Leveraging the unique social organization of California mice to study circuit-specific effects of oxytocin on behavior.

Oxytocin is a versatile neuropeptide that modulates many different forms of social behavior. Recent hypotheses pose that oxytocin enhances the salience of rewarding and aversive social experiences, and the field has been working to identify mechanisms that allow oxytocin to have diverse effects on behavior. Here we review studies conducted on the California mouse (Peromyscus californicus) that shed light on how oxytocin modulates social behavior following stressful experiences. In this species, both males and females exhibit high levels of aggression, which has facilitated the study of how social stress impacts both sexes. We review findings of short- and long-term effects of social stress on the reactivity of oxytocin neurons. We also consider the results of pharmacological studies which show that oxytocin receptors in the bed nucleus of the stria terminalis and nucleus accumbens have distinct but overlapping effects on social approach behaviors. These findings help explain how social stress can have different behavioral effects in males and females, and how oxytocin can have such divergent effects on behavior. Finally, we consider how new technological developments and innovative research programs take advantage of the unique social organization of California mice to address questions that can be difficult to study in conventional rodent model species. These new methods and questions have opened new avenues for studying the neurobiology of social behavior.

Male-selective effects of oxytocin agonism on alcohol intake: behavioral assessment in socially housed prairie voles and involvement of RAGE.

Targeting the oxytocin (OXT) peptide system has emerged as a promising new approach for the treatment of alcohol use disorder (AUD). However, further advancements in this development depend on properly modeling various complex social aspects of AUD and its treatment. Here we examined behavioral and molecular underpinnings of OXT receptor (OXTR) agonism in prairie voles, a rodent species with demonstrated translational validity for neurobiological mechanisms regulating social affiliations. To further improve translational validity of these studies, we examined effects of intranasal (IN) OXT administration in male and female prairie voles socially housed in the presence of untreated cagemates. IN OXT selectively inhibited alcohol drinking in male, but not female, animals. Further, we confirmed that exogenously administered OXT penetrates the prairie vole brain and showed that Receptor for Advanced Glycation End-products assists this penetration after IN, but not intraperitoneal (IP), OXT administration. Finally, we demonstrated that IP administration of LIT-001, a small-molecule OXTR agonist, inhibits alcohol intake in male, but not female, prairie voles socially housed in the presence of untreated cagemates. Taken together, results of this study support the promise of selectively targeting OXTR for individualized treatment of AUD.

The role of oxytocin in delay of gratification and flexibility in non-social decision making.

Oxytocin is well-known for its impact on social cognition. This specificity for the social domain, however, has been challenged by findings suggesting a domain-general allostatic function for oxytocin by promoting future-oriented and flexible behavior. In this pre-registered study, we tested the hypothesized domain-general function of oxytocin by assessing the impact of intranasal oxytocin (24 IU) on core aspects of human social (inequity aversion) and non-social decision making (delay of gratification and cognitive flexibility) in 49 healthy volunteers (within-subject design). In intertemporal choice, patience was higher under oxytocin than under placebo, although this difference was evident only when restricting the analysis to the first experimental session (between-group comparison) due to carry-over effects. Further, oxytocin increased cognitive flexibility in reversal learning as well as generosity under conditions of advantageous but not disadvantageous inequity. Our findings show that oxytocin affects both social and non-social decision making, supporting theoretical accounts of domain-general functions of oxytocin.

Actigraphy assessment of motor activity and sleep in patients with alcohol withdrawal syndrome and the effects of intranasal oxytocin.

BACKGROUND AND AIMS: The alcohol withdrawal syndrome increases autonomic activation and stress in patients during detoxification, leading to alterations in motor activity and sleep irregularities. Intranasal oxytocin has been proposed as a possible treatment of acute alcohol withdrawal. The aim of the present study was to explore whether actigraphy could be used as a tool to register symptoms during alcohol detoxification, whether oxytocin affected actigraphy variables related to motor activity and sleep compared to placebo during detoxification, and whether actigraphy-recorded motor function during detoxification was different from that in healthy controls. METHODS: This study was a part of a randomized, double blind, placebo-controlled trial in which 40 patients with alcohol use disorder admitted for acute detoxification were included. Of these, 20 received insufflations with intranasal oxytocin and 20 received placebo. Outcomes were actigraphy-recorded motor activity during 5-hour sequences following the insufflations and a full 24-hour period, as well as actigraphy-recorded sleep. Results were related to clinical variables of alcohol intake and withdrawal, including self-reported sleep. Finally, the actigraphy results were compared to those in a group of 34 healthy individuals. RESULTS: There were no significant differences between the oxytocin group and the placebo group for any of actigraphy variables registered. Neither were there any correlations between actigraphy-recorded motor function and clinical symptoms of alcohol withdrawal, but there was a significant association between self-reported and actigraphy-recorded sleep. Compared to healthy controls, motor activity during alcohol withdrawal was lower in the evenings and showed increased variability. CONCLUSION: Intranasal oxytocin did not affect actigraphy-recorded motor activity nor sleep in patients with acute alcohol withdrawal. There were no findings indicating that actigraphy can be used to evaluate the degree of withdrawal symptoms during detoxification. However, patients undergoing acute alcohol withdrawal had a motor activity pattern different from than in healthy controls.

Victory is its own reward: oxytocin increases costly competitive behavior in schizophrenia.

BACKGROUND: Aberrant sensitivity to social reward may be an important contributor to abnormal social behavior that is a core feature of schizophrenia. The neuropeptide oxytocin impacts the salience of social information across species, but its effect on social reward in schizophrenia is unknown. METHODS: We used a competitive economic game and computational modeling to examine behavioral dynamics and oxytocin effects on sensitivity to social reward among 39 men with schizophrenia and 54 matched healthy controls. In a randomized, double-blind study, participants received one dose of oxytocin (40 IU) or placebo and completed a 35-trial Auction Game that quantifies preferences for monetary v. social reward. We analyzed bidding behavior using multilevel linear mixed models and reinforcement learning models. RESULTS: Bidding was motivated by preferences for both monetary and social reward in both groups, but bidding dynamics differed: patients initially overbid less compared to controls, and across trials, controls decreased their bids while patients did not. Oxytocin administration was associated with sustained overbidding across trials, particularly in patients. This drug effect was driven by a stronger preference for winning the auction, regardless of monetary consequences. Learning rate and response variability did not differ between groups or drug condition, suggesting that differences in bidding derive primarily from differences in the subjective value of social rewards. CONCLUSIONS: Our findings suggest that schizophrenia is associated with diminished motivation for social reward that may be increased by oxytocin administration.

Intranasal oxytocin enhances EEG mu rhythm desynchronization during execution and observation of social action: An exploratory study.

Intranasal administration of oxytocin (OT) has been found to facilitate prosocial behaviors, emotion recognition and cooperation between individuals. Recent electroencephalography (EEG) investigations have reported enhanced mu rhythm (alpha: 8-13 Hz; beta: 15-25 Hz) desynchronization during the observation of biological motion and stimuli probing social synchrony after the administration of intranasal OT. This hormone may therefore target a network of cortical circuits involved in higher cognitive functions, including the mirror neuron system (MNS). Here, in a double-blind, placebo-controlled, between-subjects exploratory study, we investigated whether intranasal OT modulates the cortical activity from sensorimotor areas during the observation and the execution of social and non-social grasping actions. Participants underwent EEG testing after receiving a single dose (24 IU) of either intranasal OT or placebo. Results revealed an enhancement of alpha - but not beta - desynchronization during observation and execution of social grasps, especially over central and parietal electrodes, in participants who received OT (OT group). No differences between the social and non-social condition were found in the control group (CTRL group). Moreover, we found a significant difference over the cortical central-parietal region between the OT and CTRL group only within the social condition. These results suggest a possible action of intranasal OT on sensorimotor circuits involved in social perception and action understanding, which might contribute to facilitate the prosocial effects typically reported by behavioral studies.

Oxytocin Reduces Cigarette Consumption in Daily Smokers.

INTRODUCTION: Despite widespread knowledge of the dangers of cigarette consumption, smoking continues to be a public health concern. One compound that has shown potential for treatment in preclinical models is the neuropeptide oxytocin (OT). The purpose of the present study was to examine the effects of intranasal oxytocin on cigarette craving, behavioral economic demand for cigarettes, and cigarette consumption, in regular smokers after 18 hours of abstinence. METHOD: Otherwise healthy daily smokers (n = 35) completed two sessions where they received OT (40 IU intranasal) or placebo (PBO) and completed measures of craving and cigarette demand, and they were given six opportunities to smoke partial cigarettes in exchange for money. RESULTS: On average participants smoked few cigarettes after receiving OT than after receiving PBO, and they reported less desire for additional cigarettes during the smoking period. OT did not affect cigarette demand or standardized measures of cigarette craving. CONCLUSIONS: This study suggests that OT decreases some indices of smoking desire and consumption, providing modest support for the idea that OT might be effective for reducing cigarette smoking. IMPLICATIONS: This study provides new evidence that oxytocin might have clinical value in the treatment of addictive disorders, in this case tobacco addiction. The study adds to a growing literature suggesting that this neuropeptide, which is mainly known for its role in social bonding and attachment, may also affect mood and motivational states relevant to addiction.

Neurobiological Mechanisms of Responding to Injustice.

People are particularly sensitive to injustice. Accordingly, deeper knowledge regarding the processes that underlie the perception of injustice, and the subsequent decisions to either punish transgressors or compensate victims, is of important social value. By combining a novel decision-making paradigm with functional neuroimaging, we identified specific brain networks that are involved with both the perception of, and response to, social injustice, with reward-related regions preferentially involved in punishment compared with compensation. Developing a computational model of punishment allowed for disentangling the neural mechanisms and psychological motives underlying decisions of whether to punish and, subsequently, of how severely to punish. Results show that the neural mechanisms underlying punishment differ depending on whether one is directly affected by the injustice, or whether one is a third-party observer of a violation occurring to another. Specifically, the anterior insula was involved in decisions to punish following harm, whereas, in third-party scenarios, we found amygdala activity associated with punishment severity. Additionally, we used a pharmacological intervention using oxytocin, and found that oxytocin influenced participants' fairness expectations, and in particular enhanced the frequency of low punishments. Together, these results not only provide more insight into the fundamental brain mechanisms underlying punishment and compensation, but also illustrate the importance of taking an explorative, multimethod approach when unraveling the complex components of everyday decision-making.SIGNIFICANCE STATEMENT The perception of injustice is a fundamental precursor to many disagreements, from small struggles at the dinner table to wasteful conflict between cultures and countries. Despite its clear importance, relatively little is known about how the brain processes these violations. Taking an interdisciplinary approach, we combine methods from neuroscience, psychology, and economics to explore the neurobiological mechanisms involved in both the perception of injustice as well as the punishment and compensation decisions that follow. Using a novel behavioral paradigm, we identified specific brain networks, developed a computational model of punishment, and found that administrating the neuropeptide oxytocin increases the administration of low punishments of norm violations in particular. Results provide valuable insights into the fundamental neurobiological mechanisms underlying social injustice.

Cost effectiveness analysis of carbetocin during cesarean section in a high volume maternity unit.

AIM: To evaluate the cost effectiveness of carbetocin compared to oxytocin when used as prophylaxis against post-partum hemorrhage (PPH) during cesarean deliveries. METHODS: A systematic review of the literature was performed to identify randomized controlled trials that compared the use of carbetocin to oxytocin in the context of cesarean deliveries. Cost effectiveness analysis was then performed using secondary data from the perspective of a maternity unit within the Malaysian Ministry of Health, over a 24 h time period. RESULTS: Seven randomized controlled trials with over 2000 patients comparing carbetocin with oxytocin during cesarean section were identified. The use of carbetocin in our center, which has an average of 3000 cesarean deliveries annually, would have prevented 108 episodes of PPH, 104 episodes of transfusion and reduced the need for additional uterotonics in 455 patients. The incremental cost effectiveness ratio of carbetocin for averting an episode of PPH was US$278.70. CONCLUSION: Reduction in retreatment, staffing requirements, transfusion and potential medication errors mitigates the higher index cost of carbetocin. From a pharmacoeconomic perspective, in the context of cesarean section, carbetocin was cost effective as prophylaxis against PPH. Ultimately, the relative value placed on the outcomes above and the individual unit's resources would influence the choice of uterotonic.

Fear or greed? Oxytocin regulates inter-individual conflict by enhancing fear in men.

People may choose non-cooperation in social dilemmas either out of fear (if others choose to defect) or out of greed (when others choose to cooperate). Previous studies have shown that exogenous oxytocin motivates a "tend and defend" pattern in inter-group conflict in which oxytocin stimulates in-group cooperation and out-group defense. Using a double-blind placebo-controlled design combined with a modified Prisoner's dilemma game (PDG), we examined the effect of oxytocin on social motivations in inter-individual conflict in men. Results showed that compared with the placebo group, oxytocin-exposed participants were less cooperative in general. Specifically, oxytocin amplified the effect of fear on defection but did not influence the effect of greed. Another non-social control study confirmed participants' decisions were sensitive to social factors. Our findings suggest that even when social group conflict is removed, oxytocin promotes distrust of strangers in "me and you" inter-individual conflict by elevating social fear in men.

Species differences in behavior and cell proliferation/survival in the adult brains of female meadow and prairie voles.

Microtine rodents display diverse patterns of social organization and behaviors, and thus provide a useful model for studying the effects of the social environment on physiology and behavior. The current study compared the species differences and the effects of oxytocin (OT) on anxiety-like, social affiliation, and social recognition behaviors in female meadow voles (Microtus pennsylvanicus) and prairie voles (Microtus ochrogaster). Furthermore, cell proliferation and survival in the brains of adult female meadow and prairie voles were compared. We found that female meadow voles displayed a higher level of anxiety-like behavior but lower levels of social affiliation and social recognition compared to female prairie voles. In addition, meadow voles showed lower levels of cell proliferation (measured by Ki67 staining) and cell survival (measured by BrdU staining) in the ventromedial hypothalamus (VMH) and amygdala (AMY), but not the dentate gyrus of the hippocampus (DG), than prairie voles. Interestingly, the numbers of new cells in the VMH and AMY, but not DG, also correlated with anxiety-like, social affiliation, and social recognition behaviors in a brain region-specific manner. Finally, central OT treatment (200 ng/kg, icv) did not lead to changes in behavior or cell proliferation/survival in the brain. Together, these data indicate a potential role of cell proliferation/survival in selected brain areas on different behaviors between vole species with distinct life strategies.

Low-dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment.

Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel 'Breath Powered' nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8 IU (international units) or 24 IU OT, 1 IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8 IU OT in comparison to both placebo and 24 IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.

Longitudinal assessment of oxytocin efficacy on bone and bone marrow fat masses in a rabbit osteoporosis model through 3.0-T magnetic resonance spectroscopy and micro-CT.

UNLABELLED: This study aims to longitudinally assess the effect of oxytocin on bone and bone fat masses using micro-CT, in vivo magnetic resonance spectroscopy (MRS), and histopathological adipocyte quantification. Early in vivo oxytocin (OT) treatment to the osteoporosis (OP) rabbit model may reliably inhibit bone degeneration and reduce bone marrow fat accumulation by decreasing marrow adipocyte size and density. INTRODUCTION: This study aims to longitudinally assess the effect of early OT treatment on bone and bone fat masses in a rabbit OP model by comparing the results of MRS and micro-CT with histopathological findings. METHODS: Sixty 20-week-old female rabbits were randomly assigned into three groups. The control and OP groups were subjected to either sham surgery or bilateral ovariectomy (OVX). The OT group was subcutaneously injected with OT daily from the second week after OVX for 8 weeks. The left proximal femurs of the rabbits were evaluated through MRS, micro-CT, and histopathological examination at 0, 4, 8, 10, and 12 weeks after operation. Differences in fat fraction (FF) values, micro-CT parameters, and calculated pathological marrow adipocytes among three groups were analyzed. RESULTS: The FF values of the OP group significantly increased (p = 0.019), but the tissue mineral density (TMD) decreased (p = 0.037) from eighth week compared with those of the control group. The FF values of the OT group significantly decreased (p = 0.044), but the TMD values increased (p = 0.042) from eighth week compared with those of the OP group. The adypocyte diameter of the OT group significantly decreased (p = 0.041) from eighth week and then adypocyte density did so too from tenth week, compared with those of the OP group at the same time point. No difference in adypocyte calculation was found between the OT and control groups until the 12th week after operation. CONCLUSION: Early in vivo OT treatment slowed down bone deterioration and reduced bone marrow adiposity accumulation in a rabbit OP model, which is consistent with pathologic findings. OT treatment is a promising preventive OP therapy.

Oxytocin promotes group-serving dishonesty.

To protect and promote the well-being of others, humans may bend the truth and behave unethically. Here we link such tendencies to oxytocin, a neuropeptide known to promote affiliation and cooperation with others. Using a simple coin-toss prediction task in which participants could dishonestly report their performance levels to benefit their group's outcome, we tested the prediction that oxytocin increases group-serving dishonesty. A double-blind, placebo-controlled experiment allowing individuals to lie privately and anonymously to benefit themselves and fellow group members showed that healthy males (n = 60) receiving intranasal oxytocin, rather than placebo, lied more to benefit their group, and did so faster, yet did not necessarily do so because they expected reciprocal dishonesty from fellow group members. Treatment effects emerged when lying had financial consequences and money could be gained; when losses were at stake, individuals in placebo and oxytocin conditions lied to similar degrees. In a control condition (n = 60) in which dishonesty only benefited participants themselves, but not fellow group members, oxytocin did not influence lying. Together, these findings fit a functional perspective on morality revealing dishonesty to be plastic and rooted in evolved neurobiological circuitries, and align with work showing that oxytocin shifts the decision-maker's focus from self to group interests. These findings highlight the role of bonding and cooperation in shaping dishonesty, providing insight into when and why collaboration turns into corruption.

Peripheral administration of oxytocin increases social affiliation in the naked mole-rat (Heterocephalus glaber).

The neuropeptide oxytocin regulates a wide variety of social behaviors across diverse species. However, the types of behaviors that are influenced by this hormone are constrained by the species in question and the social organization that a particular species exhibits. Therefore, the present experiments investigated behaviors regulated by oxytocin in a eusocial mammalian species by using the naked mole-rat (Heterocephalus glaber). In Experiment 1, adult non-breeding mole-rats were given intraperitoneal injections of either oxytocin (1mg/kg or 10mg/kg) or saline on alternate days. Animals were then returned to their colony and behavior was recorded for minutes 15-30 post-injection. Both doses of oxytocin increased huddling behavior during this time period. In Experiment 2, animals received intraperitoneal injections of either oxytocin (1mg/kg), an oxytocin-receptor antagonist (0.1mg/kg), a cocktail of oxytocin and the antagonist, or saline across 4 testing days in a counterbalanced design. Animals were placed in either a 2-chamber arena with a familiar conspecific or in a small chamber with 1week old pups from their home colony and behaviors were recorded for minutes 15-30 post-injection. Oxytocin increased investigation of, and time spent in close proximity to, a familiar conspecific; these effects were blocked by the oxytocin antagonist. No effects were seen on pup-directed behavior. These data suggest that oxytocin is capable of modulating affiliative-like behavior in this eusocial species.

Oxytocin increases the influence of public service advertisements.

This paper presents a neurophysiologic model of effective public service advertisements (PSAs) and reports two experiments that test the model. In Experiment 1, we show that after watching 16 PSAs participants who received oxytocin, compared to those given a placebo, donated to 57% more causes, donated 56% more money, and reported 17% greater concern for those in the ads. In Experiment 2, we measured adrenocorticotropin hormone (ACTH) and oxytocin levels in blood before and after participants watched a PSA. As predicted by the model, donations occurred when participants had increases in both ACTH and oxytocin. Our results indicate that PSAs with social content that cause OT release will be more effective than those that do not. Our results also explain why some individuals do not respond to PSAs.

An obligate role of oxytocin neurons in diet induced energy expenditure.

Oxytocin neurons represent one of the major subsets of neurons in the paraventricular hypothalamus (PVH), a critical brain region for energy homeostasis. Despite substantial evidence supporting a role of oxytocin in body weight regulation, it remains controversial whether oxytocin neurons directly regulate body weight homeostasis, feeding or energy expenditure. Pharmacologic doses of oxytocin suppress feeding through a proposed melanocortin responsive projection from the PVH to the hindbrain. In contrast, deficiency in oxytocin or its receptor leads to reduced energy expenditure without feeding abnormalities. To test the physiological function of oxytocin neurons, we specifically ablated oxytocin neurons in adult mice. Our results show that oxytocin neuron ablation in adult animals has no effect on body weight, food intake or energy expenditure on a regular diet. Interestingly, male mice lacking oxytocin neurons are more sensitive to high fat diet-induced obesity due solely to reduced energy expenditure. In addition, despite a normal food intake, these mice exhibit a blunted food intake response to leptin administration. Thus, our study suggests that oxytocin neurons are required to resist the obesity associated with a high fat diet; but their role in feeding is permissive and can be compensated for by redundant pathways.

Prevention of postpartum haemorrhage with the oxytocin analogue carbetocin.

Postpartum haemorrhage is the leading cause of maternal mortality worldwide: 67-80% of cases are caused by uterine atony. Preventive measures include prophylactic drug use to aid uterine contraction after delivery, thus avoiding severe blood loss and reducing maternal morbidity and mortality. Carbetocin is a synthetic analogue of oxytocin with a half-life approximately 4-10 times longer than that reported for oxytocin. It combines the safety and tolerability profile of oxytocin with the sustained uterotonic activity of injectable ergot alkaloids. Furthermore, carbetocin can be administered as a single dose injection either intravenously or intramuscularly rather than as an infusion over several hours as is the case with oxytocin. Carbetocin is currently indicated for prevention of uterine atony after delivery by caesarean section in spinal or epidural anaesthesia. Data from three randomised controlled trials in caesarean delivery and a meta-analysis indicate that carbetocin significantly reduces the need for additional uterotonic agents or uterine massage to prevent excessive bleeding compared with placebo or oxytocin. The risk of headache, tremor, hypotension, flushing, nausea, abdominal pain, pruritus and feeling of warmth was similar in women who received carbetocin or oxytocin. The findings from two more recent double-blind randomised trials and one retrospective study suggest that carbetocin may also represent a good alternative to conventional uterotonic agents for prevention of postpartum haemorrhage after vaginal deliveries. A reduced need for additional uterotonics was observed with carbetocin vs. oxytocin in high-risk women and carbetocin was at least as effective as syntometrine in low-risk women. In these studies of vaginal deliveries, carbetocin was associated with a low incidence of adverse effects and demonstrated a better tolerability profile than syntometrine. Carbetocin had a long duration of action compared with intravenous oxytocin alone and a better cardiovascular side effect profile compared with syntometrine. In addition to being an effective treatment for the prevention of postpartum haemorrhage following caesarean delivery, carbetocin may also become the drug of choice for postpartum haemorrhage prevention after vaginal delivery in high-risk women and those who suffer from hypertensive disorders in pregnancy. Preeclampsia is still a contraindication to the administration of carbetocin in the EU, and further studies would be required to assess the cardiovascular effects of carbetocin before it can be advocated for routine use in preeclamptic patients. Further research is required to assess whether prophylactic carbetocin is superior to conventional uterotonic agents following vaginal delivery in low-risk women.

Cost-effectiveness analysis of active management of third-stage labour in Vietnam.

Active management of the third stage of labour (AMTSL) using oxytocin substantially reduces postpartum haemorrhage (PPH), a leading cause of maternal mortality. An economic analysis of the use of AMTSL was conducted as part of an intervention study in Thanh Hoa Province, Vietnam. A spreadsheet was used to calculate various scenarios and estimate the costs and outcomes of the routine use of AMTSL with oxytocin in Uniject compared with oxytocin in ampoules, and AMTSL compared with no AMTSL. We estimated the health outcomes from probabilities that were generated from the effectiveness portion of the AMTSL intervention project. The study also estimates the costs of treating PPH and the net incremental costs of AMTSL (costs and savings); examines the impact of different scenarios of PPH rate and Uniject cost; and estimates the potential cost per PPH case and PPH death averted. The additional net cost per woman of providing AMTSL with ampoules was just US dollar 0.20 in the base case; using Uniject devices added only US dollar 0.08 more per woman to the ampoule cost. Varying the rate of PPH had the biggest effect; if the underlying PPH rate were 8%, the incremental cost of AMTSL drops to just US dollar 0.07 per woman with ampoules and the cost to avert a case of PPH is US dollar 2.10 with ampoules and US dollar 4.52 with Uniject. The low net incremental cost of AMTSL suggests that the introduction of AMTSL in primary-level facilities in Vietnam can reduce the incidence of PPH and benefit women's health without adding much to national health care costs.

Novel in vitro system for functional assessment of oxytocin action.

One of the classical biological actions mediated by the posterior pituitary hormone oxytocin (OT) is contraction of the uterus at parturition. Moreover, premature activation of the OT system is thought to contribute to preterm labor, a major clinical problem in obstetrical practice. However, the molecular mechanisms linking activation of the OT receptor (OTR) to myometrial contractions are not fully understood. Here, we describe an in vitro system that should serve as a useful tool to study this question at a cellular level. The system consists of a collagen lattice contraction assay and two different human myometrial cell lines: a cell clone from a telomerase-immortalized human myometrial cell population (hTERT-C3) as well as a cell line derived from a primary culture of human myometrial cells (M11). Using this approach, we observed that 1 nM OT promoted an almost maximal effect on cell contraction in both cell lines tested. Furthermore, this dose-dependent, OT-induced contraction was antagonized by the specific OTR antagonist d(CH(2))(5)[Tyr(Me)(2),Thr(4),Tyr-NH(2)(9)]OVT as well as the clinically used antagonist atosiban. This cell line-based contraction assay enables the application of molecular tools aimed at suppressing or overexpressing specific genes. It is also amenable to high-throughput testing approaches. Therefore, this system represents a powerful and improved experimental model that should facilitate the study of the molecular signal transduction pathways involved in the uterotonic actions of OT.