caesarean section and epidural analgesia. Oxytocin is released in response to breastfeeding to cause milk ejection, and to induce physiological changes to promote milk production and psychological adaptations to facilitate motherhood. Stress and medical interventions during birth may influence these effects and thereby adversely affect the initiation of breastfeeding.
Neural circuitry for maternal oxytocin release induced by infant cries.
Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing1-6. Suckling triggers the release of oxytocin, but other sensory cues-specifically, infant cries-can increase the levels of oxytocin in new human mothers7, which indicates that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit that routes auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice that were presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not to pure tones, through input from the posterior intralaminar thalamus, and that repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behaviour in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.
Oxytocin signaling regulates maternally directed behavior during early life.
Oxytocin is essential in shaping social behavior across the lifespan. Although the role of oxytocin signaling in parental care has been widely investigated, little is known about its function in social behavior during early life. We studied the role of oxytocin in mouse pup social behavior during acute separation from the mother as well as upon reunion. The activity of oxytocin neurons was increased by acute maternal separation. Behaviorally, maternally separated pups emitted more ultrasonic vocalizations upon reunion, which were further modulated by nipple attachment behavior. These effects were attenuated by blocking the oxytocin receptor during maternal separation. Optogenetic silencing of oxytocin neurons during maternal separation disrupted vocal behavior during separation and reunion. Our findings reveal an important role of oxytocin in context-dependent vocal communication in mouse pups.
Oxytocin enables maternal behaviour by balancing cortical inhibition.
Oxytocin is important for social interactions and maternal behaviour. However, little is known about when, where and how oxytocin modulates neural circuits to improve social cognition. Here we show how oxytocin enables pup retrieval behaviour in female mice by enhancing auditory cortical pup call responses. Retrieval behaviour required the left but not right auditory cortex, was accelerated by oxytocin in the left auditory cortex, and oxytocin receptors were preferentially expressed in the left auditory cortex. Neural responses to pup calls were lateralized, with co-tuned and temporally precise excitatory and inhibitory responses in the left cortex of maternal but not pup-naive adults. Finally, pairing calls with oxytocin enhanced responses by balancing the magnitude and timing of inhibition with excitation. Our results describe fundamental synaptic mechanisms by which oxytocin increases the salience of acoustic social stimuli. Furthermore, oxytocin-induced plasticity provides a biological basis for lateralization of auditory cortical processing.
Close encounters with oxytocin.
The purpose of this narrative review is to use a personal perspective to describe unanticipated and pivotal findings that drew the author into the study oxytocin. Oxytocin was originally described as a "female reproductive hormone." However, supporting reproduction is only one of a myriad of functions now attributed to oxytocin. Oxytocin promotes survival and resilience in both sexes and across the lifespan, especially in the context of stress or trauma and helps to explain the health benefits of relationships. Oxytocin works in the context of individual histories and in conjunction with other molecules, as well as the autonomic nervous system and immune factors. The chemical properties of oxytocin make it biologically active, but difficult to measure. As a deeper understanding of the biology of oxytocin is emerging, we may use knowledge of the properties of oxytocin to uncover adaptive strategies that protect and heal in the face of stress and adversity in both males and females.
An Allostatic Theory of Oxytocin.
Oxytocin has garnered considerable interest for its role in social behavior, as well as for the potential of intranasal administration to treat social difficulties. However, current theoretical models for the role of oxytocin in social behavior pay little consideration to its evolutionary and developmental history. This article aims to broaden our understanding of the role of oxytocin in social behavior by adopting an ethological approach through the lens of Nikolaas Tinbergen's 'four questions' - how does oxytocin work; how does the role of oxytocin change during development; how does oxytocin enhance survival; and how did the oxytocin system evolve? We argue that oxytocin is most accurately described as an allostatic hormone that modulates both social and non-social behavior by maintaining stability through changing environments.
Oxytocin in neurodevelopmental disorders: Autism spectrum disorder and Prader-Willi syndrome.
This manuscript reviews recent work on oxytocin and its use in neurodevelopmental disorders including spectrum disorder (ASD) and Prader-Willi syndrome (PWS). Oxytocin is involved in social recognition, bonding, maternal behaviors, anxiety, food motivation, and hyperphagia. While the pathophysiology of ASD and PWS involve abnormalities in the oxytocin system, clinical trials have shown discrepant results in the effectiveness of oxytocin as a treatment for core symptoms associated with these disorders. In this review, we outline oxytocin's clinical pharmacology, safety considerations, and results in recent clinical trials. We propose that oxytocin may be most beneficial in these populations if dosed in a dynamic regimen (PRN) and paired with social interventions.
Oxytocin: A developmental journey.
The neuropeptide hormone oxytocin is involved in many processes in our bodies, linking our social lives to our internal states. I started out my career studying primate families, an interest that expanded into the role of oxytocin in family-oriented behaviors such as pair bonding and parenting in prairie voles, humans, and other primates. Starting as a post-doc with Dr. C. Sue Carter, I also became interested in the role of oxytocin during development and the way that we manipulate oxytocin clinically. During that post-doc and then as a faculty member at the University of California, Davis, I have worked on a number of these questions.
Oxytocin: recent developments.
Oxytocin is a neurohypophyseal hormone that is produced centrally by neurons in the paraventricular nucleus and supraoptic nucleus of the hypothalamus. It is released directly into higher brain centres and into the peripheral circulation where it produces a multitude of effects. Classically, oxytocin is known for inducing uterine contractions at parturition and milk ejection during suckling. Oxytocin also acts in a species and gender specific manner as an important neuromodulator. It can affect behaviours associated with stress and anxiety, as well social behaviours including sexual and relationship behaviours, and maternal care. Additionally, oxytocin has been shown to have a variety of physiological roles in peripheral tissues, many of which appear to be modulated largely by locally produced oxytocin, dispelling the notion that oxytocin is a purely neurohypophyseal hormone. Oxytocin levels are altered in several diseases and the use of oxytocin or its antagonists have been identified as a possible clinical intervention in the treatment of mood disorders and pain conditions, some cancers, benign prostatic disease and osteoporosis. Indeed, oxytocin has already been successful in clinical trials to treat autism and schizophrenia. This review will report briefly on the known functions of oxytocin, it will discuss in depth the data from recent clinical trials and highlight future targets for oxytocinergic modulation.
The oxytocin system and early-life experience-dependent plastic changes.
Early-life experience influences social and emotional behaviour in adulthood. Affiliative tactile stimuli in early life facilitate the development of social and emotional behaviour, whereas early-life adverse stimuli have been shown to increase the risk of various diseases in later life. On the other hand, oxytocin has been shown to have organizational actions during early-life stages. However, the detailed mechanisms of the effects of early-life experience and oxytocin remain unclear. Here, we review the effects of affiliative tactile stimuli during the neonatal period and neonatal oxytocin treatment on the activity of the oxytocin-oxytocin receptor system and social or emotional behaviour in adulthood. Both affiliative tactile stimuli and early-life adverse stimuli in the neonatal period acutely activate the oxytocin-oxytocin receptor system in the brain but modulate social behaviour and anxiety-related behaviour apparently in an opposite direction in adulthood. Accumulating evidence suggests that affiliative tactile stimuli and exogenous application of oxytocin in early-life stages induce higher activity of the oxytocin-oxytocin receptor system in adulthood, although the effects are dependent on experimental procedures, sex, dosages and brain regions examined. On the other hand, early-life stressful stimuli appear to induce reduced activity of the oxytocin-oxytocin receptor system, possibly leading to adverse actions in adulthood. It is possible that activation of a specific oxytocin system can induce beneficial actions against early-life maltreatments and thus could be used for the treatment of developmental psychiatric disorders.
Oxytocin and appetite.
Oxytocin has potent central effects on feeding behaviour, as well as on social and sexual behaviours, and one likely substrate for its anorectic effect is the ventromedial nucleus of the hypothalamus. This nucleus expresses a high density of oxytocin receptors, but contains very few oxytocin-containing fibres, hence it is a likely target of 'neurohormonal' actions of oxytocin, including possibly oxytocin released from the dendrites of magnocellular oxytocin neurones. As oxytocin release from dendrites is regulated independent of electrical activity and of secretion from the neurohypophysis, exactly how this release is regulated by metabolic and reproduction-related signals remains to be established fully. Intriguingly though, it looks as though this central release of oxytocin from magnocellular neurons might be instrumental in a fundamental shift in motivational behaviour - switching behaviour from being driven by the need to find and consume food, to the need to reproduce.
Barriers and Breakthroughs in Targeting the Oxytocin System to Treat Alcohol Use Disorder.
Development of better treatments for alcohol use disorder (AUD) is urgently needed. One promising opportunity for this development is the potential of targeting the oxytocin peptide system. Preclinical studies showed that administration of exogenous oxytocin or, more recently, stimulation of neurons expressing endogenous oxytocin lead to a decreased alcohol consumption across several rodent models. Initial clinical studies also showed that administration of oxytocin decreased craving for alcohol and heavy alcohol drinking. However, several more recent clinical studies were not able to replicate these effects. Thus, although targeting the oxytocin system holds promise for the treatment of AUD, more nuanced approaches toward development and application of these treatments are needed. In this mini-review we discuss potential caveats resulting in differential success of attempts to use oxytocin for modulating alcohol use disorder-related behaviors in clinical studies and evaluate three directions in which targeting the oxytocin system could be improved: (1) increasing potency of exogenously administered oxytocin, (2) developing oxytocin receptor agonists, and (3) stimulating components of the endogenous oxytocin system. Both advances and potential pitfalls of these directions are discussed.
The interplay of oxytocin and sex hormones.
The neuropeptide oxytocin has historically been associated with reproduction and maternal behavior. However, more recent research has uncovered that oxytocin has a much wider range of roles in physiology and behavior. Despite the excitement surrounding potential therapeutical applications of intranasally administered oxytocin, the results of these intervention studies have been inconsistent. Various reasons for these mixed results have been proposed, which tend to focus on methodological issues, such as study design. While methodological issues are certainly important, emerging evidence suggests that the interaction between oxytocin and sex hormones may also account for these varied findings. To better understand the purpose and function of the interaction of oxytocin with sex hormones, with a focus on estrogens, progesterone, and testosterone, we conducted a comprehensive thematic review via four perspectives: evolutionary, developmental, mechanistic, and survival. Altogether, this synergistic approach highlights the critical function of sex hormone activity for accomplishing the diverse roles of oxytocin via the modulation of oxytocin release and oxytocin receptor activity, which is also likely to contribute to the heterogeneity of outcomes after oxytocin administration.
Oxytocin in cesarean-sections. What's new?
Oxytocin is the uterotonic agent of choice in the prevention and treatment of postpartum uterine atony. Nevertheless, there is no consensus on the optimal dose and rate for use in cesarean sections. The use of high bolus doses (e.g., 10IU of oxytocin) can determine deleterious cardiovascular changes for the patient, especially in situations of hypovolemia or low cardiac reserve. Furthermore, high doses of oxytocin for prolonged periods may lead to desensitization of oxytocin receptors in myometrium, resulting in clinical inefficiency.
Regulation of oxytocin secretion.
A baby sucks at a mother's breast for comfort and, of course, for milk. Milk is made in specialized cells of the mammary gland, and for a baby to feed, the milk must be released into a collecting chamber from where it can be extracted by sucking. Milk "let-down" is a reflex response to the suckling and kneading of the nipple--and sometimes in response to the sight, smell, and sound of the baby--and is ultimately affected by the secretion of oxytocin. Oxytocin has many physiological roles, but its only irreplaceable role is to mediate milk let-down: oxytocin-deficient mice cannot feed their young; the pups suckle but no milk is let down, and they will die unless cross-fostered. Most other physiological roles of oxytocin, including its role in parturition, are redundant in the sense that the roles can be assumed by other mechanisms in the absence of oxytocin throughout development and adult life. Nevertheless, physiological function in these roles can be altered or impaired by acute interventions that alter oxytocin secretion or change the actions of oxytocin. Here we focus on the diverse stimuli that regulate oxytocin secretion and on the apparent diversity of the roles for oxytocin.
[Oxytocin and postpartum depression].
Postpartum depression (PPD) is prevalent (about 10%) with a major impact on the mother and child health. At the hormonal level, poor regulation of oxytocin rate has a key role in depression. Recently, oxytocin has been used on psychiatric therapy, intranasal or intravenously, particularly in mood disorders. But, in obstetrics, this molecule is administered during childbirth. The objective of this study was to determine if intravenous administration of oxytocin could influence thymic state of the mother in the postpartum period. Literature review, after consultation of Pubmed and Sciencedirect databases, with the following keywords: oxytocin, postpartum depression, pregnancy, social behavior. The effects of oxytocin in the PPD are part of a multifactorial mechanism (hormonal and social) that influences the hormonal effects of oxytocin. Oxytocin use in therapeutic was able to give conclusive results in psychiatry, the way and the optimal method of administration are not known. PPD is associated with administrated oxytocin during labour. Physiopathology remains unknown. It is possible that oxytocin administered during childbirth is related with the onset or worsening of the PPD without defining if it's a cause or a consequence.
Oxytocin: who needs it?
The neuropeptide oxytocin has been implicated in the initiation of maternal behavior, based on studies in rats and sheep. Females in both of these species naturally avoid infants until parturition when they begin to show an intense interest in maternal care. Oxytocin pathways in the brain appear to be important for this transition from avoidance to approach of the young. Recent studies in mice with a null mutation of the oxytocin gene suggest a different scenario. These mice, which completely lack oxytocin, exhibit full maternal and reproductive behavior, except for a deficit in milk ejection. Apparently, oxytocin is not essential for maternal behavior in this species. Consistent with the role of oxytocin for the transition from avoidance to approach in rats and sheep, nulliparous mice show full maternal behavior and therefore do not require the peptide for the initiation of maternal care. The species differences in the behavioral effects of oxytocin are associated with profound species differences in the location of oxytocin receptors in the brain. Recent transgenic studies suggest that these species differences in the neuroanatomical distribution of oxytocin receptors may be a function of inter-species variation in the flanking region of the oxytocin receptor gene. So, who needs oxytocin? For maternal care, not mice and (possibly) other species, like primates, with promiscuous parental care. Most important, in considering the behavioral or cognitive functions of oxytocin, one cannot accurately extrapolate across species unless one knows the species have the same neuroanatomical location of oxytocin receptors.
The many faces of oxytocin: implications for psychiatry.
Oxytocin is known as the 'love hormone' due its role in promoting mother-child and pair bonding. More recent research indicates that oxytocin may have broader pro-social effects on behavior and cognition, which points towards oxytocin's potential as an agent to help improve social cognition and functioning in psychiatric disorders such as schizophrenia and autism. However, new research on oxytocin has also uncovered a 'darker side', including oxytocin's possible role in social out-grouping and envy. Instead of a simple view of oxytocin as 'good' or 'bad', a more accurate depiction of oxytocin's role in social processing likely involves the presence of moderating factors. We review moderation effects in oxytocin and their implications for psychiatry. One implication is that, across diagnostic categories, oxytocin administration may have positive effects for patients with social cognitive deficits but negative effects for patients with social cognitive bias. We conclude that future intervention studies should use methods such as signal detection to measure both deficit and bias parameters of social cognition and to evaluate potential individual and contextual moderators both within and between psychiatric diagnoses in order to determine for whom oxytocin treatment may be beneficial and for whom it may actually be harmful.
Oxytocin and Rodent Models of Addiction.
Interest for the use of oxytocin as a treatment for addiction began over 40years ago. Better known for its roles in parturition, lactation and pair bonding, oxytocin also has anxiolytic properties, reduces immune and inflammatory responses, and has a role in learning and memory. In this chapter, oxytocin effects on addiction processes are described by highlighting research findings that have used oxytocin within current preclinical animal models of addiction, relapse, or craving. First, we provide a brief background of the endogenous oxytocin system followed by descriptions of the behavioral models used to study addiction, including models of drug taking and seeking. Then we review recent preclinical studies that have used oxytocin as a therapeutic intervention throughout multiple stages of the addiction cycle from a behavioral and neurobiological perspective. These models encompass the entire range of the addiction cycle including acquisition and maintenance of drug taking, withdrawal and craving during periods of drug abstinence, and ultimately relapse. We then posit several theories about how oxytocin interacts with both drug and social reward, as well as presenting a mechanistic account of how specific oxytocin receptor localization may contribute to oxytocin's efficacy as an addiction therapeutic.
The role of oxytocin in parturition.
Oxytocin and the oxytocin receptor have two important roles in labour. Evidence in all mammalian species suggests that neurohypophysical oxytocin plays a role in the expulsive phase and, although there are less supporting data, a role for oxytocin in the initiation of labour is likely. The initiation of labour may be mediated in women and rhesus monkeys by paracrine rather than endocrine mechanisms. Although initial characterisation of the oxytocin knockout mouse suggested that oxytocin is not important in this species, subsequent investigations have demonstrated that oxytocin is important for the precise timing of the onset of labour. Studies in knockout mice also confirm important interrelationships between oxytocin and prostaglandins. Oxytocin stimulates prostaglandin release in many species, mainly in the decidua/uterine epithelium. The effects of oxytocin are mediated by tissue-specific oxytocin receptor expression, which leads directly to contraction in the myometrium and prostaglandin formation in the decidua. There is a dramatic increase in oxytocin receptor expression in these tissues in late pregnancy and pharmacological inhibition delays delivery, which suggests that, in contrast to oxytocin, the oxytocin receptor is essential for normal labour.
Oxytocin: A Potential Therapeutic for Obesity.
Oxytocin is a neuropeptide involved in the homeostasis of food consumption and energy; it affects hedonic eating. Studies in obese or binge-eating patients reported the hypophagic effect of oxytocin, which reduced caloric intake after administration. Several studies have demonstrated the effect of oxytocin's increasing energy intake, decreasing food consumption, and contributing to weight loss. Oxytocin's effects on food intake and metabolism suggest its therapeutic potential for treating obesity and binge eating.
Oxytocin for promoting successful lactation.
A rise in the concentration of oxytocin causes contraction of cells around the alveoli and milk ducts, in preparation for suckling. Lactation failure may result from insufficient oxytocin. The objective of this review was to assess the effects of using oral or nasal oxytocin on lactation. We searched the Cochrane Pregnancy and Childbirth Group trials register. Randomised and quasi-randomised trials of variable doses of oxytocin and different methods of administration versus placebo in breastfeeding women using oxytocin to augment lactation. Trial quality was assessed and data were extracted by two reviewers. Four trials of 639 women were included. There was potential for significant bias in these trials. Restricted breastfeeding schedules may have contributed to inadequate production of milk by the participants. Sublingual and buccal preparations of oxytocin were associated with an increase in milk production. Oxytocin did not appear to increase the incidence of breast pain and 100 international units of oxytocin appeared to be slightly more beneficial than 10 international units. An appropriate dose of sublingual or buccal oxytocin may help augment lactation where necessary. However if women are encouraged and supported with unrestricted breastfeeding, the need for oxytocin would probably be diminished.
Challenges for measuring oxytocin: The blind men and the elephant?
Since its discovery more than a century ago, oxytocin has become one of the most intensively studied molecules in behavioral biology. In the last five years, Psychoneuroendocrinology has published more than 500 articles with oxytocin in the title, with many of these articles including measures of endogenous oxytocin concentrations. Despite longstanding interest, methods of measuring endogenous oxytocin are still in active development. The widely varying oxytocin concentrations detected by different approaches to measurement - and lack of correlation among these techniques - has led to controversy and confusion. We identify features of oxytocin that may help to explain why various approaches may be differentially sensitive to diverse conformational states of the oxytocin molecule. We propose that discrepancies in data generated by different methods of measurement are not necessarily an indicator that some methods are valid whereas others are not. Rather, we propose that current challenges in the measurement of oxytocin may be analogous to the parable of the blind men and the elephant, with different methods of sample preparation and measurement being sensitive to different states in which the oxytocin molecule can exist.
Oxytocin and microglia in the development of social behaviour.
Oxytocin is a well-established regulator of social behaviour. Microglia, the resident immune cells of the central nervous system, regulate brain development and maintenance in health and disease. Oxytocin and microglia interact: microglia appear to regulate the oxytocin system and are, in turn, regulated by oxytocin, which appears to have anti-inflammatory effects. Both microglia and oxytocin are regulated in sex-specific ways. Oxytocin and microglia may work together to promote experience-dependent circuit refinement through multiple developmental-sensitive periods contributing to individual differences in social behaviour. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'.
Oxytocin and Bone: Review and Perspectives.
Recent data demonstrate the anabolic effect of oxytocin on bone. Bone cells express oxytocin receptors. Oxytocin promotes osteoblasts differentiation and function, leading to an increased bone formation with no effect on bone resorption and an improvement of bone microarchitecture. Oxytocin is synthetized by osteoblasts, and this synthesis is stimulated by estrogen. Animal studies demonstrate a direct action of oxytocin on bone, as the systemic administration of oxytocin prevents and reverses the bone loss induced by estrogen deficiency. Although oxytocin is involved in bone formation in both sexes during development, oxytocin treatment has no effect on male osteoporosis, underlining the importance of estrogen that amplifies its local autocrine and paracrine secretion. There are few human data showing a decrease in the oxytocin serum level in anorexia nervosa independently of estrogen and in amenorrheic women associated with impaired bone microarchitecture; in post-menopausal women a higher oxytocin serum level is associated with higher bone density, but not in osteoporotic men. Oxytocin displays many effects that may be beneficial in the management of osteoporosis, cardiovascular diseases, cognitive disorders, breast cancer, diabetes and body fat gain, all age-related diseases affecting elderly women, opening exciting therapeutic perspectives, although the issue is to find a single route, dosage and schedule able to reach all these targets.
Complexity of the Hypothalamic Oxytocin System and its Involvement in Brain Functions and Diseases.
Oxytocin is classically termed a 'prosocial neuropeptide' because of its evolutionarily conserved role in promoting affiliative behaviors. Endogenous oxytocin is mainly synthesized by hypothalamic oxytocin neurons and signals through oxytocin receptors (OxtRs). Recent studies with cell type-specific and circuit-specific interrogation have uncovered that oxytocin signals exert pleiotropic neuromodulatory effects through anatomically widespread axonal projections and ubiquitously distributed OxtRs. Dysfunctions of oxytocin signals are closely relevant to brain disorders/diseases. While intranasal oxytocin administration has been demonstrated to be one potential strategy to alleviate some brain disorders/diseases, such as autism, obesity, and anxiety, conflicting clinical outcomes highlight the imperative for precision-targeted neuromodulation strategies. Dissecting the molecular, cellular, and neural circuitry mechanisms underlying oxytocinergic modulation is a prerequisite to achieving this goal. This review provides an overview of the current understanding of the oxytocin system in terms of anatomical structure, neuronal modulation, and signal pathways, and discusses the modulatory roles of oxytocin in social, feeding, emotional, and sensory-related brain functions and brain diseases.
Oxytocin alleviates liver fibrosis via hepatic macrophages.
Previous studies demonstrated oxytocin treatment effectiveness in reducing mortality and reversing liver fibrosis in mice. However, the underlying mechanism remains obscure, given the absence of oxytocin receptor expression in hepatic stellate cells, the primary liver fibrosis effector cells. A comprehensive map of cell populations in fibrotic liver was generated using single-cell sequencing. The map enabled our study of the target cells of oxytocin action in the liver in more dimensions. Furthermore, we elucidated the mechanism of the oxytocin signaling system in hepatic macrophages using oxytocin receptor-specific knockout mice and liver fibrosis animal models. The carbon tetrachloride-induced hepatic fibrosis and bile duct ligation hepatic fibrosis mouse models demonstrated that oxytocin reversed hepatic fibrosis in mice. The mapped liver cell populations demonstrated that oxytocin promoted the phenotypic switch from Ly6high to Ly6Clow in myeloid-derived macrophages. The phenotypic control of oxytocin signaling system activation on this phenotypic switch was validated using myeloid-specific oxytocin receptor knockout mice. Subsequent studies demonstrated that the calcium inward flow induced by oxytocin receptor activation activated the key orphan nuclear receptor NR4A1, which controls macrophage phenotypic switching. Specifically, calcium ions activated CREB, a key target regulator of NR4A1 expression. The findings established hepatic macrophages as a hub responsible for the oxytocin-mediated alleviation of liver fibrosis. This study revealed a novel pathway where oxytocin regulates macrophage phenotype. Previous studies revealed for the first time the expression of oxytocin receptors in the liver. The present study shows that oxytocin reverses hepatic fibrosis and that hepatic macrophages are the central hub of oxytocin-mediated alleviation of hepatic fibrosis by promoting a phenotypic switch in hepatic macrophages, transitioning from Ly6high to Ly6Clow expression. The present study reveals a novel pathway by which oxytocin regulates macrophage phenotype. In addition, the potential applications of oxytocin and its analogues, as traditional drugs for clinical application, in the treatment of liver fibrosis deserve to be further explored.
Low Serum Oxytocin Concentrations Are Associated with Painful Menstruation.
Oxytocin-dependent mechanisms are hypothesized to contribute to painful menses, but clinical trials of oxytocin antagonists for dysmenorrhea have had divergent outcomes. In contrast, broader studies have shown that increased systemic oxytocin concentrations are associated with increased pain tolerance and improved psychosocial function. We sought to confirm whether increased serum oxytocin concentrations are associated with menstrual pain and other psychosocial factors. Women with a history of primary dysmenorrhea (n = 19), secondary dysmenorrhea (n = 12), and healthy controls (n = 15) completed pain and psychosocial questionnaires, provided a medical history, and rated their pain during the first 48 h of menses. Serum samples were collected during menses to measure oxytocin concentrations. Oxytocin was significantly lower in participants with a history of primary (704 ± 33 pg/mL; p < 0.001) or secondary (711 ± 66 pg/mL; p < 0.01) dysmenorrhea compared to healthy controls (967 ± 53 pg/mL). Menstrual pain over the past 3 months (r = -0.58; p < 0.001) and during the study visit (r = -0.45; p = 0.002) was negatively correlated with oxytocin concentrations. Pain catastrophizing (r = -0.39), pain behavior (r = -0.32), and pain interference (r = -0.31) were also negatively correlated with oxytocin levels (p's < 0.05). Oxytocin was not significantly correlated with psychosocial factors. Contrary to our hypothesis, women with a history of primary or secondary dysmenorrhea had lower oxytocin concentrations during menses when compared to healthy controls. Lower circulating oxytocin concentrations were also associated with worse menstrual pain and pain-related behavior. When considering the existing literature, low circulating oxytocin may be a sign of dysfunctional endogenous pain modulation.
Effects of oxytocin outside pregnancy.
For a long time, oxytocin was regarded as a pregnancy hormone released by the hypophysis to stimulate labour and milk ejection. In the present survey, data have been collected from the literature to show the spectrum of the hitherto known functions of oxytocin outside pregnancy. It is now known that oxytocin receptors can occur almost ubiquitously in the organism, that oxytocin is also formed outside of the brain and that oxytocin has functions in a number of organs. In the first part of the survey, stimuli that contribute to an increase in oxytocin release are compiled. In the second part, details are given on the individual oxytocin targets. Although the majority of findings are based on the results of animal experiments, there are already a number of studies that indicate similar effects of oxytocin in humans. According to the current state of knowledge, oxytocin appears to be involved in functions in the following organs: male and non-pregnant female reproductive tract, pancreas, cardiovascular system, kidney, brain and breast. There are indications that oxytocin may also have actions in other organs. There continues to be a considerable need for research into oxytocin in order to better understand the physiological and pathophysiological actions and to be able to derive possible therapeutic uses. Further light on the spectrum of functions of oxytocin may be cast by the possibility of the use of oxytocin antagonists.
Oxytocin and autism: Insights from clinical trials and animal models.
Autism spectrum disorder is a highly heritable and heterogeneous neurodevelopmental disorder, characterized by impaired social interactions and repetitive behaviors. Despite its complex etiology, increasing evidence has linked autism to the oxytocin system. The oxytocin peptide has long been known as the "social hormone," and has been shown to increase attention to social cues, elevate salience of socially relevant stimuli, and increase learning and reward in social situations. Reduced oxytocin levels and mutations in the oxytocin system have been reported in autism patients, while exogenously delivered oxytocin has been shown to alleviate social interaction deficits in both patients and animal models. Here, we summarize the results of recent clinical trials using oxytocin nasal spray to treat individuals with autism, as well as studies of autism animal models with oxytocin system deficits, and the rescue of their social behavior deficits by oxytocin. Finally, we discuss factors influencing clinical outcomes and reflect on future directions.
Oxytocin in animal models of autism spectrum disorder.
Autism spectrum disorder is a behavioral disorder characterized by impairments in social interaction and communication together with the presence of stereotyped behaviors and restricted interests. Although highly genetic, its etiology is complex which correlates with the extensive heterogeneity found in its clinical manifestation, adding to the challenge of understanding its pathophysiology and develop targeted pharmacotherapies. The neuropeptide oxytocin is part of a highly conserved system involved in the regulation of social behavior, and both animal and human research have shown that variation in the oxytocin system accounts for interindividual differences in the expression of social behaviors in mammals. In autism, recent studies in human patients and animal models are starting to reveal that alterations in the oxytocin system are more common than previously anticipated. Genetic variation in the key players involved in the system (i.e., oxytocin receptor, oxytocin, and CD38) has been found associated with autism in humans, and animal models of the disorder converge in an altered oxytocin system and/or dysfunction in oxytocin related biological processes. Furthermore, oxytocin administration exerts a behavioral and neurobiological response, and thus, the oxytocin system has become a promising potential therapeutical target for autism. Animal models represent a valuable tool to aid in the research into the potential therapeutic use of oxytocin. In this review, I aim to discuss the main findings related to oxytocin research in autism with a focus on findings in animal models. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 202-213, 2017.
Oxytocin neurons mediate stress-induced social memory impairment.
Oxytocin has long been thought to play a substantial role in social behaviors, such as social attachment and parenting behavior. However, how oxytocin neurons respond to social and non-social stimuli is largely unknown, especially in high temporal resolution. Here, we recorded the in vivo real-time responses of oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVN) in freely behaving mice. Our results revealed that oxytocin neurons were activated more significantly by stressors than social stimuli. The activation of oxytocin neurons was precisely correlated with struggling behavior during stress. Furthermore, we found that oxytocin mediated stress-induced social memory impairment. Our results reveal an important role of PVN oxytocin neurons in stress-induced social amnesia.
Investigation of metal modulation of oxytocin structure receptor-mediated signaling.
Oxytocin is a 9-amino acid peptide hormone. Since its discovery in 1954, it has most commonly been studied in relation to its role in stimulating parturition and lactation. However, it is now known that oxytocin has a widely diverse set of functions throughout the body including neuromodulation, bone growth, and inflammation. Previous research has suggested that divalent metal ions may be required for oxytocin activity, but the exact metal species and specific pathways have yet to be fully elucidated. In this work, we focus on characterizing copper and zinc bound forms of oxytocin and related analogs through far-UV circular dichroism. We report that Cu(ii) and Zn(ii) bind uniquely to oxytocin and all analogs investigated. Furthermore, we investigate how these metal bound forms may affect downstream signaling of MAPK activation upon receptor binding. We find that both Cu(ii) and Zn(ii) bound oxytocin attenuates the activation of the MAPK pathway upon receptor binding relative to oxytocin alone. Interestingly, we observed that Zn(ii) bound forms of linear oxytocin facilitate increased MAPK signaling. This study lays the foundation for future work on elucidating the metal effects on oxytocin's diverse bioactivity.
The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication.
Oxytocin was discovered in 1906 as a peptide that promotes delivery and milk ejection; however, its additional physiological functions were determined 100 years later. Many recent articles have reported newly discovered effects of oxytocin on social communication, bonding, reward-related behavior, adipose tissue, and muscle and food intake regulation. Because oxytocin neurons project to various regions in the brain that contribute to both feeding reward (hedonic feeding) and the regulation of energy balance (homeostatic feeding), the mechanisms of oxytocin on food intake regulation are complicated and largely unknown. Oxytocin neurons in the paraventricular nucleus (PVN) receive neural projections from the arcuate nucleus (ARC), which is an important center for feeding regulation. On the other hand, these neurons in the PVN and supraoptic nucleus project to the ARC. PVN oxytocin neurons also project to the brain stem and the reward-related limbic system. In addition to this, oxytocin induces lipolysis and decreases fat mass. However, these effects in feeding and adipose tissue are known to be dependent on body weight (BW). Oxytocin treatment is more effective in food intake regulation and fat mass decline for individuals with leptin resistance and higher BW, but is known to be less effective in individuals with normal BW. In this review, we present in detail the recent findings on the physiological role of oxytocin in feeding regulation and the anorexigenic neural pathway of oxytocin neurons, as well as the advantage of oxytocin usage for anti-obesity treatment.
A monoclonal antibody raised against a synthetic oxytocin peptide stains mouse hypothalamic neurones.
A monoclonal antibody against oxytocin was generated in 7a5 hybridoma cells derived from myeloma cells and lymphocytes from the spleen of mice immunised with a synthetic oxytocin peptide. The 7a5 monoclonal antibody bound with oxytocin in enzyme-linked immunosorbent assays. 7a5 cell growth medium was diluted up to 5000-fold and used for immunohistochemistry. First, to test the specificity of the 7a5 antibody against oxytocin, we stained brain tissues of oxytocin knockout mice, comprising mice in which the first exon of the oxytocin-neurophysin gene is deleted. No 7a5 immunoreactivity was detected in the paraventricular nucleus (PVN) of the hypothalamus of oxytocin knockout mice; however, this area was strongly stained with the anti-vasopressin polyclonal antibody, HM07. Tissue preparations of the wild-type mouse PVN and supraoptic nucleus (SON) displayed 7a5 immunoreactivity that was indistinguishable from the staining produced with an anti-oxytocin polyclonal antibody, HM06. The immunoreactivity of HM06 in the PVN was similar to that of an anti-oxytocin monoclonal antibody, PS38. We then examined the cross-reactivity of 7a5 with arginine vasopressin. The majority of cell soma and processes stained by 7a5 were not co-stained with the vasopressin antibody in SON and PVN regions. Furthermore, the suprachiasmatic nucleus was stained by the vasopressin antibody but not by 7a5. These results demonstrate that 7a5 is a new anti-oxytocin monoclonal antibody recognising oxytocin and not vasopressin; therefore, 7a5 can be used to investigate the role of oxytocin in the brain.
Oxytocin in the Male Reproductive Tract; The Therapeutic Potential of Oxytocin-Agonists and-Antagonists.
In this review, the role of oxytocin and oxytocin-like agents (acting via the oxytocin receptor and belonging to the oxytocin-family) in the male reproductive tract is considered. Previous research (dating back over 60 years) is revised and connected with recently found aspects of the role oxytocin plays in male reproductive health. The local expression of oxytocin and its receptor in the male reproductive tract of different species is summarized. Colocalization and possible crosstalk to other agents and receptors and their resulting effects are discussed. The role of the newly reported oxytocin focused signaling pathways in the male reproductive tract, other than mediating contractility, is critically examined. The structure and effect of the most promising oxytocin-agonists and -antagonists are reviewed for their potential in treating male disorders with origins in the male reproductive tract such as prostate diseases and ejaculatory disorders.
Chronic Oxytocin Administration as a Treatment Against Impaired Leptin Signaling or Leptin Resistance in Obesity.
This review summarizes the existing literature on the effects of oxytocin administration in the treatment of obesity in different animal models and in humans, focusing on the central control of food intake, the oxytocin effects on adipose tissue, and the relationships between oxytocin and leptin. Oxytocin is a hypothalamic nonapeptide synthesized mainly in the paraventricular and supraoptic nuclei projecting to the pituitary, where it reaches the peripheral circulation, as well as to other brain regions. Moreover, leptin modulates oxytocin levels and activates oxytocin neurons in the hypothalamic paraventricular nucleus, which innervates the nucleus of the solitary tract, partly responsible for the brain-elicited oxytocin effects. Taking into account that oxytocin is located downstream leptin, it was hypothesized that oxytocin treatment would be effective in decreasing body weight in leptin-resistant DIO animals, as well as in those with leptin or with leptin receptor deficiency. Several groups have demonstrated that in such animal models (rats, mice, and rhesus monkeys), central or peripheral oxytocin administration decreases body weight, mainly due to a decrease in fat mass, demonstrating that an oxytocin treatment is able to partly overcome leptin deficiency or resistance. Moreover, a pilot clinical study demonstrated the efficiency of oxytocin in the treatment of obesity in human subjects, confirming the results obtained in the different animal models. Larger multicenter studies are now needed to determine whether the beneficial effects of oxytocin treatment can apply not only to obese but also to type 2 diabetic patients. These studies should also shed some light on the molecular mechanisms of oxytocin action in humans.
Sex and hormonal status influence the anxiolytic-like effect of oxytocin in mice.
Anxiety and depression are highly prevalent psychiatric disorders, affecting approximately 18% of the United States population. Evidence indicates that central oxytocin mediates social cognition, social bonding, and social anxiety. Although it is well-established that oxytocin ameliorates social deficits, less is known about the therapeutic effects of oxytocin in non-social contexts. We hypothesized that positive effects of oxytocin in social contexts are attributable to intrinsic effects of oxytocin on neural systems that are related to emotion regulation. The present study investigated the effect of intracerebroventricular (ICV) oxytocin administration (i.e., central action) on anxiety- and depression-like behavior in C57Bl/6J mice using non-social tests. Male and female mice received an ICV infusion of vehicle or oxytocin (100, 200, or 500 ng), then were tested in the elevated zero maze (for anxiety-like behavior) and the tail suspension test (for depression-like behavior). Oxytocin dose-dependently increased open zone occupancy and entries in the elevated zero maze and reduced immobility duration in the tail suspension test in both sexes. Oxytocin decreased anxiety and depression-like behavior in male and female mice. The observed effect of oxytocin on anxiolytic-like behavior appeared to be driven by the males. Given the smaller anxiolytic-like effect of oxytocin in the female mice and the established interaction between oxytocin and reproductive hormones (estrogen and progesterone), we also explored whether oxytocin sensitivity in females varies across estrous cycle phases and in ovariectomized females that were or were not supplemented with estrogen or progesterone. Oxytocin reduced anxiety-like behavior in female mice in proestrus/estrus, ovariectomized females (supplemented or not with estrogen or progesterone), but not females in metestrus/diestrus. Additionally, oxytocin reduced depression-like behavior in all groups tested with slight differences across the various hormonal statuses. These results suggest that the effect of oxytocin in depression- and anxiety-like behavior in mice can be influenced by sex and hormonal status.
Quick links (PubMed)
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