Oxytocin Receptor Antagonist Research Articles

Ginsenoside Rg1 enriches gut microbial indole-3-acetic acid to alleviate depression-like behavior in mice via oxytocin signaling

Background and purposeAlthough a large collection of data has shown that ginsenosides, the major active ingredients from Ginseng, have neuroprotective and anti-depressant effect, the mechanism of action is incompletely understood. This study aims to elucidate the antidepressant mechanism of ginsenoside Rg1 (Rg1), a poorly absorbed ginsenoside, from the perspective of gut microbe to brain signaling. MethodsA mouse model of depression was induced by unpredictable mild stress (UMS). Behavioral and neurochemical tests were conducted to evaluate the effect and mechanism of Rg1 on depressive behavior. Non-target and target metabolomics were performed to identify the signaling metabolites underlying the antidepressant efficacy of Rg1. Gut microbial structure was analyzed by 16S rRNA sequencing and the potential functional strains associated with Rg1 action were investigated by in vitro bacterial culture. Chemical intervention was used to explore the mechanism of Rg1 and signaling metabolite. ResultsRg1 improved UMS-induced despair, anxiety-like and social avoidance behaviors in mice, which were accompanied by increased hypothalamic oxytocin secretion and restored neural proliferation in the hippocampus. Metabolomic analysis of the gut-brain axis revealed that Rg1 increased the concentration of serum and brain indole-3-acetic acid (IAA), a bacterial metabolite that was partially attributed to the enrichment of Lactobacillus murinus in the gut microbiome. Oral supplementation of IAA mimicked the anti-depressant action of Rg1, while oxytocin receptor antagonist abrogated the anti-depressant effects of both Rg1 and IAA. ConclusionOur work provides a new gut-to-brain signaling mechanism for the antidepressant effects of Rg1. In particular, Rg1 enriches the abundance of Lactobacillus murinus, which in turn increases the level of brain IAA and potentiates hypothalamic oxytocin signal. These findings suggest a promising pathway for producing antidepressant effects through gut-brain crosstalk.

Lactic acid-fermented by-product of Shochu distillery reduces anxiety behavior in Neuropeptide Y knockout zebrafish by the regulation of isotoin neuron

The development of techniques to reduce stress in the aquaculture industry is essential for the good growth, low mortality, and high flesh quality of farmed fish. Shochu is a traditional Japanese alcoholic beverage, and the disposal of large amounts of Shochu lees waste has been a problem. As Shochu lees contain low-molecular-weight compounds, which are thought to have health benefits, the lactic acid-fermented by-product of Shochu distillery (FBPSD) was tested to estimate its anti-stress effects in neuropeptide Y-knockout zebrafish (NPY-KO), which exhibit high anxiety and low sociability, as a farmed fish model.In the Black-White preference test, NPY-KO preferred the black area over the white area due to fear, whereas NPY-KO fed the FBPSD showed a higher preference for the white area with more swimming distance than the control group. In the 3-chambers test, NPY-KO showed low sociability with the unfamiliar zebrafish group, whereas FBPSD-fed NPY-KO showed high sociability with the group. The mRNA level of isotocin, the homologue of human oxytocin, was significantly increased in the brains of FBPSD-fed zebrafish. The oxytocin receptor antagonists L-368,899 attenuated the effects of FBPSD in the 3-chambers test. These results suggest that FBPSD attenuates anxiety in NPY-KO zebrafish by activating isotocin neurons.

Distinct medial amygdala oxytocin receptor neurons projections respectively control consolation or aggression in male mandarin voles

The individuals often show consolation to distressed companions or show aggression to the intruders. The circuit mechanisms underlying switching between consolation and aggression remain unclear. In the present study, using male mandarin voles, we identified that two distinct subtypes of oxytocin receptor (OXTR) neurons in the medial amygdala (MeA) projecting to the anterior insula (AI) and ventrolateral aspect of ventromedial hypothalamus (VMHvl) response differently to stressed siblings or unfamiliar intruders using c-Fos or calcium recording. Oxytocin release and activities of PVN neurons projecting to MeA increased upon consoling and attacking. OXTR antagonist injection to the MeA reduced consoling and attacking. Apoptosis, optogenetic or pharmacogenetic manipulation of these two populations of neurons altered behavioral responses to these two social stimuli respectively. Here, we show that two subtypes of OXTR neurons in the MeA projecting to the AI or VMHvl causally control consolation or aggression that may underlie switch between consolation and aggression.

Oxytocin treatment rescues irritability-like behavior in Cc2d1a conditional knockout mice.

Irritability, a state of excessive reactivity to negative emotional stimuli, is common in individuals with autism spectrum disorder (ASD). Although it has a significant negative impact of patients' disease severity and quality of life, the neural mechanisms underlying irritability in ASD remain largely unclear. We have previously demonstrated that male mice lacking the Coiled-coil and C2 domain containing 1a (Cc2d1a) in forebrain excitatory neurons recapitulate numerous ASD-like behavioral phenotypes, including impaired social behaviors and pronounced repetitive behaviors. Here, using the bottle-brush test (BBT) to trigger and evaluate aggressive and defensive responses, we show that Cc2d1a deletion increases irritability-like behavior in male but not female mice, which is correlated with reduced number of oxytocin (OXT)-expressing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Intranasal OXT administration or chemogenetic activation of OXT neurons in the PVN rescues irritability-like behavior in Cc2d1a conditional knockout (cKO) mice. Administration of a selective melanocortin receptor 4 agonist, RO27-3225, which potentiates endogenous OXT release, also alleviates irritability-like behavior in Cc2d1a cKO mice, an effect blocked by a specific OXT receptor antagonist, L-368,899. We additionally identify a projection connecting the posterior ventral segment of the medial amygdala (MeApv) and ventromedial nucleus of the ventromedial hypothalamus (VMHvl) for governing irritability-like behavior during the BBT. Chemogenetic suppression of the MeApv-VMHvl pathway alleviates irritability-like behavior in Cc2d1a cKO mice. Together, our study uncovers dysregulation of OXT system in irritability-like behavior in Cc2d1a cKO mice during the BBT and provide translatable insights into the development of OXT-based therapeutics for clinical interventions.

Improvement of early miscarriage rates in women with adenomyosis via oxytocin receptor antagonist during frozen embryo transfer-a propensity score-matched study

BackgroundDysfunctional uterine peristalsis seems to play a pivotal role in hindering embryo implantation among women diagnosed with adenomyosis. This research aims to investigate whether administering an oxytocin receptor antagonist during a frozen embryo transfer (FET) cycle using a hormone replacement therapy (HRT) protocol can enhance in vitro fertilization (IVF) outcomes for infertile women affected by adenomyosis.MethodsBetween January 2018 and June 2022, our reproductive center conducted IVF-FET HRT cycles for infertile women diagnosed with adenomyosis. Propensity score matching was employed to select matched subjects between the two groups in a 1:1 ratio. Following this, 168 women received an oxytocin receptor antagonist during FET, constituting the study group, while the matched 168 women underwent FET without this antagonist, forming the control group. We conducted comparative analyses of baseline and cycle characteristics between the two groups, along with additional subgroup analyses.ResultsThe study group exhibited notably lower rates of early miscarriage compared to the control group, although there were no significant differences in clinical pregnancy rates, ongoing pregnancy rates, and live birth rates between the two groups. Multivariate analysis revealed a negative correlation between the use of oxytocin receptor antagonists and early miscarriage rates in women with adenomyosis. Subgroup analyses, categorized by age, infertility types, and embryo transfer day, showed a substantial decrease in early miscarriage rates within specific subgroups: women aged ≥ 37 years, those with secondary infertility, and individuals undergoing day 3 embryo transfers in the study group compared to the control group. Furthermore, subgroup analysis based on adenomyosis types indicated significantly higher clinical pregnancy rates, ongoing pregnancy rates and live birth rates in the study group compared to the control group among women with diffuse adenomyosis.ConclusionsAdministering an oxytocin receptor antagonist during FET may reduce the early miscarriage rates in women with adenomyosis.

Heart and shoal: Social cues and oxytocin receptors impact stress recovery in the zebrafish

In many species, social interactions decrease behavioral, hormonal, and neural responses to environmental stressors. While “social buffering” and its mechanisms have received considerable attention in mammals, we know less about the phenomenon in fish. The nonapeptide oxytocin regulates social behavior across vertebrates and plays an important role in social buffering in mammals. We investigated social buffering in the zebrafish by evaluating how the social environment and oxytocin receptors impact recovery from an acute stressor. Male and female fish were briefly exposed to alarm substance and recovered either in isolation or within view of a stimulus shoal. Alarm substance did not increase social approach, but social stimuli improved behavioral stress recovery. Oxytocin receptor antagonism decreased social approach during stress recovery and impaired stress recovery exclusively in individuals with access to visual social stimuli. Our findings contribute to the growing body of evidence that social stimuli buffer stress responses in fish and suggest that oxytocin receptors may play a role in socially-buffered stress recovery across taxa.

Oxytocin Receptors on Calvarial Periosteal Innervation: Therapeutic Target for Post-Traumatic Headache?

Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)-a densely innervated tissue layer covering the calvarial skull-has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH. We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia. The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model-an effect that was preventable by the administration of an OTR antagonist. Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.

Cannabis Sativa Oil Promotes Social Interaction and Ultrasonic Communication by Acting on Oxytocin Pathway.

Objective: Cannabis sativa is the most used recreational drug worldwide. In recent years, there has been a growing interest in the potential therapeutic benefits of medicinal cannabis to treat a variety of psychiatric and neurological conditions. In particular, cannabidiol (CBD), a nonpsychoactive cannabis constituent, has been investigated for its potential prosocial effects on behavior, although the molecular mechanisms underlying this effect are still largely unknown. The aim of this study was to investigate the effect of a C. sativa oil CBD rich (CS oil) on social interaction and ultrasonic communication in mice. Study Design: Twenty-seven adult male mice (B6; 129P F2) were treated daily with vehicle or CS oil for 2 weeks. At Day 14, mice were tested for behavior (social interaction test and ultrasonic communication). Forty minutes before the behavioral tests, mice were exposed to intranasal treatment with vehicle or the oxytocin receptor antagonist, L-371,257. After behavioral tests, VH- and CS oil-treated mice were sacrificed, RNA was extracted from the hypothalamus and used for quantitative Real Time-PCR experiments. Results: We found that a 2-week treatment with the CS oil on mice exerted a prosocial effect associated with an increase in ultrasonic vocalizations. These effects were inhibited by pretreating mice with an oxytocin receptor antagonist. In addition, at the molecular level, we found that CS oil treatment caused a significant increase in oxytocin and a decrease in oxytocin receptor expression levels in the brain hypothalamus. Conclusion: Our results suggest that CS oil promotes social behavior by acting on oxytocin pathway.

Administration of Atosiban, an oxytocin receptor antagonist, ameliorates autistic-like behaviors in a female rat model of valproic acid-induced autism

Autism spectrum disorder (ASD) is a pervasive developmental disorder with gender differences. Oxytocin (OXT) is currently an important candidate drug for autism, but the lack of data on female autism is a big issue. It has been reported that the effect of OXT is likely to be different between male and female ASD patients. In the study, we specifically explored the role of the OXT signaling pathway in a VPA-induced female rat’s model of autism. The data showed that there was an increase of either oxytocin or its receptor expressions in both the hippocampus and the prefrontal cortex of VPA-induced female offspring. To determine if the excess of OXT signaling contributed to autism symptoms in female rats, exogenous oxytocin and oxytocin receptor antagonists Atosiban were used in the experiment. It was found that exogenous oxytocin triggered autism-like behaviors in wild-type female rats by intranasal administration. More interestingly, several autism-like deficits including social interaction, anxiety, and repeat stereotypical sexual behavior in the VPA female offspring were significantly attenuated by oxytocin receptor antagonists Atosiban. Moreover, Atosiban also effectively improved the synaptic plasticity impairment induced by VPA in female offspring. Our results suggest that oxytocin receptor antagonists significantly improve autistic-like behaviors in a female rat model of valproic acid-induced autism.

Mating-induced release of oxytocin in the mouse lateral septum: Implications for social fear extinction

In mammals, some physiological conditions are associated with the high brain oxytocin (OXT) system activity. These include lactation in females and mating in males and females, both of which have been linked to reduced stress responsiveness and anxiolysis. Also, in a murine model of social fear conditioning (SFC), enhanced brain OXT signaling in lactating mice, specifically in the lateral septum (LS), was reported to underlie reduced social fear expression. Here, we studied the effects of mating in male mice on anxiety-related behaviour, social (and cued) fear expression and its extinction, and the activity of OXT neurons reflected by cFos expression and OXT release in the LS and amygdala. We further focused on the involvement of brain OXT in the mating-induced facilitation of social fear extinction. We could confirm the anxiolytic effect of mating in male mice irrespective of the occurrence of ejaculation. Further, we found that only successful mating resulting in ejaculation (Ej+) facilitated social fear extinction, whereas mating without ejaculation (Ej-) did not. In contrast, mating did not affect cues fear expression. Using the cellular activity markers cFos and pErk, we further identified the ventral LS (vLS) as a potential region participating in the effect of ejaculation on social fear extinction. In support, microdialysis experiments revealed a rise in OXT release within the LS, but not the amygdala, during mating. Finally, infusion of an OXT receptor antagonist into the LS before mating or into the lateral ventricle (icv) after mating demonstrated a significant role of brain OXT receptor-mediated signaling in the mating-induced facilitation of social fear extinction.

Environmental enrichment enhances ethanol preference over social reward in male swiss mice: Involvement of oxytocin-dopamine interactions

The impact of environmental enrichment (EE) on natural rewards, including social and appetitive rewards, was investigated in male Swiss mice. EE, known for providing animals with various stimuli, was assessed for its effects on conditioned place preference (CPP) associated with ethanol and social stimuli. We previously demonstrated that EE increased the levels of the prosocial neuropeptide oxytocin (OT) in the hypothalamus and enhanced ethanol rewarding effects via an oxytocinergic mechanism. This study also investigated the impact of EE on social dominance and motivation for rewards, measured OT-mediated phospholipase C (PLC) activity in striatal membranes, and assessed OT expression in the hypothalamus. The role of dopamine in motivating rewards was considered, along with the interaction between OT and D1 receptors (DR) in the nucleus accumbens (NAc). Results showed that EE mice exhibited a preference for ethanol reward over social reward, a pattern replicated by the OT analogue Carbetocin. EE mice demonstrated increased social dominance and reduced motivation for appetitive taste stimuli. Higher OT mRNA levels in the hypothalamus were followed by diminished OT receptor (OTR) signaling activity in the striatum of EE mice. Additionally, EE mice displayed elevated D1R expression, which was attenuated by the OTR antagonist (L-368-889). The findings underscore the reinforcing effect of EE on ethanol and social rewards through an oxytocinergic mechanism. Nonetheless, they suggest that mechanisms other than the prosocial effect of EE may contribute to the ethanol pro-rewarding effect of EE and Carbetocin. They also point towards an OT-dopamine interaction potentially underlying some of these effects.

Effect of oxytocin receptor antagonist (GSK-221-149-A) on mandibular bone porosity in peri-menopausal rats

The period of peri-menopause (PMP) is characterized by hormonal fluctuations that impact the strength and health of bones. Oxytocin (OX), a small peptide known to be present in bone tissue, is the focus of this study. The objective of this research is to gain a better understanding of how OX precisely functions in the remodeling process of the mandibular bone. This understanding is seen as a crucial step in preventing the loss of both cortical and trabecular bone during the PMP. The current findings indicate that OX plays a role in preserving both compact and trabecular bone tissues, enhancing the mineral-to-matrix ratio, and regulating bone markers. Furthermore, it reduces porosity in both cortical and trabecular bone levels. Interestingly, these effects are reversed when an oxytocin receptor antagonist (GSK-221,149-A) is introduced, suggesting that OX’s bone-preserving action is primarily mediated through the oxytocin receptor, rather than other mechanisms.

Crosstalk amongst oxytocin and vasopressin synthesizing neurons of the paraventricular nucleus of the hypothalamus increases blood pressure in mice

The paraventricular nucleus of the hypothalamus (PVH) orchestrates neuroendocrine release and autonomic outflow to maintain body fluid homeostasis and cardiovascular function. Emerging evidence supports the notion that neuropeptides synthesized by PVH neurons create paracrine signals that alter physiology and behavior by affecting the activity of neighboring neurons. Here, we test the hypothesis that PVH neurons synthesizing oxytocin (hereafter referred to a PVHOT) create a paracrine signal that regulates blood pressure. Mice with the expression of Cre-recombinase directed to the OT gene were bred that mice that express a CAG-driven LoxP-flanked stop-codon preceding a channelrhodopsin-2 (ChR2) and eYFP fusion gene at the Rosa26 locus. This produced mice expressing only Cre-recombinase (controls) or mice with ChR2-eYFP expression directed to cells that express oxytocin (OT-ChR2). Confocal image analysis found that ~90% of eYFP expressing neurons were also immunolabeled for OT and electrophysiological recordings obtained from these neurons revealed that pulses of blue light elicited the firing of action potentials. These results confirm directed and functional expression of ChR2 within PVHOT. In vivo optogenetic excitation of PVHOT increased blood pressure and decreased heart rate in OT-ChR2 mice relative to controls. Ganglionic blockade with hexamethonium had no effect on the increased blood pressure elicited by optogenetic excitation of PVHOT but it completely abolished the bradycardia that was previously observed. These results suggest that excitation of PVHOT recruits a neuroendocrine signal that promotes vasoconstriction, which elicits the baroreflex to induce bradycardia by engaging the autonomic nervous system. Consistent with this interpretation, optogenetic excitation of PVHOT increased circulating levels of OT; however, the elevated blood pressure persisted after systemic administration of an OT receptor antagonist. Intriguingly, in vitro optogenetic excitation of PVHOT evoked Ca2+ flux in CHO cells expressing OT or vasopressin receptors (V1aR), suggesting that robust firing of PVHOT is followed by local release of OT. Optogenetic excitation of PVHOT augmented firing of neurons of the PVH that synthesize vasopressin and tended to increase circulating levels of this neuropeptide. Remarkably, systemic administration of a V1aR antagonist completely abolished the increase in blood pressure and bradycardia that were previously observed with in vivo optogenetic excitation of PVHOT. Collectively, these results reveal that robust firing of PVHOT creates an oxytocinergic paracrine signal that increases blood pressure by activating V1aR(s) and increasing circulating vasopressin. AHA 23POST1020034 to KE. NHLBI F31HL1162540 to CBH. NHLBI R01HL136595, R35HL150750, R01HL145028 and NCCIH R65AT012142 to ADK & EGK. This is the full abstract presented at the American Physiology Summit 2024 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.

Naloxone increases conditioned fear responses during social buffering in male rats.

Social buffering is the phenomenon in which the presence of an affiliative conspecific mitigates stress responses. We previously demonstrated that social buffering completely ameliorates conditioned fear responses in rats. However, the neuromodulators involved in social buffering are poorly understood. Given that opioids, dopamine, oxytocin and vasopressin play an important role in affiliative behaviour, here, we assessed the effects of the most well-known antagonists, naloxone (opioid receptor antagonist), haloperidol (dopamine D2 receptor antagonist), atosiban (oxytocin receptor antagonist) and SR49059 (vasopressin V1a receptor antagonist), on social buffering. In Experiment 1, fear-conditioned male subjects were intraperitoneally administered one of the four antagonists 25 min prior to exposure to a conditioned stimulus with an unfamiliar non-conditioned rat. Naloxone, but not the other three antagonists, increased freezing and decreased walking and investigation as compared with saline administration. In Experiment 2, identical naloxone administration did not affect locomotor activity, anxiety-like behaviour or freezing in an open-field test. In Experiment 3, after confirming that the same naloxone administration again increased conditioned fear responses, as done in Experiment 1, we measured Fos expression in 16 brain regions. Compared with saline, naloxone increased Fos expression in the paraventricular nucleus of the hypothalamus and decreased Fos expression in the nucleus accumbens shell, anterior cingulate cortex and insular cortex and tended to decrease Fos expression in the nucleus accumbens core. Based on these results, we suggest that naloxone blocks social buffering of conditioned fear responses in male rats.

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-1β, 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.

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.

Comparison of terbutaline and atosiban as tocolytic agents in intrauterine repair of myelomeningocele: a retrospective cohort study

BackgroundMyelomeningocele (MMC) is a neural tube defect disease. Antenatal repair of fetal MMC is an alternative to postnatal repair. Many agents can be used as tocolytics during the in utero fetal repair such as β2-agonists and oxytocin receptor antagonists, with possible maternal and fetal repercussions. This study aims to compare maternal arterial blood gas analysis between terbutaline or atosiban, as tocolytic agents, during intrauterine MMC repair. MethodsRetrospective cohort study. Patients were divided into two groups depending on the main tocolytic agent used during intrauterine MMC repair: atosiban (16) or terbutaline (9). Maternal arterial blood gas samples were analyzed on three moments: post induction (baseline, before the start of tocolysis), before extubation, and two hours after the end of the surgery. ResultsTwenty-five patients were included and assessed. Before extubation, the terbutaline group showed lower arterial pH (7.347 ± 0.05 vs. 7.396 ± 0.02 for atosiban, p = 0.006) and higher arterial lactate (28.33 ± 12.76 mg.dL−1 vs. 13.06 ± 6.35 mg.dL−1, for atosiban, p = 0.001) levels. ConclusionsPatients who received terbutaline had more acidosis and higher levels of lactate, compared to those who received atosiban, during intrauterine fetal MMC repair.

Age-Dependent Effects of Oxytocin and Oxytocin Receptor Antagonists on Bladder Contractions: Implications for the Treatment of Overactive Bladder Syndrome.

Overactive bladder (OAB) is an age-related disorder characterised by unstable bladder contractions resulting in disruptive lower urinary tract symptoms (LUTS), thus creating a profound impact on an individual's quality of life. The development of LUTS may be linked to the overexpression of oxytocin receptors (OXTRs) within the bladder detrusor muscle, resulting in increased baseline myogenic tone. Thus, it is hypothesised that targeting OXTRs within the bladder using oxytocin antagonists may attenuate myogenic tone within the bladder, thereby providing a new therapeutic avenue for treating OAB. Organ bath contractility and immunohistochemistry techniques were conducted on bladder tissue sourced from young rats (7-8 weeks and 10-12 weeks) and older rats (4-5 months and 7-9 months). Organ bath studies revealed that oxytocin (OT) significantly increased bladder contractions, which were significantly attenuated by [β-Mercapto-β,β-cyclopentamethylenepropionyl1, O-Me-Tyr2, Orn8]-Oxytocin) (1 µM) (**** p < 0.0001) and atosiban (10 µM) in both young and older rats (** p < 0.01); in contrast, cligosiban (1 µM and 10 µM) did not inhibit OT-induced contractions in both young and older rats (p ≥ 0.05). Interestingly, cligosiban (1 µM and 10 µM) significantly reduced the frequency of spontaneous contractions within the bladder of both young (*** p < 0.001) and older rats (**** p < 0.0001), while atosiban (10 µM) only demonstrated this effect in older rats (** p < 0.01). Furthermore, immunohistochemistry (IHC) analysis revealed significant colocalization of nuclear-specific oxytocin receptors (OXTRs) in the contractile (smooth muscle) cells within young (** p < 0.01) and older rats (* p < 0.05), indicating OT may be a key modulator of bladder contractility.

Expression of bond-related behaviors affects titi monkey responsiveness to oxytocin and vasopressin treatments.

Social bonds influence physiology and behavior, which can shape how individuals respond to physical and affective challenges. Coppery titi monkey (Plecturocebus cupreus) offspring form selective bonds with their fathers, making them ideal for investigating how father-daughter bonds influence juveniles' responses to oxytocin (OT) and arginine-vasopressin (AVP) manipulations. We quantified the expression of father-daughter bond-related behaviors in females (n = 10) and gave acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or an OT receptor antagonist (OTA) to subjects prior to a parent preference test. While females spent more time in proximity to their parents than strangers, we found a large degree of individual variation. Females with greater expression of bonding behaviors responded to OT treatments in a dose-dependent manner. Subjects also spent less time in proximity to strangers when treated with High OT (p = 0.003) and Low OT (p = 0.007), but more time when treated with High AVP (p = 0.007), Low AVP (p = 0.009), and OTA (p = 0.001). Findings from the present study suggest that variation in the expression of bond-related behaviors may alter responsiveness to OT and AVP, increasing engagement with unfamiliar social others. This enhanced sociality with strangers may promote the formation of pair bonds with partners.

Hypothalamic Paraventricular Stimulation Inhibits Nociceptive Wide Dynamic Range Trigeminocervical Complex Cells via Oxytocinergic Transmission.

Oxytocinergic transmission blocks nociception at the peripheral, spinal, and supraspinal levels through the oxytocin receptor (OTR). Indeed, a neuronal pathway from the hypothalamic paraventricular nucleus (PVN) to the spinal cord and trigeminal nucleus caudalis (Sp5c) has been described. Hence, although the trigeminocervical complex (TCC), an anatomical area spanning the Sp5c, C1, and C2 regions, plays a role in some pain disorders associated with craniofacial structures (e.g., migraine), the role of oxytocinergic transmission in modulating nociception at this level has been poorly explored. Hence, in vivo electrophysiological recordings of TCC wide dynamic range (WDR) cells sensitive to stimulation of the periorbital or meningeal region were performed in male Wistar rats. PVN electrical stimulation diminished the neuronal firing evoked by periorbital or meningeal electrical stimulation; this inhibition was reversed by OTR antagonists administered locally. Accordingly, neuronal projections (using Fluoro-Ruby) from the PVN to the WDR cells filled with Neurobiotin were observed. Moreover, colocalization between OTR and calcitonin gene-related peptide (CGRP) or OTR and GABA was found near Neurobiotin-filled WDR cells. Retrograde neuronal tracers deposited at the meningeal (True-Blue, TB) and infraorbital nerves (Fluoro-Gold, FG) showed that at the trigeminal ganglion (TG), some cells were immunopositive to both fluorophores, suggesting that some TG cells send projections via the V1 and V2 trigeminal branches. Together, these data may imply that endogenous oxytocinergic transmission inhibits the nociceptive activity of second-order neurons via OTR activation in CGRPergic (primary afferent fibers) and GABAergic cells.