Traditional Japanese medicine Kamikihito ameliorates sucrose preference, chronic inflammation and obesity induced by a high fat diet in middle-aged mice.

The high prevalence of obesity has become a pressing global public health problem and there exists a strong association between increased BMI and mortality at a BMI of 25 kg/m2 or higher. The prevalence of obesity is higher among middle-aged adults than among younger groups and the combination of aging and obesity exacerbate systemic inflammation. Increased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha (TNFα) are hallmarks of obesity, and promote the secretion of hepatic C-reactive protein (CRP) which further induces systematic inflammation. The neuropeptide oxytocin has been shown to have anti-obesity and anti-inflammation effects, and also suppress sweet-tasting carbohydrate consumption in mammals. Previously, we have shown that the Japanese herbal medicine Kamikihito (KKT), which is used to treat neuropsychological stress disorders in Japan, functions as an oxytocin receptors agonist. In the present study, we further investigated the effect of KKT on body weight (BW), food intake, inflammation, and sweet preferences in middle-aged obese mice. KKT oral administration for 12 days decreased the expression of pro-inflammatory cytokines in the liver, and the plasma CRP and TNFα levels in obese mice. The effect of KKT administration was found to be different between male and female mice. In the absence of sucrose, KKT administration decreased food intake only in male mice. However, while having access to a 30% sucrose solution, both BW and food intake was decreased by KKT administration in male and female mice; but sucrose intake was decreased in female mice alone. In addition, KKT administration decreased sucrose intake in oxytocin deficient lean mice, but not in the WT lean mice. The present study demonstrates that KKT ameliorates chronic inflammation, which is strongly associated with aging and obesity, and decreases food intake in male mice as well as sucrose intake in female mice; in an oxytocin receptor dependent manner.

The Inhibition of TREK-1 K+ Channels via Multiple Compounds Contained in the Six Kamikihito Components, Potentially Stimulating Oxytocin Neuron Pathways.

Oxytocin, a significant pleiotropic neuropeptide, regulates psychological stress adaptation and social communication, as well as peripheral actions, such as uterine contraction and milk ejection. Recently, a Japanese Kampo medicine called Kamikihito (KKT) has been reported to stimulate oxytocin neurons to induce oxytocin secretion. Two-pore-domain potassium channels (K2P) regulate the resting potential of excitable cells, and their inhibition results in accelerated depolarization that elicits neuronal and endocrine cell activation. We assessed the effects of KKT and 14 of its components on a specific K2P, the potassium channel subfamily K member 2 (TREK-1), which is predominantly expressed in oxytocin neurons in the central nervous system (CNS). KKT inhibited the activity of TREK-1 induced via the channel activator ML335. Six of the 14 components of KKT inhibited TREK-1 activity. Additionally, we identified that 22 of the 41 compounds in the six components exhibited TREK-1 inhibitory effects. In summary, several compounds included in KKT partially activated oxytocin neurons by inhibiting TREK-1. The pharmacological effects of KKT, including antistress effects, may be partially mediated through the oxytocin pathway.

The oxytocin receptor is essential for the protective effect of pair housing on post-stroke depression in mice.

The beneficial effect of social interaction in mitigating the incidence of post-stroke depression (PSD) and ameliorating depressive symptoms has been consistently demonstrated through preclinical and clinical studies. However, the underlying relationship with oxytocin requires further investigation. In light of this, the present study aimed to explore the protective effect of pair housing on the development of PSD and the potential relationship with oxytocin receptors. The PSD model was induced by middle cerebral artery occlusion (MCAO) for 50 min, followed by 4-week isolated housing and restrained stress. Subsequently, each mouse in the pair-housing group (PH) was pair-housed with an isosexual healthy partner. Another group was continuously administrated fluoxetine (10 mg/Kg, i.p, once a day) for 3 weeks. To elucidate the potential role of oxytocin, we subjected pair-housed PSD mice to treatment with an oxytocin receptor (OXTR) antagonist (L368,889) (5 mg/Kg, i.p, once a day) for 3 weeks. At 31 to 32 days after MCAO, anxiety- and depressive-like behaviors were assessed using sucrose consumption, forced swim test, and tail-suspension test. The results showed that pair housing significantly improved post-stroke depression to an extent comparable to that of fluoxetine treatment. Furthermore, pair housing significantly decreased corticosterone in serum, increasing OXT mRNA expression in the hypothalamus. Treatment with L368,889 essentially reversed the effect of pair housing, with no discernible sex differences apart from changes in body weight. Pair housing increased hippocampal serotonin (5-HT), but treatment with L368,889 had no significant impact. Additionally, pair housing effectively reduced the number of reactive astrocytes and increased Nissl's body in the cortex and hippocampal CA3 regions. Correspondingly, treatment with L368,889 significantly reversed the changes in the Nissl's body and reactive astrocytes. Moreover, pair housing downregulated mRNA levels of TNF-α, IL-1ß, and IL-6 in the cortex caused by PSD, which was also reversed by treatment with L368,889. In conclusion, pair housing protects against the development of PSD depending on OXT and OXTR in the brain, with no significant divergence based on sex. These findings provide valuable insights into the potential of social interaction and oxytocin as therapeutic targets for PSD. Further research into the underlying mechanisms of these effects may contribute to the development of novel treatments for PSD.

Exogenous oxytocin increases gaze to humans in male cats.

Although oxytocin (OT) plays a role in bonding between heterospecifics and conspecifics, the effects of OT on the formation of such interspecific social behavior have only been investigated between humans and dogs (Canis familiaris). In this study, for comparative evaluation of the effects of OT between dog-human and cat-human social interaction, we investigated the effects of exogenous OT on the behavior of domestic cats (Felis silvestris catus) toward humans. We intranasally administered OT or saline to 30 cats using a nebulizer and recorded their behavior (gaze, touch, vocalization, and proximity). The results showed an interaction between the administration condition and sex for gaze duration. Post hoc analyses revealed a significant increase in gaze in the OT condition in male cats but not in females. There were no significant differences in gaze toward owners and strangers in any condition or sex. The male-specific OT-mediated increase in gaze toward humans observed in this study differs from previous research on dogs wherein such effects were observed only in females. These findings suggest an overall effect of exogenous OT on cats' social relationship with humans as well as the possibility of different mechanisms between cat-human and dog-human relationships.

No impairment of contextual fear memory consolidation by oxytocin receptor antagonism in male rats.

Oxytocin is a peptide released into brain regions associated with the processing of aversive memory and threat responses. Given the expression of oxytocin receptors across this vigilance surveillance system of the brain, we investigated whether pharmacological antagonism of the receptor would impact contextual aversive conditioning and memory. Adult male rats were conditioned to form an aversive contextual memory. The effects of peripheral administration of either the competitive antagonist Atosiban or noncompetitive antagonist L-368,899 were compared to saline controls. Oxytocin receptor antagonism treatment did not significantly impact the consolidation of aversive contextual memory in any of the groups. We conclude that peripheral antagonism of oxytocin signalling did not impact the formation of aversive memory.

Extracellular acidification increases uterine contraction in pregnant mouse by increasing intracellular calcium.

AIMS: As uterine extracellular pH decreases during the ischemic conditions of labor, but its effects on myometrial contraction are largely unknown, there is a need to elucidate its physiological effects and mechanisms of action. Furthermore, it is not known if any of the effects of extracellular acidification are affected by pregnancy, thus we also determined how gestation affects the response to acidification. METHODS: Nonpregnant, mid-, and term-pregnant myometrial strips were obtained from humanely killed mice. Contractions were recorded under spontaneous, depolarized, and oxytocin-stimulated conditions. The extracellular pH of the perfusate was changed from 7.4 to 6.9 or 7.9 in HEPES-buffered physiological saline. Intracellular pH was measured using SNARF, and intracellular calcium was measured using Indo-1. Statistical differences were tested using the appropriate t-test. RESULTS: Extracellular acidification significantly increased the frequency and amplitude of spontaneous contractions in pregnant, but not nonpregnant, myometrium, whereas alkalinization decreased contractions. Intracellular acidification, via Na-butyrate, transiently increased force in pregnant tissue. Intracellular pH was gradually acidified when extracellular pH was acidified, but extracellular acidification increased contractility before any significant change in intracellular pH. If myometrial force was driven by oxytocin or high-K depolarization, then extracellular pH did not further increase force. Intracellular calcium changes mirrored those of force in the spontaneously contracting pregnant myometrium, and if calcium entry was prevented by nifedipine, extracellular acidification could not induce a rise in force. CONCLUSION: Extracellular acidification increases excitability, calcium entry, and thus force in pregnant mouse myometrium, and this may contribute to increasing contractions during labor when ischemic conditions and acidemia occur.

Intranasal oxytocin suppresses seizure-like behaviors in a mouse model of NGLY1 deficiency.

NGLY1 deficiency is a genetic disease caused by biallelic mutations of the Ngly1 gene. Although epileptic seizure is one of the most severe symptoms in patients with NGLY1 deficiency, preclinical studies have not been conducted due to the lack of animal models for epileptic seizures in NGLY1 deficiency. Here, we observed the behaviors of male and female Ngly1-/- mice by video monitoring and found that these mice exhibit spontaneous seizure-like behaviors. Gene expression analyses and enzyme immunoassay revealed significant decreases in oxytocin, a well-known neuropeptide, in the hypothalamus of Ngly1-/- mice. Seizure-like behaviors in Ngly1-/- mice were transiently suppressed by a single intranasal administration of oxytocin. These findings suggest the therapeutic potential of oxytocin for epileptic seizure in patients with NGLY1 deficiency and contribute to the clarification of the disease mechanism.

Intranasal oxytocin as a treatment for anxiety and autism: From subclinical to clinical applications.

Animal and human studies have demonstrated that intranasal oxytocin (OT) can penetrate the brain and induce cognitive, emotional, and behavioral changes, particularly in social functioning. Consequently, numerous investigations have explored the potential of OT as a treatment for anxiety and autism, conditions characterized by social deficits. Although both subclinical and clinical studies provide converging evidence of the therapeutic effects of OT in reducing anxiety levels and improving social symptoms in autism, results are not always consistent. Additionally, the pharmacological mechanism of OT requires further elucidation for its effective clinical application. Therefore, this review aims to examine the contentious findings concerning the effects of OT on anxiety and autism, offer interpretations of the inconsistent results from the perspectives of individual differences and varying approaches to OT administration, and shed light on the underlying mechanisms of OT. Ultimately, standardization of dosage, frequency of administration, formulation characteristics, and nasal spray devices is proposed as essential for future human studies and clinical applications of OT treatment.

In vitro inhibition of uterine contractions using electrospun nanofibers loaded with nifedipine and ML7.

OBJECTIVE: To formulate a nanofiber-based controlled drug delivery system that could be effective in preventing uterine contractions and can be used for the treatment of preterm labor. PATIENTS AND METHODS: We utilized uterine tissue samples obtained from ten pregnant women who underwent cesarean section at term to investigate the effect of nanofibers on spontaneous and induced myometrial contractions. We prepared nifedipine and ML7-loaded nanofibers using the electrospinning method with Poly(D,L-lactide-co-glycolide) (PLGA) polymer, resulted in seven groups of nanofibers, including a control group. Group I served as the control, Group II was non-drug loaded nanofiber, Group III was nifedipine (10-5 M) loaded nanofiber, Group IV was ML7 (3x10-5 M) loaded nanofiber, Group V was ML7 (3x10-5 M) and nifedipine (10-5 M) nanofiber, Group VI was ML7 (3x10-5 M) and nifedipine (3x10-5 M) nanofiber, and Group VII was ML7 (3x10-5 M) and nifedipine (10-4 M) nanofiber. To evaluate the contractile response, the nanofibers loaded with different doses of ML7 and nifedipine were applied onto the tissue strips, and in vitro organ bath experiments were performed. Full-thickness uterine samples were cleared of the serosa and surrounding tissues, and eight strips (3x10 mm) were prepared from each sample. The seven different nanofiber formulations were gently placed and sutured onto the strips, with one strip always kept as the time control. We recorded spontaneous, KCl-induced, and stimulated cumulative oxytocin-induced contractions from all samples in all groups. After completing all experiments, the viability of the strips was checked, and weight measurement was recorded. RESULTS: The administration of drug-loaded polymers resulted in a significant decrease in both the frequency and intensity of spontaneous and induced contractions in all groups (p<0.01). No significant difference was observed between the control group and the non-drug-loaded nanofiber group in post hoc analysis (p=0.704). In terms of amplitude and frequency of contractions, the most significant decrease was observed in group VII at cumulative oxytocin doses compared to the control and non-drug-loaded nanofiber groups (p<0.05). Moreover, group VI also showed a significant decrease in contraction intensity and frequency compared to the control and non-drug-loaded nanofiber groups (p<0.05). While the use of nifedipine and/or ML7-loaded nanofibers decreased both intensity and frequency of contraction, this attenuation was not significant compared to the control and empty polymer groups. However, a more significant inhibition was observed when ML7 was used with nifedipine at doses of 3x10-5 M and 10-4 M. CONCLUSIONS: The results indicate that human uterine contractions can be inhibited using calcium channel blocker (nifedipine) and myosin light chain kinase inhibitor (ML7) loaded nanofibers in uterine tissue strips. These results strongly suggested the potential for the development of locally effective and safe controlled drug release systems to prevent premature birth.

Oxytocin and social learning in socially anxious men and women.

OBJECTIVE: This study extended a classic self-referential learning paradigm by investigating the effects of intranasally-administered oxytocin in high and low socially anxious participants during social learning, as a function of social anxiety levels and sex. METHODS: In a randomized double-blinded design, 160 participants were either given intranasal oxytocin (24 I.U.) or placebo. Subsequently, while lying in an MR scanner, participants were shown neutral faces that were paired with positively, neutrally, or negatively valenced self-referential sentences, during which we measured self-reported arousal and sympathy of the facial stimuli, pupil dilation, and changes in the brain-oxygen-level dependent signal. Four-factor mixed analyses of variance with the between-subjects factors group (high socially anxious vs. low socially anxious), substance (oxytocin vs. placebo), and sex (male vs. female) and the within-subjects factor sentence valence (positive vs. neutral vs. negative) were conducted for each measure, respectively. RESULTS: Administration of intranasal oxytocin yielded an increase in sympathy ratings in high socially anxious compared to low socially anxious individuals and decreased arousal ratings for positively-conditioned faces in low socially anxious participants. As an objective physiological measure of arousal, pupil dilation mirrored the behavioral results. Oxytocin effects on neural activation in the insula interacted with anxiety levels and sex: low socially anxious individuals yielded lower activation under oxytocin than placebo; the converse was observed in high socially anxious individuals. This interaction also differed between sexes, as men yielded higher activation levels than women. These findings were more prominent for positively- and negatively-conditioned faces. Within the amygdala, high socially anxious men yielded higher activation than high socially anxious women in the left hemisphere, and low socially anxious men yielded higher activation than low socially anxious women from positively- and negatively-conditioned faces, though no influence of oxytocin was detected. CONCLUSION: These results suggest oxytocin-induced behavioral, physiological, and neural changes as a function of social learning in socially low and high anxious individuals. These findings challenge the amygdalocentric view of the role of emotions in social learning, instead contributing to the growing body of findings implicating the insula therein, revealing an interaction between oxytocin, sex, and emotional valence. Such discoveries raise an interesting set of questions regarding the computational goals of regions such as the insula in emotional learning and how neural activity can play a diagnostic or prognostic role in social anxiety, potentially leading to new treatment opportunities that may combine oxytocin and neurofeedback differentially for men and women.

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.

Impact of intrapartum oxytocin administration on neonatal sucking behavior and breastfeeding.

This study aimed to examine the effect of intrapartum oxytocin administration on neonatal sucking behavior and breastfeeding. A total of 64 pairs (29 in the group treated with intrapartum oxytocin and 35 in the control group) of normal infants within 24-48 h of birth and their mothers were recruited. Sucking ability was evaluated by measuring Non-Nutritive Sucking (NNS) for 5 min. Data on the rate of exclusive breastfeeding at 1 month postpartum were collected. In the adjusted multiple regression models, intrapartum oxytocin exposure was significantly associated with fewer total NNS bursts (95% confidence interval (CI), -7.02 to -0.22), longer pause times (95% CI, 1.33 to 10.21), and greater pause-time variability (95% CI, 3.63 to 63.92). Effects estimated using structural equation modeling revealed that intrapartum oxytocin exposure had a significant negative and direct effect on the practice of exclusive breastfeeding 1 month postpartum (ß = -0.238, p = 0.047). However, no NNS-mediated indirect effects were observed. This report demonstrates that infants born to mothers who receive intrapartum oxytocin may have impaired sucking ability for at least the first 48 h after birth, and breastfeeding support should be provided.

Oxytocin Modifies the Excitability and the Action Potential Shape of the Hippocampal CA1 GABAergic Interneurons.

Oxytocin (OT) is a neuropeptide that modulates social-related behavior and cognition in the central nervous system of mammals. In the CA1 area of the hippocampus, the indirect effects of the OT on the pyramidal neurons and their role in information processing have been elucidated. However, limited data are available concerning the direct modulation exerted by OT on the CA1 interneurons (INs) expressing the oxytocin receptor (OTR). Here, we demonstrated that TGOT (Thr4,Gly7-oxytocin), a selective OTR agonist, affects not only the membrane potential and the firing frequency but also the neuronal excitability and the shape of the action potentials (APs) of these INs in mice. Furthermore, we constructed linear mixed-effects models (LMMs) to unravel the dependencies between the AP parameters and the firing frequency, also considering how TGOT can interact with them to strengthen or weaken these influences. Our analyses indicate that OT regulates the functionality of the CA1 GABAergic INs through different and independent mechanisms. Specifically, the increase in neuronal firing rate can be attributed to the depolarizing effect on the membrane potential and the related enhancement in cellular excitability by the peptide. In contrast, the significant changes in the AP shape are directly linked to oxytocinergic modulation. Importantly, these alterations in AP shape are not associated with the TGOT-induced increase in neuronal firing rate, being themselves critical for signal processing.

A single administration of carbetocin before electroejaculation increases the insemination doses produced from each ejaculate in rams.

The aim of the study was to determine the effect of carbetocin administration (a long-acting analog of oxytocin) 20 or 10 min before electroejaculation (EE) on the duration of semen collection procedure, quantitative and qualitative characteristics of the ejaculate, and stress biomarkers in rams. Semen was collected from 12 Corriedale rams (age, 2.5-5.5 years old) with EE, in a Latin-square design, administrating carbetocin (0.2 mg/100 kg of body weight i.v.) 20 or 10 min before EE, or without carbetocin administration (CB-20, CB-10, and CON treatments, respectively). Each treatment was applied to different rams every 3-4 days, allowing all the rams to receive all three treatments. Carbetocin administered 20 or 10 min before EE increased the number of sperm ejaculated (P = 0.01), the semen concentration (P = 0.02), the number of insemination doses collected in a single collection (P = 0.01), and the number of insemination doses collected/electrical pulses administered (P = 0.05) compared to control rams. Carbetocin administered 20 or 10 min before semen collection prolonged the time required for EE and the number of pulses administered during EE compared to CON rams (P < 0.03 for both). The CB-10 rams required the administration of more electrical pulses during ejaculation than CON rams (P = 0.001), and CB-20 treatment tended to require more electrical pulses than CON rams (P = 0.06). The volume of the ejaculate was greater in CB-10 than in CON rams (P = 0.01), and that of CB-20 treatment tended to be greater than CON rams (P = 0.08). The percentage of sperm with intact membrane was greater in CB-20 than in CON rams (P = 0.01). Total protein, albumin, and globulin concentrations were lower immediately after carbetocin administration 20 or 10 min before EE. The treatments did not affect cortisol concentration, glycemia, rectal and surface temperatures, heart rate, and facial expressions. Carbetocin administration before EE of rams improved the quantitative and qualitative characteristics of the ejaculate, duplicating the number of insemination doses collected. It can be a promising treatment to obtain a greater quantity of doses to inseminate with a lower frequency of semen collections, reducing the negative impacts of EE on animal welfare.

Effects of chronic intranasal oxytocin on visual attention to faces vs. natural scenes in older adults.

Aging is associated with changes in face processing, including desensitization to face cues like gaze direction and an attentional preference to faces with positive over negative emotional valence. A parallel line of research has shown that acute administration of oxytocin (OT) increases visual attention to social stimuli such as human faces. The current study examined effects of chronic OT administration among older adults on fixation duration to faces that varied in emotional expression, gaze direction, age, and sex. One hundred and twelve generally healthy older adults (aged 55-95 years) underwent a randomized, placebo-controlled, double-blind, between-subject clinical trial in which they self-administered either OT or placebo (P) intranasally twice a day for 4 weeks. The behavioral task involved rating the trustworthiness of faces (i.e., social stimuli) and natural scenes (i.e., non-social control stimuli) during eye tracking and was conducted before and after the intervention. Fixation duration to both the faces and the natural scenes declined from pre- to post-intervention, however this decline was less pronounced among older adults in the OT compared to the P group for faces but not scenes. Further, face cues (emotional expression, gaze direction, age, sex) did not moderate the treatment effect. This study provides first evidence that chronic intranasal OT maintains salience of social cues over time in older adults, perhaps buffering effects of habituation. These findings enhance understanding of OT effects on social cognition among older adults, and would benefit from follow up with a young adult comparison group to directly speak to specificity of observed effects to older adults and reflection of the aging process.

Delivery by cesarean section leads to heavier adult bodyweight in prairie voles (Microtus ochrogaster).

Delivery by cesarean section now makes up 32.1 % of all births in the United States. Meta-analyses have estimated that delivery by cesarean section is associated with a > 50 % increased risk for childhood obesity by 5 years of age. While this association is independent of maternal obesity, breastfeeding, and heritable factors, studies in humans have been unable to test for a causal role of cesarean delivery in this regard. Here, we set out to use an animal model to experimentally test whether delivery by cesarean section would increase offspring weight in adulthood. Delivery by cesarean section may exert neurodevelopmental consequences by impacting hormones that are important at birth as well as during metabolic regulation in later life, such as oxytocin and vasopressin. The prairie vole (Microtus ochrogaster) has long been studied to investigate the roles of oxytocin and vasopressin in brain development and social behavior. Here, we establish that prairie voles tolerate a range of ambient temperatures, including conventional 22° housing, which makes them translationally appropriate for studies of diet-induced obesity. We also studied vole offspring for their growth, sucrose preference, home cage locomotor activity, and food consumption after birth by either cesarean section or vaginal delivery. At sacrifice, we collected measures of weight, length, and adipose tissue to analyze body composition in adulthood. Voles delivered by cesarean section had consistently greater bodyweights than those born vaginally, despite having lower food consumption and greater locomotive activity. Cesarean-delivered animals were also longer, though this did not explain their greater body weights. While cesarean delivery had no effect on vasopressin, it resulted in less oxytocin immunoreactivity within the hypothalamus in adulthood. These results support the case that cesarean section delivery plays a causal role in increasing offspring body weight, potentially by affecting the oxytocin system.

Optimal starting dosing regimen of intravenous oxytocin for labor induction based on the population kinetic-pharmacodynamic model of uterine contraction frequency.

BACKGROUND: Intravenous oxytocin is commonly used for labor induction. However, a consensus on the initial dosing regimen is lac with conflicting research findings and varying guidelines. This study aimed to develop a population kinetic-pharmacodynamic (K-PD) model for oxytocin-induced uterine contractions considering real-world data and relevant influencing factors to establish an optimal starting dosing regimen for intravenous oxytocin. METHODS: This retrospective study included pregnant women who underwent labor induction with intravenous oxytocin at Peking University Third Hospital in 2020. A  population K-PD model was developed to depict the time course of uterine contraction frequency (UCF), and covariate screening identified significant factors affecting the pharmacokinetics and pharmacodynamics of oxytocin. Model-based simulations were used to optimize the current starting regimen based on specific guidelines. RESULTS: Data from 77 pregnant women with 1095 UCF observations were described well by the K-PD model. Parity, cervical dilation, and membrane integrity are significant factors influencing the effectiveness of oxytocin. Based on the model-based simulations, the current regimens showed prolonged onset times and high infusion rates. This study proposed a revised approach, beginning with a rapid infusion followed by a reduced infusion rate, enabling most women to achieve the target UCF within approximately 30 min with the lowest possible infusion rate. CONCLUSION: The K-PD model of oxytocin effectively described the changes in UCF during labor induction. Furthermore, it revealed that parity, cervical dilation, and membrane integrity are key factors that influence the effectiveness of oxytocin. The optimal starting dosing regimens obtained through model simulations provide valuable clinical references for oxytocin treatment.

The presence of estradiol benzoate in the cervical relaxation treatment for non-surgical embryo collection does not impair embryonic morphological quality, cryosurvival, and gene expression profile.

Non-surgical embryo recovery (NSER) is usually preceded by a cervical relaxation in ovine donors, based on estradiol benzoate (EB), prostaglandin (PGF), and oxytocin (OT). However, it is hypothesized that, due to poorly understood mechanisms, EB can result in embryotoxic actions. To evaluate this, 20 min before NSER superovulated sheep were induced to cervical relaxation with 0.0 (G0.0), 0.5 (G0.5), or 1.0 mg (G1.0) of EB associated with 37.5 µg of PGF 16 h before NSER and 50 IU of OT. In doing so, the efficiency and duration of the NSER procedure showed no compromise (P > 0.05). Additionally, the presence of EB did not affect (P > 0.05) the embryo's morphological quality, the development dynamics, or the abundance of transcripts associated with embryonic quality (OCT4 and NANOG), cellular stress (HSP90 and PRDX1), and apoptosis (BCL2 and BAX). A similar result (P > 0.05) was also observed when comparing embryonic cryosurvival at 24 (52.0, 52.0, and 54.0) and 48 h (60.0, 54.0, and 58.0) of in vitro culture (G0.0, G0.5, and G1.0, respectively). Thus, we can conclude that EB use does not compromise embryonic quality and cryoresistance.

µ-Opioid receptor antagonism facilitates the anxiolytic-like effect of oxytocin in mice.

Mood and anxiety disorders are leading causes of disability worldwide and are major contributors to the global burden of diseases. Neuropeptides, such as oxytocin and opioid peptides, are important for emotion regulation. Previous studies have demonstrated that oxytocin reduced depression- and anxiety-like behavior in male and female mice, and opioid receptor activation reduced depression-like behavior. However, it remains unclear whether the endogenous opioid system interacts with the oxytocin system to facilitate emotion regulation in male and female mice. We hypothesized that opioid receptor blockade would inhibit the anxiolytic- and antidepressant-like effects of oxytocin. In this study, we systemically administered naloxone, a preferential µ-opioid receptor antagonist, and then intracerebroventricularly administered oxytocin. We then tested mice on the elevated zero maze and the tail suspension tests, respective tests of anxiety- and depression-like behavior. Contrary to our initial hypothesis, naloxone potentiated the anxiolytic-like, but not the antidepressant-like, effect of oxytocin. Using a selective µ-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, and a selective κ-opioid receptor antagonist, norbinaltorphimine, we demonstrate that µ-opioid receptor blockade potentiated the anxiolytic-like effect of oxytocin, whereas κ-opioid receptor blockade inhibited the oxytocin-induced anxiolytic-like effects. The present results suggest that endogenous opioids can regulate the oxytocin system to modulate anxiety-like behavior. Potential clinical implications of these findings are discussed.