Plasma Oxytocin Research Articles

The impact of childhood trauma exposure on social functioning in schizophrenia: the moderated mediation role of oxytocin and oxytocin receptor gene polymorphisms.

Childhood trauma has been linked to increased risk of schizophrenia and social dysfunction, and oxytocin and its receptor gene have been implicated in regulating social behavior. This study investigated the potential role of oxytocin and oxytocin receptor gene (OXTR) in mediating the effects of childhood trauma on social functioning in schizophrenia. The study consisted of 382 patients with schizophrenia and 178 healthy controls who were assessed using the Taiwanese version of the Childhood Trauma Questionnaire (CTQ-SF), the Social Functioning Scale (SFS), and plasma oxytocin levels. DNA was extracted to genotype the OXTR and ten single-nucleotide polymorphisms (SNPs; rs2254298, rs237885, rs237887, rs237899, rs53576, rs9840864, rs13316193, rs7632287, rs1042778, and rs237895) were selected. Patients with schizophrenia showed higher CTQ-SF scores (t = 12.549, p < 0.001), lower SFS scores (t = -46.951, p < 0.001), and lower plasma oxytocin levels (t = -5.448, p < 0.001) compared to healthy controls. The study also found significant differences in OXTR SNPs between both groups, with risk alleles being more prevalent in patients with schizophrenia (t = 2.734, p = 0.006). Results indicated a significant moderated mediation effect, with oxytocin and the OXTR SNPs partially mediating the relationship between childhood trauma exposure and social functioning in patients with schizophrenia (index of mediation = 0.038, 95% CI [0.033-0.044]). The findings suggest that oxytocin and its receptor gene may be promising targets for interventions aimed at improving social functioning in patients with a history of childhood trauma and schizophrenia. However, further research is needed to fully understand these effects and the potential of oxytocin-based interventions in this population.

Oxytocin levels and self-reported anxiety during interactions between humans and cows.

Positive social interactions with farm animals may have therapeutic benefits on humans by increasing brain oxytocin secretion, as inferred from circulating oxytocin levels. The aim of this observational study was to investigate acute changes in human plasma oxytocin levels and state anxiety associated with interactions with dairy cows. Data were collected from 18 healthy female nursing students who performed stroking and brushing of an unfamiliar cow for 15 min. Blood samples were drawn before entering the cowshed (T1, baseline), and after 5 (T2) and 15 (T3) min of interaction with a cow. At T1 and T3, the students filled out the Norwegian version of the Spielberger State-Trait Anxiety Inventory-State Subscale (STAI-SS). Across participants, no significant changes in average plasma oxytocin concentration were detected between time points (p>0.05). There was, however, a modest decline in the STAI-SS scores between T1 and T3 (p=0.015) and a positive correlation between the change in individual level of state anxiety between T1 and T3 and the change in OT concentration of the same individual between T2 and T3 (p = 0.045). The results suggest that friendly social interactions with cows are beneficial in lowering state anxiety, but any relationship with release of OT into the circulation was complex and variable across individuals. The acute reduction in state anxiety lends support to the value of interacting with farm animals in the context of Green Care for people with mental health challenges.

Oxytocin Levels in Children with Separation Anxiety and Their Mothers before and after Treatment.

The purpose of this study was to compare the plasma oxytocin levels of children with separation anxiety disorder (SAD) and their mothers with those of healthy controls and to examine the relationship between oxytocin levels and changes in anxiety three months after treatment. Thirty children aged 6-12 years with SAD, 30 healthy children, and mothers of both groups were included in the study. All cases were evaluated with semi-structured interview and Clinical Global Impression Scale. All cases and mothers of both groups filled out scales to determine various psychological variables (anxiety, depression, and attachment). The patient group children were re-evaluated with their mothers after three months, following treatment. Plasma oxytocin levels were evaluated from both groups and their mothers before and after treatment. The plasma oxytocin levels of mothers of children with SAD were significantly lower than those of the controls and increased significantly three months after their children were treated. No difference was found between the plasma oxytocin levels of children with SAD and the control group, and these children's levels decreased significantly after treatment. A positive correlation was found between changes in the plasma oxytocin levels of children with SAD and the change in anxiety scores. Our results show that the change in plasma oxytocin levels in both children and mothers after treatment suggests that oxytocin may be important in the etiology of SAD.

Exploring the role of ex vivo metabolism on blood and plasma measurements of oxytocin among women in the third stage of labour: A post hoc study.

To examine the role of ex vivo oxytocin metabolism in post-dose peptide measurements. The stability of oxytocin (Study 1) and oxytocinase activity (Study 2) in late-stage pregnancy blood was quantified using liquid-chromatography tandem mass-spectrometry (LC-MS/MS) and a fluorogenic assay, respectively. Analyses were conducted using blood from pregnant women (>36 weeks gestation) evaluated in lithium heparin (LH), ethylenediaminetetraacetic acid (EDTA) and BD P100 blood collection tubes with or without protease inhibitors. In addition, plasma oxytocin concentrations following administration of oxytocin 240 IU inhaled, 5IU intravenous or 10IU intramuscular in women in third stage of labour (TSL) were analysed using enzyme-linked immunosorbent assay (ELISA) and LC-MS/MS to understand how quantified peptide concentrations differ between these analytical methods (Study 3). Study 1: Oxytocin was stable in blood collected into EDTA tubes with or without protease inhibitors but not in LH tubes. Study 2: Blood collected into all EDTA-containing collection tubes led to near-complete inhibition of oxytocinase (≤100 min). In plasma, a 35% reduction in oxytocinase activity was observed in LH tubes with EDTA added. In plasma from late-stage pregnancy compared to nonpregnant participants, the oxytocinase activity was approximately 11-fold higher. Study 3: Plasma oxytocin concentrations from nonpregnant or women in TSL following exogenous oxytocin administration were ≤33 times higher when analysed using ELISA vs. LC-MS/MS methods. Collection of blood from late-stage pregnant women into tubes containing EDTA inhibits oxytocinase effectively stabilizing oxytocin, suggesting low concentrations of oxytocin after dose administration reflect rapid in vivo metabolism.

Prolonged ketamine therapy differentially rescues psychobehavioural deficits via modulation of nitro-oxidative stress and oxytocin receptors in the gut-brain-axis of chronically-stressed mice

Ketamine is an anaesthetic known to have short but rapid-acting anti-depressant effects; however, the neurobehavioural effects of its prolonged use and its role on the oxytocin system in the gut-brain axis are largely undetermined. Female BALB/c mice were either exposed to the chronic unpredictable mild stress (CUMS) paradigm for 21 days and then treated with ketamine in four doses for 14 days or exposed to CUMS and treated simultaneously in four doses of ketamine during the last two weeks of CUMS exposure. After each dose, the forced swim test was conducted to assess depressive-like behaviour. Before sacrifice, all the mice were subjected to behavioural tests to assess anxiety, memory, and social interaction. Prolonged treatment of depression with ketamine did not rescue depressive-like behaviour. It did, however, improve depression-associated anxiety-like behaviours, short-term memory and social interaction deficits when compared to the stressed untreated mice. Furthermore, ketamine treatment enhanced plasma oxytocin levels, expression of oxytocin receptors; as well as abrogated nitro-oxidative stress biomarkers in the intestinal and hippocampal tissues. Taken together, our findings indicate that while short-term use of ketamine has anti-depressant benefits, its prolonged therapeutic use does not seem to adequately resolve depressive-like behaviour in mice.

Comparison of plasma oxytocin level in women with natural and surgical menopause.

We aimed to investigate plasma oxytocin level in women with natural and surgical menopause and its relation with other metabolic parameters. This study included 89 postmenopausal women admitted to menopausal outpatient clinics and gave written consent to participate. Participants were allocated into natural (Group 1; n = 61) and surgical (Group 2; n = 28) menopause groups based on causative process for the onset of menopause. After the clinical evaluation and physical examination, blood samples are collected for biochemical profile and plasma oxytocin levels. The complete blood count, lipid profile, thyroid panel, blood glucose concentration, vitamin D and liver enzymes were measured by autoanalyzer, plasma oxytocin level was measured spectrophotometrically by ELISA method. The groups were comparable for age, body mass index, menopause duration, gravity and blood parameters measured except significantly different plasma oxytocin levels between the two groups as 6.8 (3.2-20.6) ng/ml in natural menopause group and 4.2 (2.9-18.2) ng/ml in surgical menopause group (p < 0.001). Plasma oxytocin level was also negatively correlated with age (r = -0.245, p = 0.022) and menopausal duration (r = -0.275, p = 0.01). Our results point out that oxytocin might be a target hormone to manage menopause associated disorders and/or it should be considered for its role in the differences in the incidences of postmenopausal diseases and quality of life in the course of natural and surgical menopausal transition.

Inaccuracies in plasma oxytocin extraction and enzyme immunoassay techniques

Numerous studies have reported extensive associations between plasma oxytocin (OXT) concentrations and various human physiological and neurobehavioral processes. Measurement of OXT is fraught with difficulty due to its low molecular weight and plasma concentrations, with no consensus as to the optimal conditions for pre-analytical sample extraction, standards for immunoassay validation or the ideal protease inhibitors to prevent OXT degradation. Previous attempts at determining the efficacy of various purification techniques such as solid phase extraction (SPE) or ultrafiltration have only utilized human plasma samples, making it difficult to dissect out whether the effect of interference comes from the extraction process itself or cross-reactivity with other proteins. By testing these on pure OXT solutions, we demonstrate poor recovery efficacy and reliability of reversed phase SPE (maximum 58.1%) and ultrafiltration (<1%) techniques, and the potential for the former to introduce interference into enzyme immunoassay (EIA) measurements. The clonality of antibodies used in EIA kits also potentially contributes to the differences in the readings obtained, and we validate an EIA kit which did not require pre-analytical sample extraction with low cross-reactivity and high reliability (intraclass correlation coefficient 0.980 (95% CI 0.896–0.999). Biochemical techniques used for measuring plasma OXT concentrations must therefore be internally validated prior to translation into clinical studies.

The relationship between endogenous oxytocin and vasopressin levels and the Prader-Willi syndrome behaviour phenotype.

Oxytocin and vasopressin systems are altered in Prader Willi syndrome (PWS). However, investigations into endogenous oxytocin and vasopressin levels as well as clinical trials evaluating the effect of exogenous oxytocin on PWS symptoms have had mixed results. It is also unknown whether endogenous oxytocin and vasopressin levels are associated with certain PWS behaviours. We compared plasma oxytocin and vasopressin and saliva oxytocin levels in 30 adolescents and adults with PWS to 30 typically developing age-matched controls. We also compared neuropeptide levels between gender and genetic subtypes within the PWS cohort and examined the relationship between neuropeptide levels and PWS behaviours. While we did not measure a group difference in plasma or saliva oxytocin levels, plasma vasopressin was significantly lower in individuals with PWS compared to controls. Within the PWS cohort, saliva oxytocin levels were higher in females compared to males and individuals with the mUPD compared to the deletion genetic subtype. We also found the neuropeptides correlated with different PWS behaviours for males and females and for genetic subtypes. For the deletion group, higher plasma and saliva oxytocin levels were related to fewer behaviour problems. For the mUPD group, higher plasma vasopressin levels were related to more behaviour problems. These findings support existing evidence of a vasopressin system defect in PWS and for the first time identify potential differences in the oxytocin and vasopressin systems across PWS genetic subtypes.

Oxytocin in response to MDMA provocation test in patients with arginine vasopressin deficiency (central diabetes insipidus): a single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial

Disruptions of the hypothalamic-pituitary axis can cause an arginine vasopressin deficiency, also known as central diabetes insipidus. Patients with this condition are at high risk of additional oxytocin deficiency owing to the close anatomical proximity of oxytocin-producing neurons; however, no conclusive evidence for such a deficiency has been reported. We aimed to use 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy), a strong activator of the central oxytocinergic system, as a biochemical and psychoactive provocation test to investigate oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus). This single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial included patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls (matched 1:1 by age, sex, and BMI) and was conducted at the University Hospital Basel, Basel, Switzerland. We used block randomisation to assign participants to receive either a single oral dose of MDMA (100 mg) or placebo in the first experimental session; patients received the opposite treatment at the next session, with a wash-out period of at least 2 weeks between the two sessions. Participants and investigators assessing the outcomes were masked to assignment. Oxytocin concentrations were measured at 0, 90, 120, 150, 180, and 300 min after MDMA or placebo. The primary outcome was the area under the plasma oxytocin concentration curve (AUC) after drug intake. The AUC was compared between groups and conditions using a linear mixed-effects model. Subjective drug effects were assessed throughout the study using ten-point visual analogue scales. Acute adverse effects were assessed before and 360 min after drug intake using a 66-item list of complaints. This trial is registered with ClinicalTrials.gov, NCT04648137. Between Feb 1, 2021, and May 1, 2022, we recruited 15 patients with arginine vasopressin deficiency (central diabetes insipidus) and 15 healthy controls. All participants completed the study and were included in the analyses. In healthy controls, median plasma oxytocin concentration was 77 pg/mL (IQR 59-94) at baseline and increased by 659 pg/mL (355-914) in response to MDMA, resulting in an AUC of 102 095 pg/mL (41 782-129 565); in patients, baseline oxytocin concentration was 60 pg/mL (51-74) and only slightly increased by 66 pg/mL (16-94) in response to MDMA, resulting in an AUC of 6446 pg/mL (1291-11 577). The effect of MDMA on oxytocin was significantly different between groups: the AUC for oxytocin was 82% (95% CI 70-186) higher in healthy controls than in patients (difference 85 678 pg/mL [95% CI 63 356-108 000], p<0·0001). The increase in oxytocin in healthy controls was associated with typical strong subjective prosocial, empathic, and anxiolytic effects, whereas only minimal subjective effects were observed in patients, in agreement with the lack of increase in oxytocin concentrations. The most frequently reported adverse effects were fatigue (eight [53%] healthy controls and eight [53%] patients), lack of appetite (ten [67%] healthy controls and eight [53%] patients), lack of concentration (eight [53%] healthy controls and seven [47%] patients), and dry mouth (eight [53%] healthy controls and eight [53%] patients). In addition, two (13%) healthy controls and four (27%) patients developed transient mild hypokalaemia. These findings are highly suggestive of clinically meaningful oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus), laying the groundwork for a new hypothalamic-pituitary disease entity. Swiss National Science Foundation, Swiss Academy of Medical Sciences, and the G&J Bangerter-Rhyner Foundation.

Oral Oxytocin Facilitates Responses to Emotional Faces in Reward and Emotional-Processing Networks in Females

Introduction: Oxytocin (OXT) is proposed as a potential therapeutic peptide for social dysfunction due to its modulatory actions on socioemotional regulation in humans. While the majority of studies have used intranasal OXT administration, we have recently shown that oral (lingual spray), but not intranasal, administration can significantly enhance activity of the brain reward system in response to emotional faces in males; however, its effects on females are unknown. Methods: Seventy healthy females participated in the current randomized, placebo-controlled, pharmaco-imaging clinical trial, and the results were compared with our previous data from 75 males who underwent the same protocol. Participants were randomly assigned to OXT (24 IU) or placebo (PLC) groups and completed an implicit emotional face paradigm (angry/fear/happy/neutral) where they were only required to identify face gender. Results: In line with previous results in males, oral OXT significantly increased plasma OXT concentration changes and enhanced putamen responses to all emotional faces compared to PLC in females. Additionally, OXT increased left amygdala activity to happy and angry faces and enhanced putamen-superior temporal gyrus functional coupling during processing of happy faces in females which was significantly different from males. Conclusion: Our findings suggest that oral OXT enhances responses in both reward and emotional-processing networks in females as well as males, and additionally, in females, it strengthens coupling between reward and social cognition regions.

Human endogenous oxytocin and its neural correlates show adaptive responses to social touch based on recent social context.

Both oxytocin (OT) and touch are key mediators of social attachment. In rodents, tactile stimulation elicits the endogenous release of OT, potentially facilitating attachment and other forms of prosocial behavior, yet the relationship between endogenous OT and neural modulation remains unexplored in humans. Using a serial sampling of plasma hormone levels during functional neuroimaging across two successive social interactions, we show that contextual circumstances of social touch influence not only current hormonal and brain responses but also later responses. Namely, touch from a male to his female romantic partner enhanced her subsequent OT release for touch from an unfamiliar stranger, yet females' OT responses to partner touch were dampened following stranger touch. Hypothalamus and dorsal raphe activation reflected plasma OT changes during the initial social interaction. In the subsequent interaction, precuneus and parietal-temporal cortex pathways tracked time- and context-dependent variables in an OT-dependent manner. This OT-dependent cortical modulation included a region of the medial prefrontal cortex that also covaried with plasma cortisol, suggesting an influence on stress responses. These findings demonstrate that modulation between hormones and the brain during human social interactions can flexibly adapt to features of social context over time.

Developmental Exposure to Flame Retardant Toxicants (PBDEs) Produces Autistic-Like Reprogramming of Behavior and Hypothalamic Oxytocin in a Thyroid- and Sex-Dependent Manner

Introduction: The prevalence of psychosocial neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) is rising at an alarming rate. ASD etiology is multifactorial, resulting from sex-specific genetic susceptibilities that may interact with environmental toxicant exposures during critical developmental periods. In humans, PBDEs are thyroid-disrupting chemicals associated with altered socioemotional behavior, decreased IQ and hyperactivity. We have previously demonstrated autistic-like effects produced by perinatal exposure to PBDEs in female mice (Kozlova et al, 2022; PMID: 34687351). Maternal thyroid hormone (TH) status affects fetal brain development and has been linked to ASD. Since thyroid hormones regulate oxytocin (OXT) and/or vasopressin neuroendocrine systems critical for social behavior, PBDEs may produce autistic-like actions via disruption of the thyroid system. Therefore, this study tested the hypothesis that developmental exposure to PBDEs produce neurobehavioral and hypothalamic OXT deficits in a TH-dependent manner. Materials and Methods: C57BL/6N dams were exposed human relevant doses of the penta-PBDE mixture, DE-71, at 0.1 mg/kg/d (L-DE-71), 0.4 mg/kg/d (H-DE-71) or with corn oil vehicle control (VEH/CON) for 10 wks (pre-conception: 4 wk, gestation: 3 wk, lactation: 3 wk). A subset of dams was treated with levothyroxine, a synthetic analogue of thyroxine (T4) (8 μg/100 g bw; GD 12-PND 21). Other dams were administered the thyroid synthesis inhibitor, 6-propyl-2-thiouracil (PTU; 50 mg/L; GD 14-PND 21). Results: Compared to VEH/CON, T4 and insulin-like growth factor-1 were attenuated in L-DE-71 dams at PND 0 but normalized in L-DE-71 + T4. In contrast, dam plasma OXT was not altered by DE-71 and elevated by T4 supplementation. L-DE-71 adult male and female offspring showed deficient social novelty preference; maternal T4 supplementation prevented this only in females. In contrast, T4 supplementation was equally effective at normalizing exaggerated repetitive behavior in L-DE-71 male and female offspring. DE-71 reduced OXT immunofluorescence IOD in the paraventricular nucleus of the hypothalamus (PVH) in male (L- and H-DE-71) and female offspring (L-DE-71) and in supraoptic nucleus (SON) in male offspring (L-DE-71) at PND 30. T4 supplementation normalized OXT content in L-DE-71 female and H-DE-71 male PVH. DE-71 had no effect on plasma OXT but was upregulated in VEH/CON +T4 female and DE-71+T4 male offspring. RT-qPCR analysis performed at PND15-30 showed that L-DE-71 downregulated hypothalamic Trh and cortical Oatp1c1 and Dio3 in females and upregulated hypothalamic Dio2, Esr1 and Esr2 and cortical Oatp1c1 in males. PTU’s actions do not exactly mimic those of DE-71. Conclusions: These results suggest that PBDEs disrupt social behavior and central OXT in a TH-dependent and sex-dependent manner. We provide novel information about possible TH-responsive genes that may contribute to neurodevelopmental disorders such as ASD. This work is supported by a Society of Toxicology Syngenta Fellowship Award in Human Health Applications of New Technologies and University of California President's Pre-Professoriate Fellowship to E.V.K. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

8 Comparison of oxytocin and pro-inflammatory cytokines in saliva and plasma in the post-partum mare as potential biomarkers of well-being

Although evaluating cortisol concentrations is a common method to assess stress in many species including horses, interpretation of results in these studies has proven challenging. Therefore, researchers are investigating alternative analytes as biomarkers of well-being. Historically thought to serve primary roles in parturition and lactation, oxytocin (OT) has been shown to act as a neurotransmitter to promote prosocial behavior and buffer stress. Pro-inflammatory cytokines (PICs) have been shown in humans to influence production of neurotransmitters such as serotonin and dopamine, implicating their potential role in psychosocial stress. Analyte levels are often measured in blood, but this sampling procedure can result in acute stress responses that may influence experimental results and conclusions. Evaluating analytes in saliva can serve as a less-invasive method to assess biomarkers of well-being. The purpose of this study was to determine the feasibility of measuring OT and PICs in saliva as an alternative to plasma sampling in horses. As studies have demonstrated that OT and PICs are elevated during parturition and lactation, 4 postpartum Quarter Horse mares (15.0 ± 0.82 yr) were chosen for this study. Plasma (P) and saliva (S) samples were collected 30 min post-foaling (P1, S1) and 30 min post first suckling (P2, S2). Samples were analyzedfor OT, IL1-β, IL-8, IL-6, and TNF-α via electrochemiluminescent (ECL) assay (Salimetrics). Data were analyzed using the PROC GLM and PROC CORR in SAS v 9.4. Mean analyte concentrations, with the exception of IL-8, differed by sample type (S OT = 45.16 ± 36.65 pg/mL, P OT = 96.10 ± 41.0 pg/mL, P < 0.05; S IL1-β = 13.98 ± 2.03 pg/mL, P IL1- β = 1.01 ± 0.18 pg/mL, P < 0.01; S IL-6 = 0.35 ± 0.14 pg/mL, P IL-6 = 1.32 ± 0.46 pg/mL, P < 0.01, S TNF-α = 0.36 ± 0.16 pg/mL, P TNF- α = 3.40 ± 0.86 pg/mL, P < 0.01). There were no differences in analyte concentrations due to time point. Though not significant (P > 0.5), time point comparisons across sample type showed moderate to strong Pearson correlations among OT (S1-P1; r = −0.56; S2-P2; r = −0.47), IL-8 (S1-P1; r = −0.69), IL-6 (S1-P1; r = 0.82), and TNF-α (S1-P1; r = 0.48). The established roles of OT and PICs in prosocial behavior and psychosocial stress suggest that measurement of these analytes may provide a targeted approach to assess biopsychosocial responses. While this assay has not yet been validated for use in horses, this study illustrates that PICs can be quantified in equine saliva which supports this less-invasive approach for studying biomarkers of well-being in horses.

Oxytocin Dosing and Maternal-Fetal Effects Using a Pharmacokinetic Model

Objective- Although oxytocin is widely used in labor and childbirth, questions remain regarding the pharmacokinetics (PK), pharmacodynamics (PD) and dose of oxytocin in pregnant people as well as the potential effects on the fetus and newborn. The objective of the current study was to use published studies to investigate the PK/PD and dose of oxytocin in pregnancy, examine the placental transfer of oxytocin through the development of a physiologically-based PK (PBPK) model, and postulate whether the model predicts the effect(s) of oxytocin on fetuses and newborn infants. Methods- A literature review of articles related to oxytocin in the areas of PK/PD, placental transfer and its influence on newborns were reviewed and summarized. A PBPK model for oxytocin was developed to predict maternal-fetal transfer. Results- Previous studies have demonstrated a positive relationship between the plasma oxytocin concentration and uterine contractions during labor. An ex vivo study demonstrated maternal to fetal and fetal to maternal oxytocin transfer, but a clinical study investigating oxytocin concentrations in umbilical blood could not confirm these results. Previous studies have suggested that a high concentration of oxytocin is related to fetal bradycardia and possibly autism in the child. Conclusion- The current study developed a PBPK model to measure the placental transfer of oxytocin and its potential for adverse effects on the fetus and developing child. Further research is needed to determine oxytocin’s efficacy and safety in the maternal population and in their fetuses and developing children, and modeling techniques such as PBPK will contribute to that understanding.

Sniffing oxytocin: Nose to brain or nose to blood?

In recent years ample studies have reported that intranasal administration of the neuropeptide oxytocin can facilitate social motivation and cognition in healthy and clinical populations. However, it is still unclear how effects are mediated since intranasally administered oxytocin can both directly enter the brain (nose to brain) and increase peripheral vascular concentrations (nose to blood). The relative functional contributions of these routes are not established and have received insufficient attention in the field. The current study used vasoconstrictor pretreatment to prevent intranasal oxytocin (24 IU) from increasing peripheral concentrations and measured effects on both resting-state neural (electroencephalography) and physiological responses (electrocardiogram, electrogastrogram and skin conductance). Results demonstrated that intranasal oxytocin alone produced robust and widespread increases of delta-beta cross-frequency coupling (CFC) from 30 min post-treatment but did not influence peripheral physiological measures. As predicted, vasoconstrictor pretreatment greatly reduced the normal increase in peripheral oxytocin concentrations and, importantly, abolished the majority of intranasal oxytocin effects on delta-beta CFC. Furthermore, time-dependent positive correlations were found between increases in plasma oxytocin concentrations and corresponding increases in delta-beta CFC following oxytocin treatment alone. Our findings suggest a critical role of peripheral vasculature-mediated routes on neural effects of exogenous oxytocin administration with important translational implications for its use as an intervention in psychiatric disorders.

Brief versus long maternal separation in lactating rats: Consequences on maternal behavior, emotionality, and brain oxytocin receptor binding.

Maternal separation is a widely used animal model to study early life adversity in offspring. However, only a few studies have focused on the impact of disrupting the maternal bond from the mother's perspective. Such studies reveal alterations in behavior, whereas the underlying neuroendocrine mechanisms remain largely unknown. In this study, we compared the consequences of daily brief maternal separation (BMS; 15 min) versus long maternal separation (LMS; 180 min) during the first week postpartum with respect to behavioral and neuroendocrine changes in lactating Sprague-Dawley dams. Mothers were tested for their maternal care before and after separation, maternal motivation to retrieve pups, as well as anxiety-related and stress-coping behaviors. In addition, we analyzed their basal plasma corticosterone levels and oxytocin receptor binding in selected brain regions of the limbic system and maternal network. LMS dams showed higher levels of behavioral alterations compared to BMS and non-maternally separated (NMS) dams, including increased licking and grooming of the pups and decreased maternal motivation. Anxiety-related behavior was not affected by either separation paradigm, whereas passive stress-coping behavior tended to increase in the LMS group. Plasma corticosterone concentrations were not different between groups. Oxytocin receptor binding was higher in the medial preoptic area and tended to be higher in the prelimbic cortex of LMS dams, only. Our results demonstrate that especially daily prolonged maternal separation impacts on the mothers' behavior and oxytocin system, which suggests that enhanced oxytocin receptor binding could be a compensatory mechanism for potentially decreased central oxytocin release due to limited pup contact.

Relationship between plasma dopamine concentration and temperament in horses

Dopamine (DA) is a neurotransmitter associated with animal behaviors. Along with other neurotransmitters such as oxytocin (OXT) and serotonin (5-HT), DA is also involved in determining the temperament of animals. However, the involvement of DA in horse temperament has not been well elucidated. Therefore, in this study, we aimed to determine the correlation between plasma DA concentration and OXT and 5-HT concentrations and behavioral temperament (eg, docility and friendliness, fearfulness, dominance, and trainability) of horses. Blood samples were collected from 31 horses and the concentrations of DA, OXT, and 5-HT were measured using enzyme-linked immunosorbent assay. The temperament of horses was assessed and scored by 3 researchers. The correlation between the plasma concentration of DA and OXT or 5-HT was statistically analyzed using SPSS software and linear regression analysis was performed to determine the association between DA concentration and OXT and 5-HT concentrations. Meanwhile, the DA concentration associated with each type of temperament was analyzed via one-way analysis of variance with LSD post hoc analysis as well as Student's t-test (for trainability). Plasma DA concentration was not found to be correlated with either OXT or 5-HT concentrations. Furthermore, we found no correlation between plasma DA concentration and dominance and trainability. However, our results suggest the possibility of predicting the degree of fearfulness of horses using plasma DA concentrations. We conclude that plasma DA concentration has a potentiality to be used as a biomarker to predict the fearfulness of horses.

Adverse childhood experiences mediate the negative association between borderline personality disorder symptoms and plasma oxytocin

BackgroundInterpersonal dysfunction is a core symptom of borderline personality disorder (BPD) and may be closely linked to adverse childhood experiences. According to a recent model on the pathology of BPD, the neuropeptide oxytocin might play an important role in the development and maintenance of the disorder. However, so far, only few studies with small adult samples have reported reduced baseline oxytocin levels in BPD that may be linked to adverse childhood experiences.MethodsWe examined baseline plasma oxytocin levels in 131 female patients with BPD and 124 non-BPD female controls across a large age span (12–50 years). Additionally, 113 female patients with less than five DSM-IV BPD features were included to examine the association between plasma oxytocin levels and the number of fulfilled BPD criteria. We also explored associations between plasma oxytocin and adverse childhood experiences as well as depressive symptoms in BPD.ResultsPatients with BPD had reduced plasma oxytocin levels compared to non-BPD controls and this was independent of age. Plasma oxytocin was negatively associated with the number of fulfilled BPD criteria. The exploratory regression model revealed no association between plasma oxytocin and depressive symptoms but an association between plasma oxytocin and adverse childhood experiences, which in fact mediated the relationship between BPD criteria und plasma oxytocin.ConclusionIn a large sample of individuals with BPD across a large age span, our results replicate and extend previous reports of reduced plasma oxytocin levels that might be related to adverse childhood experiences thus providing further evidence for a prominent role of oxytocin in BPD.

Maternal and newborn plasma oxytocin levels in response to maternal synthetic oxytocin administration during labour, birth and postpartum – a systematic review with implications for the function of the oxytocinergic system

BackgroundThe reproductive hormone oxytocin facilitates labour, birth and postpartum adaptations for women and newborns. Synthetic oxytocin is commonly given to induce or augment labour and to decrease postpartum bleeding.AimTo systematically review studies measuring plasma oxytocin levels in women and newborns following maternal administration of synthetic oxytocin during labour, birth and/or postpartum and to consider possible impacts on endogenous oxytocin and related systems.MethodsSystematic searches of PubMed, CINAHL, PsycInfo and Scopus databases followed PRISMA guidelines, including all peer-reviewed studies in languages understood by the authors. Thirty-five publications met inclusion criteria, including 1373 women and 148 newborns. Studies varied substantially in design and methodology, so classical meta-analysis was not possible. Therefore, results were categorized, analysed and summarised in text and tables.ResultsInfusions of synthetic oxytocin increased maternal plasma oxytocin levels dose-dependently; doubling the infusion rate approximately doubled oxytocin levels. Infusions below 10 milliunits per minute (mU/min) did not raise maternal oxytocin above the range observed in physiological labour. At high intrapartum infusion rates (up to 32 mU/min) maternal plasma oxytocin reached 2–3 times physiological levels.Postpartum synthetic oxytocin regimens used comparatively higher doses with shorter duration compared to labour, giving greater but transient maternal oxytocin elevations. Total postpartum dose was comparable to total intrapartum dose following vaginal birth, but post-caesarean dosages were higher.Newborn oxytocin levels were higher in the umbilical artery vs. umbilical vein, and both were higher than maternal plasma levels, implying substantial fetal oxytocin production in labour. Newborn oxytocin levels were not further elevated following maternal intrapartum synthetic oxytocin, suggesting that synthetic oxytocin at clinical doses does not cross from mother to fetus.ConclusionsSynthetic oxytocin infusion during labour increased maternal plasma oxytocin levels 2–3-fold at the highest doses and was not associated with neonatal plasma oxytocin elevations. Therefore, direct effects from synthetic oxytocin transfer to maternal brain or fetus are unlikely. However, infusions of synthetic oxytocin in labour change uterine contraction patterns. This may influence uterine blood flow and maternal autonomic nervous system activity, potentially harming the fetus and increasing maternal pain and stress.

Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion

Oxytocin (OT) is a prominent regulator of many aspects of mammalian social behavior and stored in large dense-cored vesicles (LDCVs) in hypothalamic neurons. It is released in response to activity-dependent Ca2+ influx, but is also dependent on Ca2+ release from intracellular stores, which primes LDCVs for exocytosis. Despite its importance, critical aspects of the Ca2+-dependent mechanisms of its secretion remain to be identified. Here we show that lysosomes surround dendritic LDCVs, and that the direct activation of endolysosomal two-pore channels (TPCs) provides the critical Ca2+ signals to prime OT release by increasing the releasable LDCV pool without directly stimulating exocytosis. We observed a dramatic reduction in plasma OT levels in TPC knockout mice, and impaired secretion of OT from the hypothalamus demonstrating the importance of priming of neuropeptide vesicles for activity-dependent release. Furthermore, we show that activation of type 1 metabotropic glutamate receptors sustains somatodendritic OT release by recruiting TPCs. The priming effect could be mimicked by a direct application of nicotinic acid adenine dinucleotide phosphate, the endogenous messenger regulating TPCs, or a selective TPC2 agonist, TPC2-A1-N, or blocked by the antagonist Ned-19. Mice lacking TPCs exhibit impaired maternal and social behavior, which is restored by direct OT administration. This study demonstrates an unexpected role for lysosomes and TPCs in controlling neuropeptide secretion, and in regulating social behavior.