Oxytocin Research & Studies

People with narcolepsy have intrusive episodes of muscle weakness known as cataplexy, which are usually triggered by strong, positive emotions. As cataplexy occurs almost exclusively during social interactions, we examined whether it is promoted by the prosocial neuropeptide oxytocin. In a mouse model of narcolepsy, social reunification triggered cataplexy, and an oxytocin antagonist blocked socially induced cataplexy episodes. Oxytocin tone and the activity of oxytocin receptor-expressing neurons in the central amygdala both increased just before cataplexy triggered by social stimuli. Chemo- and optogenetic manipulations demonstrated that oxytocin-responsive neurons in the central amygdala drive cataplexy by inhibiting brainstem neurons that suppress muscle atonia. In addition, chocolate, a rewarding stimulus associated with strong, positive emotions, also engages this oxytocin-amygdala pathway and triggers cataplexy in narcoleptic mice. Together, these findings show that oxytocin acts through the amygdala to promote cataplexy triggered by social and other rewarding stimuli, offering new opportunities for treating cataplexy.

Embryonic development in many species, including case reports in humans, can be temporarily halted before implantation during a process called diapause. Facultative diapause occurs under conditions of maternal metabolic stress such as nursing. While molecular mechanisms of diapause have been studied, a natural inducing factor has yet to be identified. Here, we show that oxytocin induces embryonic diapause in mice. We show that gestational delays were triggered during nursing or optogenetic stimulation of oxytocin neurons simulating nursing patterns. Mouse blastocysts express oxytocin receptors, and oxytocin induced delayed implantation-like dispersion in cultured embryos. Last, oxytocin receptor-knockout embryos transferred into wild-type surrogates had low survival rates during diapause. Our results indicate that oxytocin coordinates timing of embryonic development with uterine progression through pregnancy, providing an evolutionarily conserved mechanism for ensuring successful reproduction.

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.

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.

There has been a long history of research on the effects of oxytocin on feeding behaviour. The classic-held view is that the neurohormone is anorexigenic at least in rodents, although the data for humans are not so clear cut. Likewise, a physiological role for oxytocin is disputed. Thus, although pharmacological, anatomical and physiological data suggest oxytocin may have a function in satiety signalling, this view is not supported by the latest research using the genetic recording and manipulation of oxytocin neurones. Here, we avoid a discussion of the pharmacological effects of oxytocin and examine evidence, from both sides of the argument, concerning whether the endogenous oxytocin system has a role in the regulation of normal feeding.

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.

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.

The neuropeptide oxytocin (OT) has a solid reputation as a facilitator of social interactions such as parental and pair bonding, trust, and empathy. The many results supporting a pro-social role of OT have generated the hypothesis that impairments in the endogenous OT system may lead to antisocial behavior, most notably social withdrawal or pathological aggression. If this is indeed the case, administration of exogenous OT could be the "serenic" treatment that psychiatrists have for decades been searching for.In the present review, we list and discuss the evidence for an endogenous "hypo-oxytocinergic state" underlying aggressive and antisocial behavior, derived from both animal and human studies. We furthermore examine the reported effects of synthetic OT administration on aggression in rodents and humans.Although the scientific findings listed in this review support, in broad lines, the link between a down-regulated or impaired OT system activity and increased aggression, the anti-aggressive effects of synthetic OT are less straightforward and require further research. The rather complex picture that emerges adds to the ongoing debate questioning the unidirectional pro-social role of OT, as well as the strength of the effects of intranasal OT administration in humans.

Oxytocin has been linked to many domains within the realm of "social cognition." For example, research has shown that oxytocin affects trusting behavior, cooperation, as well as the perception and processing of facial expressions. Furthermore, oxytocin increases empathy and seems to exert differential effects on in-group versus out-group preferences. However, there are some conflicting results that point towards a modulatory effect of oxytocin, depending on a variety of contextual and within-subject factors. Research about the underlying mechanisms (e.g., neural circuits and genetics) indicates that the modulation of amygdala activity by oxytocin is elementary for the understanding of social cognitive processes. As regards genetics, several variants of the oxytocin receptor gene (OXTR) have been extensively studied in relation to social cognition. Taken together, oxytocin is an important modulator of social cognitive processes, although substantially more research is needed in order to understand the complexity of oxytocinergic effects on social perception, cognition, and interpersonal behavior.

Social signals are identified through processing in sensory systems to trigger appropriate behavioral responses. Social signals are received primarily in most mammals through the olfactory system. Individuals are recognized based on their unique blend of odorants. Such individual recognition is critical to distinguish familiar conspecifics from intruders and to recognize offspring. Social signals can also trigger stereotyped responses like mating behaviors. Specific sensory pathways for individual recognition and eliciting stereotyped responses have been identified both in the early olfactory system and its connected cortices. Oxytocin is emerging as a major state modulator of sensory processing with distinct functions in early and higher olfactory brain regions. The brain state induced through Oxytocin influences social perception. Oxytocin acting on different brain regions can promote either exploration and recognition towards same- or other-sex conspecifics, or association learning. Region-specific deletion of Oxytocin receptors suffices to disrupt these behaviors. Together, these recent insights highlight that Oxytocin's function in social behaviors cannot be understood without considering its actions on sensory processing.

Social anxiety is a form of anxiety characterized by continuous fear of one or more social or performance situations. Although multiple treatment modalities (cognitive behavioral therapy, selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors, benzodiazepines) exist for social anxiety, they are effective for only 60% to 70% of patients. Thus, researchers have looked for other candidates for social anxiety treatment. Our review focuses on the peptide oxytocin as a potential therapeutic option for individuals with social anxiety. Animal research both in nonprimates and primates supports oxytocin's role in facilitation of prosocial behaviors and its anxiolytic effects. Human studies indicate significant associations between social anxiety and oxytocin receptor gene alleles, as well as social anxiety and oxytocin plasma levels. In addition, intranasal administration of oxytocin in humans has favorable effects on social anxiety symptomology. Other disorders, including autism, schizophrenia, and anorexia, have components of social anxiety in their pathophysiology. The therapeutic role of oxytocin for social dysfunction in these disorders is discussed.

One of the most meaningful results recently achieved in bone research has been to reveal that the pituitary hormones have profound effect on bone, so that the pituitary-bone axis has become one of the major topics in skeletal physiology. Here, we discuss the relevant evidence about the posterior pituitary hormone oxytocin (OT), previously thought to exclusively regulate parturition and breastfeeding, which has recently been established to directly regulate bone mass. Both osteoblasts and osteoclasts express OT receptors (OTR), whose stimulation enhances bone mass. Consistent with this, mice deficient in OT or OTR display profoundly impaired bone formation. In contrast, bone resorption remains unaffected in OT deficiency because, even while OT stimulates the genesis of osteoclasts, it inhibits their resorptive function. Furthermore, in addition to its origin from the pituitary, OT is also produced by bone marrow osteoblasts acting as paracrine-autocrine regulator of bone formation modulated by estrogens. In turn, the power of estrogen to increase bone mass is OTR-dependent. Therefore, OTR(-/-) mice injected with 17β-estradiol do not show any effects on bone formation parameters, while the same treatment increases bone mass in wild-type mice. These findings together provide evidence for an anabolic action of OT in regulating bone mass and suggest that bone marrow OT may enhance the bone-forming action of estrogen through an autocrine circuit. This established new physiological role for OT in the maintenance of skeletal integrity further suggests the potential use of this hormone for the treatment of osteoporosis.

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.

Novel sites of oxytocin receptor expression have recently been detected, including breast cancer cells, bone cells, myoblasts, cardiomyocytes and endothelial cells. These discoveries have greatly expanded the possible spectrum of oxytocin action beyond its classic role as an inducer of uterine contractions and milk ejection. Additional advances in the understanding of oxytocin receptor structure-function relationships, receptor trafficking and novel receptor-linked signaling cascades have made this receptor an attractive model for the study of G-protein-linked receptor function. Finally, the tocolytic efficiency of the oxytocin receptor antagonist atosiban, recently approved for clinical use in Europe, has opened new avenues for the prevention and treatment of preterm labor.