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Background and Purpose: With increasing life expectancy, benign prostatic hyperplasia (BPH) consequently affects more ageing men, illustrating the urgent need for advancements in BPH therapy. One emerging possibility may be the use of oxytocin antagonists to relax smooth muscle cells in the prostate, similar to the currently used (although often associated with side effects) α1‐adrenoceptor blockers. Experimental Approach: For the first time we used live‐imaging, combined with a novel image analysis method, to investigate the multidirectional contractions of the human prostate and determine their changes in response to oxytocin and the oxytocin antagonists atosiban and cligosiban. Human prostate samples were obtained and compared from patients undergoing prostatectomy due to prostate cancer as well as from patients with transurethral resection of prostate tissue due to severe BPH. Key Results: The two cohorts of tissue samples showed spontaneous multidirectional contractions, which significantly increased after the addition of oxytocin. Different to atosiban, which showed ambiguous effects of short duration, only long‐acting cligosiban reliably prevented, as well as counteracted, any contractile oxytocin effect. Furthermore, cligosiban visibly reduced not only oxytocin‐induced contractions, but also showed intrinsic activity to relax prostatic tissue. Conclusion and implications: Thus, the oxytocin antagonist cligosiban could be an interesting candidate in the search for novel BPH treatment options. [ABSTRACT FROM AUTHOR]

Chemogenetic activation of oxytocin receptor‐expressing neurons in the parabrachial nucleus (OxtrPBN neurons) acts as a satiation signal for water. In this research, we investigated the effect of activating OxtrPBN neurons on satiation for different types of fluids. Chemogenetic activation of OxtrPBN neurons in male and female transgenic OxtrCre mice robustly suppressed the rapid, initial (15‐min) intake of several solutions after dehydration: water, sucrose, ethanol and saccharin, but only slightly decreased intake of Ensure®, a highly caloric solution (1 kcal/mL; containing 3.72 g protein, 3.27 g fat, 13.42 g carbohydrates, and 1.01 g dietary fibre per 100 mL). OxtrPBN neuron activation also suppressed cumulative, longer‐term (2‐h) intake of lower caloric, less palatable solutions, but not highly caloric, palatable solutions. These results suggest that OxtrPBN neurons predominantly control initial fluid‐satiation responses after rehydration, but not longer‐term intake of highly caloric, palatable solutions. The suppression of fluid intake was not because of anxiogenesis, but because OxtrPBN neuron activation decreased anxiety‐like behaviour. To investigate the role of different PBN subdivisions on the intake of different solutions, we examined FOS as a proxy marker of PBN neuron activation. Different PBN subdivisions were activated by different solutions: the dorsolateral PBN similarly by all fluids; the external lateral PBN by caloric but not non‐caloric solutions; and the central lateral PBN primarily by highly palatable solutions, suggesting PBN subdivisions regulate different aspects of fluid intake. To explore the possible mechanisms underlying the minimal suppression of Ensure® after OxtrPBN neuron activation, we demonstrated in in vitro slice recordings that the feeding‐associated agouti‐related peptide (AgRP) inhibited OxtrPBN neuron firing in a concentration‐related manner, suggesting possible inhibition by feeding‐related neurocircuitry of fluid satiation neurocircuitry. Overall, this research suggests that although palatable beverages like sucrose‐ and ethanol‐containing beverages activate fluid satiation signals encoded by OxtrPBN neurons, these neurons can be inhibited by hunger‐related signals (agouti‐related peptide, AgRP), which may explain why these fluids are often consumed in excess of what is required for fluid satiation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chemotherapy‐induced neuropathic pain (CINP) currently has limited effective treatment. Although the roles of oxytocin (OXT) and the oxytocin receptor (OXTR) in central analgesia have been well documented, the expression and function of OXTR in the peripheral nervous system remain unclear. Here, we evaluated the peripheral antinociceptive profiles of OXTR in CINP. Experimental Approach: Paclitaxel (PTX) was used to establish CINP. Quantitative real‐time polymerase chain reaction (qRT‐PCR), in situ hybridization, and immunohistochemistry were used to observe OXTR expression in dorsal root ganglia (DRG). The antinociceptive effects of OXT were assessed by hot‐plate and von Frey tests. Whole‐cell patch clamp was performed to record sodium currents, excitability of DRG neurons, and excitatory synapse transmission. Key Results: Expression of OXTR in DRG neurons was enhanced significantly after PTX treatment. Activation of OXTR exhibited antinociceptive effects, by decreasing the hyperexcitability of DRG neurons in PTX‐treated mice. Additionally, OXTR activation up‐regulated the phosphorylation of protein kinase C (pPKC) and, in turn, impaired voltage‐gated sodium currents, particularly the voltage‐gated sodium channel 1.7 (NaV1.7) current, that plays an indispensable role in PTX‐induced neuropathic pain. OXT suppressed excitatory transmission in the spinal dorsal horn as well as excitatory inputs from primary afferents in PTX‐treated mice. Conclusion and Implications: The OXTR in small‐sized DRG neurons is up‐regulated in CINP and its activation relieved CINP by inhibiting the neural excitability by impairment of NaV1.7 currents via pPKC. Our results suggest that OXTR on peripheral sensory neurons is a potential therapeutic target to relieve CINP. [ABSTRACT FROM AUTHOR]

Maternal prenatal psychosocial stress is associated with adverse hypothalamic–pituitary–adrenal axis (HPAA) function among infants. Although the biological mechanisms influencing this process remain unknown, altered DNA methylation is considered to be one potential mechanism. We investigated associations between maternal prenatal psychological distress, infant salivary DNA methylation, and stress physiology at 12 months. Mother's distress was measured via depression and anxiety in early and late pregnancy in a cohort of 80 pregnant adolescents. Maternal hair cortisol was collected during pregnancy. Saliva samples were collected from infants at 12 months to quantify DNA methylation of three stress‐related genes (FKBP5, NR3C1, OXTR) (n = 62) and diurnal cortisol (n = 29). Multivariable linear regression was used to test for associations between prenatal psychological distress, and infant DNA methylation and cortisol. Hair cortisol concentrations in late pregnancy were negatively associated with two sites of FKBP5 (site 1: B = −22.33, p =.003; site 2: B = −15.60, p =.012). Infants of mothers with elevated anxiety symptoms in late pregnancy had lower levels of OXTR2 CpG2 methylation (B = −2.17, p =.03) and higher evening salivary cortisol (B = 0.41, p =.03). Furthermore, OXTR2 methylation was inversely associated with evening cortisol (B = −0.14, p‐value ≤.001). Our results are, to our knowledge, the first evidence that the methylation of the oxytocin receptor may contribute to the regulation of HPAA during infancy. [ABSTRACT FROM AUTHOR]

Oxytocin (OX) is a posterior pituitary hormone secreted into the blood from axon terminals projecting from the posterior pituitary. Recent reports indicate OX plays an important role in the progression of inflammatory diseases such as rheumatoid arthritis. Pulpitis is caused by the activation of the biological defense mechanism of the dental pulp against cariogenic bacteria. However, the role of OX in the pathogenesis of pulpitis remains unknown. The aim of this study was to examine the effect of OX on CXC chemokine ligand 10 (CXCL10) production in human dental pulp stem cells (HDPSCs). Expression of the oxytocin receptor (OXR) on HDPSCs was detected by Western blot analysis and immunofluorescence. CXCL10 production in HDPSCs was measured using an enzyme‐linked immunosorbent assay kit. Western blot analysis was performed to determine the phosphorylation levels of signal transduction molecules, including nuclear factor kappa B, mitogen‐activated protein kinases (MAPKs), and Akt in HDPSCs. HDPSCs expressed OXR. OX significantly decreased CXCL10 production in tumor necrosis factor (TNF)‐α‐stimulated HDPSCs. The p38 MAPK and Akt pathways were related to the OX‐suppressed CXCL10 production in TNF‐α‐stimulated HDPSCs. These results indicate that OX appears to modulate the immune response in pulpitis via suppression of CXCL10 production by HDPSCs. [ABSTRACT FROM AUTHOR]

Summary: Background: Despite the importance of oxytocinergic signalling for satiety regulation and energy balance, the impact of exposure to synthetic oxytocin during childbirth on obesity during childhood remains unknown. Objectives: To examine the association between oxytocin exposure during labour and the risk of being overweight or obese during childhood. Methods: Synthetic oxytocin exposure data of mothers from the Danish Medical Birth Registry were linked with self‐reported anthropometric data of their children from the Danish National Birth Cohort (5 months–11 years of age). Multinomial logistic regression and latent class growth analyses were performed to determine the association between oxytocin exposure and obesity during childhood. Results: With the exception of the normal weight‐to‐overweight group between ages 5 and 12 months, none of the other analyses revealed a significant association between synthetic oxytocin use and the risk of being overweight until the age of 11 years. Furthermore, latent class growth analysis did not reveal an association between oxytocin exposure at birth and the risk of being overweight or obese during childhood. Conclusions: Our analysis of a large cohort of children who varied in their synthetic oxytocin exposure status at childbirth did not reveal an association between oxytocin exposure and the risk of childhood overweight/obesity. [ABSTRACT FROM AUTHOR]

Background: Individuals with alcohol use disorder (AUD) exhibit a disruption of social behavior and dysregulation of oxytocin signaling in the brain, possibly reflecting decreased activation of oxytocin receptors (OxTRs) in reward pathways in response to social stimuli. We hypothesize that daily binge ethanol intake causes a deficit in social reward and oxytocin signaling in the ventral tegmental area (VTA). Methods: After 9 weeks of daily binge ethanol intake (blood ethanol concentration >80 mg%), OxTR‐cre mice underwent conditioned place preference for social reward. Separate groups of mice were tested for the effects of binge ethanol on voluntary social interactions, food reward, locomotion, and anxiety‐like behaviors. A subset of mice underwent transfection of OxTR‐expressing VTA neurons (VTAOxtr) with a light‐sensitive opsin, followed by operant training to respond to light delivered to VTA. Results: Ethanol‐naïve male mice increased the time spent on the side previously paired with novel mice while ethanol‐treated mice did not. Binge ethanol did not affect conditioned place preference for food reward in males, but this response was weakened in ethanol‐treated females. Ethanol treatment also caused a sex‐specific impairment of voluntary social interactions with novel mice. There were minimal differences between groups in measures of anxiety and locomotion. Ethanol‐naïve mice had significantly greater operant responding for activation of VTAOxtr than sham‐transfected mice but ethanol‐treated mice did not. There was no difference in the number of VTAOxtr after binge ethanol. Conclusions: Daily binge ethanol causes social reward deficits that cannot be explained by nonspecific effects on other behaviors, at least in males. Only ethanol‐naïve mice exhibited positive reinforcement caused by activation of VTAOxtr while daily binge ethanol did not alter the number of VTAOxtr in either males or females. Thus, subtle dysregulation of VTAOxtr function may be related to the social reward deficits caused by daily binge ethanol. [ABSTRACT FROM AUTHOR]

Early‐life experience influences social and emotional behaviour in adulthood. Affiliative tactile stimuli in early life facilitate the development of social and emotional behaviour, whereas early‐life adverse stimuli have been shown to increase the risk of various diseases in later life. On the other hand, oxytocin has been shown to have organizational actions during early‐life stages. However, the detailed mechanisms of the effects of early‐life experience and oxytocin remain unclear. Here, we review the effects of affiliative tactile stimuli during the neonatal period and neonatal oxytocin treatment on the activity of the oxytocin–oxytocin receptor system and social or emotional behaviour in adulthood. Both affiliative tactile stimuli and early‐life adverse stimuli in the neonatal period acutely activate the oxytocin–oxytocin receptor system in the brain but modulate social behaviour and anxiety‐related behaviour apparently in an opposite direction in adulthood. Accumulating evidence suggests that affiliative tactile stimuli and exogenous application of oxytocin in early‐life stages induce higher activity of the oxytocin–oxytocin receptor system in adulthood, although the effects are dependent on experimental procedures, sex, dosages and brain regions examined. On the other hand, early‐life stressful stimuli appear to induce reduced activity of the oxytocin–oxytocin receptor system, possibly leading to adverse actions in adulthood. It is possible that activation of a specific oxytocin system can induce beneficial actions against early‐life maltreatments and thus could be used for the treatment of developmental psychiatric disorders. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma (MM) is one of the most aggressive tumors. We conducted bioinformatics analysis using Cancer Cell Line Encyclopedia (CCLE) datasets to identify new molecular markers in MM. Overexpression of oxytocin receptor (OXTR), which is a G‐protein–coupled receptor for the hormone and neurotransmitter oxytocin, mRNA was distinctively identified in MM cell lines. Therefore, we assessed the role of OXTR and its clinical relevance in MM. Kaplan‐Meier and Cox regression analyses were applied to assess the association between overall survival and OXTR mRNA expression using The Cancer Genome Atlas (TCGA) datasets. The function of OXTR and the efficacy of its antagonists were investigated in vitro and in vivo using MM cell lines. Consistent with the findings from CCLE datasets analysis, OXTR mRNA expression was highly increased in MM tissues compared with other cancer types in the TCGA datasets, and MM cases with high OXTR expression showed poor overall survival. Moreover, OXTR knockdown dramatically decreased MM cell proliferation in cells with high OXTR expression via tumor cell cycle disturbance, whereas oxytocin treatment significantly increased MM cell growth. OXTR antagonists, which have high selectivity for OXTR, inhibited the growth of MM cell lines with high OXTR expression, and oral administration of the OXTR antagonist, cligosiban, significantly suppressed MM tumor progression in a xenograft model. Our findings suggest that OXTR plays a crucial role in MM cell proliferation and is a promising therapeutic target that may broaden potential therapeutic options and could be a prognostic biomarker of MM. [ABSTRACT FROM AUTHOR]

Objective: To highlight the emerging understanding of oxytocin (OT) and oxytocin receptors (OTRs) in modulating menstrual‐related migraine (MRM). Background: MRM is highly debilitating and less responsive to therapy, and attacks are of longer duration than nonmenstrually related migraine. A clear understanding of the mechanisms underlying MRM is lacking. Methods: We present a narrative literature review on the developing understanding of the role of OT and the OTR in MRM. Literature on MRM on PubMed/MEDLINE database including clinical trials and basic science publications was reviewed using specific keywords. Results: OT is a cyclically released hypothalamic hormone/neurotransmitter that binds to the OTR resulting in inhibition of trigeminal neuronal excitability that can promote migraine pain including that of MRM. Estrogen regulates OT release as well as expression of the OTR. Coincident with menstruation, levels of both estrogen and OT decrease. Additionally, other serum biochemical factors, including magnesium and cholesterol, which positively modulate the affinity of OT for OTRs, both decrease during menstruation. Thus, during menstruation, multiple menstrually associated factors may lead to decreased circulating OT levels, decreased OT affinity for OTR, and decreased expression of the trigeminal OTR. Consistent with the view of migraine as a threshold disorder, these events may collectively result in decreased inhibition promoting lower thresholds for activation of meningeal trigeminal nociceptors and increasing the likelihood of an MRM attack. Conclusion: Trigeminal OTR may thus be a novel target for the development of MRM therapeutics. [ABSTRACT FROM AUTHOR]

Introduction: The oxytocin (Oxt) system, while typically associated with the neural regulation of social behaviors, also plays a role in an individual's vulnerability to develop alcohol use disorders (AUD). In humans, changes to the Oxt system, due to early life experience and/or genetic mutations, are associated with increased vulnerability to AUD. While a considerable amount is known about Oxt's role in AUD in males, less is known or understood, about how Oxt may affect AUD in females, likely due to many clinical and preclinical studies of AUD not directly considering sex as a biological variable. This is unfortunate given that females are more vulnerable to the effects of alcohol and have increased alcohol consumption, as compared to males. Therefore, in the current study we wanted to determine whether genetic disruption of the Oxt receptor (Oxtr), that is, Oxtr knockout (−/−) mice, affected stress‐induced alcohol consumption in males and females. We hypothesized that genetic disruption of the Oxtr would result in increased stress‐induced alcohol consumption in both males and females compared to wild‐type (+/+) controls. Though, we predicted that these disruptions might be greater in female Oxtr −/− mice. Methods: To test this hypothesis, a two‐bottle preference test was utilized along with the forced swim test (FST), and pre‐ and poststress alcohol consumption and preference measured within each sex (males and females were run separately). As a follow‐up experiment, a taste preference test, to control for possible genotypic differences in taste, was also performed. Results: In males, we found no significant genotypic differences in alcohol consumption or preference. However, in females, we found that genetic disruption of the Oxtr resulted in a greater consumption of alcohol both pre‐ and poststress compared to controls. Conclusion: These data suggest that in females, disruptions in Oxt signaling may contribute to increased vulnerability to alcohol‐associated addiction. [ABSTRACT FROM AUTHOR]

Chronic social defeat stress (CSDS) can induce anxiety and depression in male rodents, but the prevalence of anxiety and depression is much higher in females, and effects of CSDS on adult females and its underlying mechanism remain unclear. Oxytocin is a stress‐buffering hormone in the brain that modulates the physiological effects of stress. Strikingly, research regarding the effect of oxytocin on emotional changes caused by CSDS is still lacking in females. Thus, we focused on the involvement of the oxytocin system in changes in emotional regulation induced by CSDS in female voles. Seventy‐day‐old female mandarin voles (Microtus mandarinus) were exposed to aggressive adult females for 14 days, and the effects of CSDS on emotion and regulation of oxytocin system were characterized. In addition, we injected vehicle, oxytocin and oxytocin receptor antagonist into the nucleus accumbens (Nacc) of female voles to investigate the involvement of Nacc oxytocin in the effect of CSDS on emotion. Herein, we reported that CSDS increased anxiety and depression‐like behaviour and the circulating level of corticosterone, but decreased the number of oxytocin projections and the protein and mRNA expression levels of oxytocin receptor in the Nacc. Injection of oxytocin into the Nacc reversed the effects of CSDS on anxiety‐like and depressive‐like behaviour, whereas combined injections of oxytocin and oxytocin receptor antagonist eliminated these effects. In conclusion, CSDS increases the levels of anxiety and depression possibly via a reduction in oxytocin projections and the oxytocin receptor level in the Nacc. Nacc oxytocin may be involved in the effects of CSDS on emotional behaviours. [ABSTRACT FROM AUTHOR]

Significant prior evidence indicates that centrally acting oxytocin robustly modulates stress responsiveness and anxiety‐like behaviour, although the neural mechanisms behind these effects are not entirely understood. A plausible neural basis for oxytocin‐mediated stress reduction is via inhibition of corticotrophin‐releasing hormone (CRH) neurones in the paraventricular nucleus of the hypothalamus (PVN) that regulate activation of the hypothalamic‐pituitary‐adrenal axis. Previously, we have shown that, following s.c. injection of 2.0 mol L−1 NaCl, oxytocin synthesising neurones are activated in the rat PVN, an oxytocin receptor (Oxtr)‐dependent inhibitory tone develops on a subset of parvocellular neurones and stress‐mediated increases in plasma corticosterone levels are blunted. In the present study, we utilised transgenic male CRH‐reporter mice to selectively target PVN CRH neurones for whole‐cell recordings. These experiments reveal that acute salt loading produces tonic inhibition of PVN CRH neurones through a mechanism that is largely independent of synaptic activity. Further studies reveal that a subset of CRH neurones within the PVN synthesise mRNA for Oxtr(s). Salt induced Oxtr‐dependent inhibitory tone was eliminated in individual PVN CRH neurones filled with GDP‐β‐S. Additional electrophysiological studies suggest that reduced excitability of PVN CRH neurones in salt‐loaded animals is associated with increased activation of inwardly rectifying potassium channels. Nevertheless, substantial effort to recapitulate the core effects of salt loading by activating Oxtr(s) with an exogenous agonist produced mixed results. Collectively, these results enhance our understanding of how oxytocin receptor‐mediated signalling modulates the function of CRH neurones in the PVN. [ABSTRACT FROM AUTHOR]

Parental care and sensory stimulation are critical environmental factors that influence oxytocin (OXT) and its receptor (OXTR). Because developmental Oxt mRNA expression is enhanced by sensory‐rich early life experience and reduced by sensory deprivation, we predicted that compared to wild‐type (WT) littermates, mice with congenital loss of OXTR (OXTR KO), as a genetically induced deprivation, would show impaired Oxt mRNA expression in the offspring hypothalamus during development. Oxt mRNA levels of male and female OXTR KO mice were not different from WT littermates from postnatal day (P)0 to P6, although, by P8, OXTR KO showed significantly decreased Oxt mRNA expression in the hypothalamus compared to WT littermates. At P14, male and female OXTR KO mice had significantly decreased Oxt mRNA expression specifically in the paraventricular nucleus (PVN), but not the supraoptic nucleus (SON), compared to WT littermates. We investigated whether this effect persisted in adulthood (P90) and found a significant genotype by sex interaction where male OXTR KO mice displayed a reduction in Oxt expression specific to the PVN compared to male WT littermates. By contrast, male and female OXTR KO adults had increased Oxt mRNA levels in the SON. These findings suggest that OXTR plays a role in developmental Oxt mRNA expression with sex by genotype interactions apparent at adulthood. We then measured OXT and neural activation in the PVN and SON at P14. We observed more OXT‐immunoreactive cells in the PVN of OXTR KO mice but significantly fewer c‐Fos immunoreactive cells. There were no genotype differences in immunoreactivity for OXT and no c‐Fos activity in the SON at P14. Combined, these data suggest that OXTR WT P14 mice have more PVN activity and are more likely to release OXT than OXTR KO mice. Future experiments are warranted to understand which OXTR‐expressing neural circuits modulate the development of the PVN oxytocin system. [ABSTRACT FROM AUTHOR]

Certain aspects of social behavior help animals make adaptive decisions during encounters with other animals. When mice choose to approach another conspecific, the motivation and preference behind the interaction is not well understood. Estrogen and oxytocin are known to influence a wide array of social behaviors, including social motivation and social preference. The present study investigated the effects of estrogen and oxytocin on social preference using aromatase (ArKO), estrogen receptor (ER) α (αERKO), ERβ (βERKO), oxytocin (OTKO), oxytocin receptor (OTRKO) knockout and their respective wild‐type (WT) male mice. Mice were presented with gonadally‐intact versus castrated male (IC), intact male versus ovariectomized female (IF), or intact male versus empty cage (IE) stimuli sets for 5 days. ArWT showed no preference for either stimuli in IC and IF and intact male preference in IE, but ArKO mice preferred a castrated male or an ovariectomized female, or had no preference for either stimulus in IC, IF and IE stimuli sets, respectively, suggesting reduced intact male preference. α and β WT mice preferred a castrated male, showed no preference, and preferred an intact male in IC, IF and IE, respectively. αERKO mice displayed similar modified social preference patterns as ArKO, whereas the social preference of βERKO mice remained similar to βWT. OTWT preferred a castrated male whereas OTKO, OTRWT and OTRKO mice failed to show any preference in IC and none showed preference for either stimuli in IF. Collectively, these findings suggest that estrogen regulates social preference in male mice and that impaired social preference in oxytocin‐deficient mice may be due to severe deficits in social recognition. [ABSTRACT FROM AUTHOR]

Oxytocin (OT) is a hypothalamic nonapeptide that mediates a host of physiological and behavioral processes including reproductive physiology and social attachments. While the OT sequence structure is highly conserved among mammals, New World monkeys (NWMs) represent an unusual "hot spot" in OT structure variability among mammals. At least 6 distinct OT ligand variants among NWMs exist, yet it is currently unclear whether these evolved structural changes result in meaningful functional consequences. NWMs offer a new area to explore how these modifications to OT and its canonical G‐protein coupled OT receptor (OTR) may mediate specific cellular, physiological and behavioral outcomes. In this review, we highlight relationships between OT ligand and OTR structural variability, specifically examining coevolution between OT ligands, OTRs, and physiological and behavioral phenotypes across NWMs. We consider whether these evolved modifications to the OT structure alter pharmacological profiles at human and marmoset OTRs, including changes to receptor binding, intracellular signaling and receptor internalization. Finally, we evaluate whether exogenous manipulation using OT variants in marmoset monkeys differentially enhance or impair behavioral processes involved in social relationships between pairmates, opposite‐sex strangers, and parents and their offspring. Overall, it appears that changes to OT ligands in NWMs result in important changes ranging from cellular signaling to broad measures of social behavior. [ABSTRACT FROM AUTHOR]

Introduction: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus and the upper two-thirds of the vagina in otherwise phenotypically normal females. It is found isolated or associated with renal, skeletal and other malformations. Despite ongoing research, the etiology is mainly unknown. For a long time, the hypothesis of deficient hormone receptors as the cause for MRKHS has existed, supported by previous findings of our group. The aim of the present study was to identify unknown genetic causes for MRKHS and to compare them with data banks including a review of the literature.Material and Methods: DNA sequence analysis of the oxytocin receptor (OXTR) and estrogen receptor-1 gene (ESR1) was performed in a group of 93 clinically well-defined patients with uterovaginal aplasia (68 with the isolated form and 25 with associated malformations).Results: In total, we detected three OXTR variants in 18 MRKHS patients with one leading to a missense mutation, and six ESR1 variants in 21 MRKHS patients, two of these causing amino acid changes and therefore potentially disease.Conclusions: The identified variants on DNA level might impair receptor function through different molecular mechanisms. Mutations of ESR1 and OXTR are associated with MRKHS. Thus, we consider these genes potential candidates associated with the manifestation of MRKHS. [ABSTRACT FROM AUTHOR]

Oxytocin is known to be implicated in a variety of functions, such as learning, stress, anxiety, feeding, and pain perception. Oxytocin is also important for social memory and attachment, human bonding, sexual and maternal behaviour, and aggression. Human disorders characterized by aberrant social interactions, such as autism and schizophrenia, may also involve abnormal oxytocin levels. GSK712043, GSK711320, and GSK664004, three antagonists exhibiting subnanomolar affinity for the human oxytocin receptor (hOTR) and high selectivity over vasopressin receptors were successfully labelled with carbon-11 with suitable yields (0.5-1GBq @EOS), high molar activity (275-700 GBq/μmol), and radiochemical purities. The in vivo regional uptake of these radiotracers was determined in porcine brain. [11C]GSK711320 baseline scan showed no significant brain uptake, and limited initial uptake was observed following administration of [11C]GSK712043 or [11C]GSK664004. The [11C]GSK712043 and [11C]GSK664004 kinetics were slow and peaked at around 2%ID/L at 90 minutes post-injection. For both tracers, the distribution of activity was homogeneous throughout the brain. All the tracers showed high uptake in the pituitary gland, especially [11C]GSK711320; however, its uptake could not be blocked by pretreatment with the known OTR antagonist, L368,899. In vivo evaluation of these candidates demonstrated that they are not suitable as central OTR PET imaging agents. [ABSTRACT FROM AUTHOR]

Oxytocin receptor ( OXTR) acts as a key behavioral modulator of the central nervous system, affecting social behavior, stress, affiliation and cognitive functions. Variants of the Oxtr gene are known to influence behavior both in animals and humans; however, canine Oxtr polymorphisms are less characterized in terms of possible relevance to function, selection criteria in breeding and domestication. In this report, we provide a detailed characterization of common variants of the canine Oxtr gene. In particular (1) novel polymorphisms were identified by direct sequencing of wolf and dog samples, (2) allelic distributions and pairwise linkage disequilibrium patterns of several canine populations were compared, (3) neighbor joining (NJ) tree based on common single nucleotide polymorphisms ( SNPs) was constructed, (4) mRNA expression features were assessed, (5) a novel splice variant was detected and (6) in vitro functional assays were performed. Results indicate marked differences regarding Oxtr variations between purebred dogs of different breeds, free-ranging dog populations, wolf subspecies and golden jackals. This, together with existence of explicitly dog-specific alleles and data obtained from the NJ tree implies that Oxtr could indeed have been a target gene during domestication and selection for human preferred aspects of temperament and social behavior. This assumption is further supported by the present observations on gene expression patterns within the brain and luciferase reporter experiments, providing a molecular level link between certain canine Oxtr polymorphisms and differences in nervous system function and behavior. [ABSTRACT FROM AUTHOR]

Contents The aim of the study was to localize oxytocin receptors ( OTR) and measure mRNA expression of OTR in the canine uterus with and without the influence of progesterone. Uterine samples were taken from nine anoestrous and eight dioestrous bitches during ovariohysterectomy. Histological changes were evaluated in haematoxylin and eosin ( HE)-stained samples. Purified polyclonal antibody for OTR was used in immunohistochemistry to localize receptors in uterine layers. Relative mRNA concentration of OTR was evaluated with real-time PCR from full-thickness uterine samples taken from the middle horn and the body. Myometrial smooth muscle cells, endometrial luminal epithelium ( LE) and deep and superficial glandular epithelium were positively stained for oxytocin receptors in non-pregnant animals. No significant difference in staining intensity was detected between uterine middle horn and body. However, the staining intensity of LE was significantly higher in dioestrous than in anoestrous uteri ( p < .05). Leucocytes and endothelium of blood vessels were also positively stained for OTR. Real-time PCR showed no significant differences in OTR mRNA expression between the middle horn and the body of the uterus, or between anoestrous and dioestrous uterus. No correlation was noted between OTR mRNA expression and blood progesterone concentration. In conclusion, despite the apparent inactivity, the uterus of the non-pregnant bitch expresses OTR. The distribution or relative expression of OTR does not differ between uterine horn and body in dioestrus or anoestrus except in LE. LE may have more oxytocin-dependent activity during dioestrus than anoestrus. [ABSTRACT FROM AUTHOR]

Neuropeptides such as oxytocin (OXT) are known facilitators of social behavior across species. Variants of the OXT receptor gene ( OXTR) have been tested for association with autism spectrum disorder (ASD) across manifold ethnicities, yielding both positive and negative findings. A recent meta-analysis, comprising 16 single nucleotide polymorphisms (SNPs), has corroborated the implication of OXTR in the etiology of ASD. Here, we genotyped and tested two additional variants (rs237889 and rs237897) for association with ASD in two German predominantly high-functioning ASD samples. We found nominal over-transmission (OR = 1.48, CI95 = 1.06-2.08, P = 0.022) for the minor A allele of variant rs237889G>A in sample 1 ( N = 135 complete parent-offspring trios, 29 parent child duos), but not in sample 2 (362 trios, 69 duos). Still, in a meta-analysis comprising four different studies including the two unreported German data sets ( N = 542 families), this finding was confirmed (OR = 1.12; CI95 = 1.01-1.24, random effects P = 0.012). In addition, carriers of the minor risk allele rs237889-A showed significantly increased severity scores, as assessed through the autism diagnostic interview - revised (ADI-R), with highly significant increases in social interaction deficits. Our results corroborate the implication of common OXTR variants in the etiology of ASD. There is a need for functional studies to delineate the neurobiological implications of this and other association findings. (172/250). Autism Res 2016, 9: 1036-1045. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Prenatal stress ( PNS) affects a number of traits in the offspring, including stress axis regulation, emotionality and cognition; however, much less is known about the effects of PNS on social memory and the underlying central mechanisms. In the present study, we investigated social preference, social memory under basal and stress conditions and olfactory memory for social and nonsocial odours in the adult offspring of dams exposed to social stress during late pregnancy. Given the key roles that the central oxytocin and vasopressin systems play in facilitating social memory, we further investigated the effects of PNS on the central expression of mRNA for oxytocin ( Oxtr) and vasopressin-1a ( Avpr1a) receptors. PNS did not affect social preference in either sex; however, social memory was impaired under basal conditions in PNS females but not PNS males. Accordingly, Avpr1a mRNA expression in the lateral septum and bed nucleus of stria terminalis (BNST) was unaltered in males but was significantly lower in PNS females compared to controls. No differences in Oxtr m RNA expression were detected between control and PNS offspring in either sex in any of the brain regions examined. Social memory deficits in PNS females persisted when social odours were used; however, this does not appear to be a result of impaired olfaction because memory for nonsocial odours was similar in control and PNS females. Under acute stress conditions, deficits in social memory were observed in both male and female control offspring; however, PNS males were unaffected. Moreover, acute stress facilitated social memory in PNS females and this was associated with an up-regulation of Avpr1a m RNA in the lateral septum and BNST. Our data support a role for altered signalling via central Avpr1a in PNS-induced sex-dependent changes in social memory and may have implications for understanding the aetiology of neurodevelopmental disorders characterised by social behaviour deficits in humans. [ABSTRACT FROM AUTHOR]

Carbetocin, a long-acting oxytocin analogue, has been reported to elicit interesting and peculiar behavioural effects. The present study investigated the molecular pharmacology of carbetocin, aiming to better understand the molecular basis of its action in the brain. Using bioluminescence resonance energy transfer biosensors, we characterised the effects of carbetocin on the three human oxytocin/vasopressin receptors expressed in the nervous system: the oxytocin receptor ( OXTR) and the vasopressin V1a (V1aR) and V1b (V1bR) receptors. Our results indicate that (i) carbetocin activates the OXTR but not the V1aR and V1bR at which it may act as an antagonist; (ii) carbetocin selectively activates only the OXTR/Gq pathway displaying a strong functional selectivity; (iii) carbetocin is a partial agonist at the OXTR/Gq coupling; (iv) carbetocin promotes OXTR internalisation via a previously unreported β-arrestin-independent pathway; and (v) carbetocin does not induce OXTR recycling to the plasma membrane. Altogether, these molecular pharmacology features identify carbetocin as a substantially different analogue compared to the endogenous oxytocin and, consequently, carbetocin is not expected to mimic oxytocin in the brain. Whether these unique features of carbetocin could be exploited therapeutically remains to be established. [ABSTRACT FROM AUTHOR]

The drive to approach and explore novel conspecifics is inherent to social animals and may promote optimal social functioning. Juvenile animals seek out interactions with novel peers more frequently and find these interactions to be more rewarding than their adult counterparts. In the present study, we aimed to establish a behavioural paradigm to measure social novelty-seeking in juvenile rats and to determine the involvement of the opioid, dopamine, oxytocin and vasopressin systems in this behaviour. To this end, we developed the social novelty preference test to assess the preference of a juvenile rat to investigate a novel over a familiar (cage mate) conspecific. We show that across the juvenile period both male and female rats spend more time investigating a novel conspecific than a cage mate, independent of subject sex or repeated exposure to the test. We hypothesised that brain systems subserving social information processing and social motivation/reward (i.e. the opioid, dopamine, oxytocin, vasopressin systems) might support social novelty preference. To test this, receptor antagonists of each of these systems were administered i.c.v. prior to exposure to the social novelty preference test and, subsequently, to the social preference test, to examine the specificity of these effects. We find that μ-opioid receptor antagonism reduces novel social investigation in both the social novelty preference and social preference tests while leaving the investigation of a cage mate (social novelty preference test) or an object (social preference test) unaffected. In contrast, central blockade of dopamine D2 receptors (with eticlopride), oxytocin receptors (with des- Gly- NH2,d( CH2)5[ Tyr( Me)2, Thr4] OVT) or vasopressin V1a receptors [with ( CH2)5 Tyr( Me2) AVP] failed to alter social novelty preference or social preference. Overall, we have established a new behavioural test to study social novelty-seeking behaviour in the juvenile rat and show that the μ-opioid system facilitates this behaviour, possibly by reducing risk avoidance and enhancing the hedonic and/or motivational value of social novelty. [ABSTRACT FROM AUTHOR]

Objective To compare the expression of oxytocin receptor in the uterine junctional zone of the fundus and isthmus in the proliferative and secretory phases in women with and without adenomyosis. Design Experimental prospective clinical study. Setting Tertiary gynecologic medical center. Population Twenty-nine women with adenomyosis (15 in proliferative phase, 14 in secretory phase) and 27 women without adenomyosis (15 in proliferative phase, 12 in secretory phase). Methods Samples from the uterine fundus and isthmus were obtained at hysterectomy. The expression of oxytocin receptor was evaluated using immunohistochemistry. Main outcome measures Immuno-reactive score was used evaluate semi-quantitatively the oxytocin receptor expression. Results In normal uteri, the expression of oxytocin receptor in the isthmus was significantly higher than in the fundus in the proliferative phase ( p < 0.01) but the opposite distribution pattern was observed in the secretory phase. Conversely, in adenomyosis uteri, the expression of oxytocin receptor in the fundus was significantly higher than in the isthmus in the proliferative phase ( p < 0.05); however, this difference was not significant in the secretory phase. Moreover, oxytocin receptor expression in the fundus of adenomyosis uteri was higher than that in the control uteri in both the proliferative and secretory phases. Conclusions The expression pattern of oxytocin receptor in the normal junctional zone is disrupted in women with adenomyosis. This may be one possible explanation for the symptomatology of the condition. [ABSTRACT FROM AUTHOR]

At 18 months, children engage in a variety of social behaviors that reflect their nascent ability to understand the intentions of other people (e.g. joint attention, empathy, cooperation and self-recognition). Although numerous contextual factors have been shown to predict social cognition in young children, the genetic underpinnings of social-cognitive traits has been understudied in this age group. Owing to the known effects of oxytocin on adult social cognition and psychopathology, this study hypothesized that variability in the oxytocin receptor gene ( OXTR) would be associated with social cognition in children at 18 months. Participants consisted of 350 children (182 males; 168 females) who were part of an ongoing longitudinal study that aimed to assess environmental and genetic contributions to children's cognitive and socio-emotional functioning. At 18 months, social cognition was measured using previously validated and developmentally sensitive tasks assessing children's joint attention, empathy, cooperation and self-recognition. Five potentially functional OXTR variants were genotyped: rs1042778, rs2254298, rs11131149, rs237897 and rs237899. A family-based association design was used to control for population admixture and stratification, and additional non-genomic covariates were controlled. Results showed that variability in rs11131149 was significantly associated with social cognition ( P = 0.009), with more copies of the major allele related to higher social cognition, and more copies of the minor (risk) allele associated with lower social cognition. A haplotype consisting of rs11131149-rs2254298 was also associated with social cognition ( P = 0.020). Implications for normative and pathological development are discussed, and key areas for future research are proposed. [ABSTRACT FROM AUTHOR]

ABSTRACT Features of the early postnatal environment profoundly shape later physical and behavioral phenotypes. The amount of licking/grooming that rat dams direct towards their offspring has durable consequences, including behavioral and physiological dimensions of stress reactivity, cognition, and reproductive behavior. We examined how natural variation in maternal care alters social behavior in adult offspring and how this relates to anxiety behavior and oxytocin receptor density. Male and female offspring of mothers who received high levels of licking spent significantly more time in social contact with unfamiliar individuals than did offspring whose dams provided less grooming. Reduced anxiety behavior was associated with greater social interaction. No differences in oxytocin receptor binding assessed by 125I-OVTA autoradiography were detected between groups. The present investigation characterizes a novel impact of maternal care on adult social interaction behavior, replicates anxiety behavior differences, and illustrates connections between social behavior and anxiety in adulthood across maternal treatment groups. © 2013 Wiley Periodicals, Inc. Dev Psychobiol 56: 1017-1026, 2014. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to evaluate the effect of local injection of vasopressin on blood loss and secondary impact on complications during cesarean section in patients with placenta previa. Material and Methods We retrospectively reviewed the medical records of all patients diagnosed with placenta previa admitted to our hospital. Two consecutive periods were compared. During period B, 59 patients underwent the local injection of a vasopressin solution (4 U in 20 mL of saline) into the placental implantation site after placental delivery. During period A, 50 patients underwent cesarean section without vasopressin injection, and were analyzed as a control group. The estimated blood loss was recorded, as were the complications during surgery. In addition, the expression of the vasopressin V1α receptor in uterine smooth muscle was evaluated by immunohistochemistry. Results The mean estimated blood loss was significantly lower in the vasopressin group than in the control group. There were no statistically significant differences with surgical complications. The vasopressin V1α receptor was highly expressed in smooth muscle cells in the lower segment of the uterine body, whereas the immunoreactivity for the oxytocin receptor was faint in the lower segment. Conclusion The local injection of vasopressin into the placental implantation site significantly reduced the blood loss without increasing the morbidity. [ABSTRACT FROM AUTHOR]

Maternal care is the newborn's first experience of social interaction, and this influences infant survival, development and social competences throughout life. We recently found that postpartum blocking of the endocannabinoid receptor-1 ( CB1 R) altered maternal behaviour. In the present study, maternal care was assessed by the time taken to retrieve pups, pups' ultrasonic vocalisations ( USVs) and pup body weight, comparing CB1 R deleted ( CB1 R KO) versus wild-type ( WT) mice. After culling on postpartum day 8, hippocampal expression of oxytocin receptor ( OXTR), brain-derived neurotrophic factor ( BDNF) and stress-mediating factors were evaluated in CB1 R KO and WT dams. Comparisons were also performed with nulliparous ( NP) CB1 R KO and WT mice. Compared to WT, CB1 R KO dams were slower to retrieve their pups. Although the body weight of the KO pups did not differ from the weight of WT pups, they emitted fewer USVs. This impairment of the dam-pup relationship correlated with a significant reduction of OXTR m RNA and protein levels among CB1 R KO dams compared to WT dams. Furthermore, WT dams exhibited elevated OXTR m RNA expression, as well as increased levels of mineralocorticoid and glucocorticoid receptors, compared to WT NP mice. By contrast, CB1 R KO dams showed no such elevation of OXTR expression, alongside lower BDNF and mineralocorticoid receptors, as well as elevated corticotrophin-releasing hormone m RNA levels, when compared to CB1 R KO NP. Thus, it appears that the disruption of endocannabinoid signalling by CB1 R deletion alters expression of the OXTR, apparently leading to deleterious effects upon maternal behaviour. [ABSTRACT FROM AUTHOR]

Oxysterols such as 7β-hydroxycholesterol (7β- HC) and 7-ketocholesterol (7- KC) have been linked to the pathophysiology of neurodegenerative diseases. This study was carried out to examine the effect of oxysterols on global gene expression in the rat prefrontal cortex ( PFC). 7β- HC, 7- KC, or cholesterol was injected into the rat PFC and RNA was extracted from this brain region at 24-h post-injection and analyzed. Microarray analyses identified 1365 genes, whose expressions were affected by both 7β- HC and 7- KC. Among these, down-regulated genes outnumbered up-regulated genes. Pathway analysis showed that down-regulated genes had roles in carbohydrate metabolism, cell signaling and nucleic acid metabolism; and the majority of these encode G-protein coupled receptors ( GPCRs). Expression of selected genes were validated by quantitative real-time PCR. Western blots confirmed down-regulation of oxytocin receptor (Oxtr) at 1 day post-7β- HC treatment. Immunohistochemical analysis showed localization of Oxtr in neurons of the PFC. Electron microscopy identified the presence of Oxtr-immunoreactivity in axon terminals. Together, these findings provide insights into molecular mechanisms through which oxysterols could exert their pathophysiological effects, and suggest that increased oxysterols may affect synaptic function by transcriptional repression of GPCRs. [ABSTRACT FROM AUTHOR]

We characterised the behavioural phenotype of mice heterozygous ( O xtr +/−) for the oxytocin receptor gene ( O xtr) and compared it with that of O xtr null mice ( O xtr −/−), which display autistic-like behaviours, including impaired sociability and preference for social novelty, impaired cognitive flexibility, and increased aggression. Similar to O xtr −/− mice, the O xtr +/− showed impaired sociability and preference for social novelty but, unlike the null genotype, their cognitive flexibility and aggression were normal. By autoradiography, O xtr +/− mice were found to have approximately 50% fewer oxytocin receptors ( OXTRs) in all of the examined brain regions. Thus, because a partial reduction in O xtr gene expression is sufficient to compromise social behaviour, the O xtr acts as a haploinsufficient gene. Furthermore, the inactivation of the O xtr gene affects specific behaviours in a dose-dependent manner: social behaviour is sensitive to even a partial reduction in O xtr gene expression, whereas defects in aggression and cognitive flexibility require the complete inactivation of the O xtr gene to emerge. We then investigated the rescue of the O xtr +/− social deficits by oxytocin ( OT) and Thr4 Gly7 OT ( TGOT) administered i.c.v. at different doses. TGOT was more potent than OT in rescuing sociability and social novelty in both genotypes. Furthermore, the TGOT doses that reverted impaired sociability and preference for social novelty in Oxtr +/− were lower than those required in O xtr −/−, thus suggesting that the rescue effect is mediated by OXTR in O xtr +/− and by other receptors (presumably vasopressin V1a receptors) in O xtr −/−. In line with this, a low dose of the selective oxytocin antagonist desGly DTyr OVT blocks the rescue effect of TGOT only in the O xtr +/− genotype, whereas the less selective antagonist SR49059 blocks rescue in both genotypes. In conclusion, the O xtr +/− mouse is a unique animal model for investigating how partial loss of the O xtr gene impair social interactions, and for designing pharmacological rescue strategies. [ABSTRACT FROM AUTHOR]

What's known on the subject? and What does the study add? There is also evidence that the etiology of premature ejaculation is partially genetic. So far, all molecular genetic studies of premature ejaculation have focused on serotonergic and dopaminergic genes. Serotonergic and dopaminergic neurotransmission aside, studies on both animals and humans have shown that both oxytocin and vasopressin are also involved in ejaculatory function. The present study is, to our knowledge, the first to investigate effects of polymorphisms in oxytocin and vasopressin receptor genes on ejaculatory function. Although a large sample (1517 men) was available for the present study, we could not detect any clear-cut effects of any gene varant on ejaculatory function. We detected a heterozygote effect of one polymorphism (rs75775) in the oxytocin receptor gene. Rare variants of the vasopressin receptor 1A gene may theoretically have a stronger impact on ejaculatory function, but would need a very large sample in order to be established. Based on our results, we conclude that the oxytocin and vasopressin receptor genes are unlikely targets for successful pharmacogenetic interventions. OBJECTIVES To investigate associations between single nucleotide polymorphisms (SNPs) linked to the oxytocin, and arginine vasopressin 1A and 1B receptor genes and ejaculatory function., To investigate these associations in a large, population-based sample., PATIENTS AND METHODS In all, 1517 male twins and non-twin brothers of twins aged 18-45 years (mean = 26.43; sd= 4.87) provided questionnaire data regarding ejaculatory function and relevant covariates and saliva samples for genotyping., A Bayesian linear mixed-effects model, which appropriately controls for between-subjects dependence, was used to estimate genotype associations., We corrected for multiple testing using a linkage disequilibrium correlation measure., RESULTS We found a heterozygote effect on one SNP in the oxytocin receptor gene (rs75775), so that individuals heterozygous for this SNP had significantly elevated risk for premature ejaculation symptoms compared with carriers of either homozygote., Several SNPs in the arginine vasopressin receptor genes had rare or very rare genotypes. This study may be underpowered to detect potential effects of rare genotypic variants in arginine vasopressin receptor genes., CONCLUSIONS Our results regarding the oxytocin receptor polymorphisms support previous studies that indicate a complex relationship between oxytocin and ejaculatory function., Oxytocin receptor genes are, for example, unlikely suitable targets for pharmacogenetic intervention studies., Rare variants in arginine vasopressin receptor genes may have significant effects on premature ejaculation, but would need larger sample sizes or case-control designs to be detected. [ABSTRACT FROM AUTHOR]

Aggressive antisocial behaviours are the most common reasons why adolescents are referred to mental health clinics. Antisocial behaviours are costly in social and financial terms. The aetiology of aggressive behaviours is unknown but growing evidence suggests it is heritable, and certain genetic variants have been implicated as contributing factors. The purpose of this study was to determine whether genes regulating the hormone oxytocin (OXT) were associated with aggressive antisocial behaviour. The case-control study sample consisted of 160 cases of children displaying extreme, persistent and pervasive aggressive behaviour. This case sample was compared with 160 adult controls. We used polymerase chain reaction (PCR) to determine the genotype for three oxytocin gene ( OXT) single nucleotide polymorphisms (SNPs): rs3761248, rs4813625 and rs877172; and five oxytocin receptor gene ( OXTR) SNPs: rs6770632, rs11476, rs1042778, rs237902 and rs53576. Genotypic analyses were performed using stata, while differences in haplotypic and allelic frequencies were analysed using Unphased. We also performed within-case analyses ( n = 236 aggressive cases) examining genotypic and allelic associations with callous-unemotional (CU) scores (as measured by the psychopathic screening device). OXTR SNPs rs6770632 and rs1042778 may be associated with extreme, persistent and pervasive aggressive behaviours in females and males, respectively. These and haplotype results suggest gender-specific effects of SNPs. No significant differences were detected with respect to CU behaviours. These results may help to elucidate the biochemical pathways associated with aggressive behaviours, which may aid in the development of novel medications. [ABSTRACT FROM AUTHOR]

Oxytocin receptor (OTR) expressed in the rat penis and mediated the contractility of the corpus cavernosum smooth muscle both in vitro and in vivo, and OTR could maintain penile detumescence; however, the expression of OTR in diabetic rat penis remains unknown. In the present study, we investigated the expression of OTR in diabetic rat penis. The experimental rats were randomly divided into control group and STZ-diabetic rats group. The expressions of mRNA and protein were examined by real-time quantitative PCR, Western blotting and immunohistochemistry respectively. Erectile function was evaluated by measuring intracavernous pressure following electrostimulation of the cavernous nerves. mRNA and protein expression of OTR significantly increased in diabetic rats group compared with the control group. Erectile function of diabetic rats group significantly decreased compared with the control group. Our data showed that the expression of OTR significantly increased in diabetic rats group and OTR may involve in the development of diabetic erectile dysfunction. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 114, 1424–1435. Oxytocin receptor is a seven transmembrane receptor widely expressed in the CNS that triggers Gi or Gq protein-mediated signaling cascades leading to the regulation of a variety of neuroendocrine and cognitive functions. We decided to investigate whether and how the promiscuous receptor/G protein coupling affects neuronal excitability. As an experimental model, we used the immortalized gonadotropin-releasing hormone-positive GN11 cell line displaying the features of immature, migrating olfactory neurons. Using RT-PCR analysis, we detected the presence of oxytocin receptors whose stimulation by oxytocin led to the accumulation of inositol phosphates and to the inhibition of cell proliferation, and the expression of several inward rectifier (IR) K+ channel subtypes. Moreover, electrophysiological and pharmacological inspections using whole-cell patch-clamp recordings evidenced that in GN11 cells, IR channel subtypes are responsive to oxytocin. In particular, we found that: (i) peptide activation of receptor either inhibited or stimulated IR conductances, and (ii) IR current inhibition was mediated by a pertussis toxin-resistant G protein presumably of the Gq/11 subtype, and by phospholipase C, whereas IR current activation was achieved via receptor coupling to a pertussis toxin-sensitive Gi/o protein. The findings suggest that neuronal excitability might be tuned by a single peptide receptor that mediates opposing effects on distinct K+ channels through the promiscuous coupling to different G proteins. [ABSTRACT FROM AUTHOR]

Oxytocin in the hypothalamus is the biological basis of social recognition, trust, love and bonding. Previously, we showed that CD38, a proliferation marker in leukaemia cells, plays an important role in the hypothalamus in the process of oxytocin release in adult mice. Disruption of Cd38 ( Cd38 −/−) elicited impairment of maternal behaviour and male social recognition in adult mice, similar to the behaviour observed in Oxt and oxytocin receptor ( Oxtr) gene knockout ( Oxt −/− and Oxtr −/−, respectively) mice. Locomotor activity induced by separation from the dam was higher and the number of ultrasonic vocalisation calls was lower in Cd38 −/− than Cd38 +/+ pups. However, these behavioural changes were much milder than those observed in Oxt −/− and Oxtr −/− mice, indicating less impairment of social behaviour in Cd38 −/− pups. These phenotypes appeared to be caused by the high plasma oxytocin levels during development from the neonatal period to 3-week-old juvenile mice. ADP-ribosyl cyclase activity was markedly lower in the knockout mice from birth, suggesting that weaning for mice is a critical time window of plasma oxytocin differentiation. Breastfeeding was an important exogenous source of plasma oxytocin regulation before weaning as a result of the presence of oxytocin in milk and the dam’s mammary glands. The dissimilarity between Cd38 −/− infant behaviour and those of Oxt −/− or Oxtr −/− mice can be explained partly by this exogenous source of oxytocin. These results suggest that secretion of oxytocin into the brain in a CD38-dependent manner may play an important role in the development of social behaviour. [ABSTRACT FROM AUTHOR]

The aim of this study was to localize oxytocin receptor (OTR) in the stomach and to investigate the effect of OT on gastric motility in rats. Western blot and immunohistochemistry methods were used to localize OTR in stomach. The motility of stomach was recorded in vivo (recording of the intragastric pressure), in vitro (recording of the contraction of muscle strips) and on isolated smooth muscle cells. OTR was expressed on cells of both circular and longitudinal muscle of stomach. Systemic administration of OT induced an early transient decrease and a subsequent increase on intragastric pressure. Devazepide (1 mg kg−1, i.v.), a cholecystokinin-1 (CCK1) receptor antagonist, completely abolished the transient response but did not influence the subsequent one. OT (10−9–10−6 mol L−1) dose-dependently increased the contraction of the muscle strips of gastric body, antrum, and pyloric sphincter, and decreased the average cell length of isolated smooth muscle cells. Tetrodotoxin and atropine did not influence the effect of OT on muscle strips. Pretreatment with atosiban, an OTR antagonist, inhibited the spontaneous contraction of muscle strips and abolished the excitatory effect of OT on the muscle strips and the isolated cells. These results suggest that the OTR is expressed on the smooth muscle of the stomach and mediates excitatory effect of OT on gastric motility. [ABSTRACT FROM AUTHOR]

Oxytocin receptor (OTR) is a membrane protein known to mediate oxytocin (OT) effects, in both normal and neoplastic cells. We report here that human osteosarcoma (U2OS, MG63, OS15 and SaOS2), breast cancer (MCF7), and primary human fibroblastic cells (HFF) all exhibit OTR not only on the cell membrane, but also in the various nuclear compartments including the nucleolus. Both an OTR-GFP fusion protein and the native OTR appear to be localized to the nucleus as detected by transfection and/or confocal immunofluorescence, respectively. Treatment with oxytocin causes internalization of OTR and the resulting vesicles accumulate in the vicinity of the nucleus and some of the perinuclear OTR enters the nucleus. Western blots indicate that OTR in the nucleus and on the plasma membrane are likely to be the same biochemical and immunological entities. It appears that OTR is first visible in the nucleoli and subsequently disperses within the nucleus into 4–20 spots while some of the OTR diffuses throughout the nucleoplasm. The behaviour and kinetics of OTR-GFP and OTR are different, indicating interference by GFP in both OTR entrance into the nucleus and subsequent relocalization of OTR within the nucleus. There are important differences among the tested cells, such as the requirement of a ligand for transfer of OTR in nuclei. A constitutive internalization of OTR was found only in osteosarcoma cells, while the nuclear localization in all other tested cells was dependent on ligand binding. The amount of OTR-positive material within and in the vicinity of the nucleus increased following a treatment with oxytocin in both constitutive and ligand-dependent type of cells. The evidence of OTR compartmentalization at the cell nucleus (either ligand-dependent or constitutive) in different cell types suggests still unknown biological functions of this protein or its ligand and adds this G-protein-coupled receptor to other heptahelical receptors displaying this atypical and unexpected nuclear localization. [ABSTRACT FROM AUTHOR]

The oxytocin (OT)-oxytocin receptor (OTR) system of the mammalian uterus has mainly been studied in relation to its involvement in the onset of labor. The aim of this study was to elucidate the in vivo expression and localization pattern of OTR in the mouse endometrium and embryo during implantation, as well as OTR mRNA expression in the in vitro developing mouse embryo. The expression of OTR or OT was detected immunohistochemically in uterine tissue sections of 5- to 8-week-old female mice between days 4 and 10 of an established pregnancy. In addition, the expression of OTR mRNA was detected by means of reverse transcription polymerase chain reaction (RT-PCR) in mouse oocytes and embryos up to the blastocyst stage. The mean ratios of normalized expression levels of OTR gene in all samples were also calculated. The recorded increase in OTR mRNA immediately after fertilization could mean a possible role of OT in this process, as OTR mRNA gradually decreased after the four-cell stage of pre-embryonic development. The differential expression of OTR during embryonic apposition and embryonic invasion/placentation in the mouse uterus suggests a potential role of OT in the implantation process of the mouse. It is possible that the interaction of OTR with the hormones included in the ovulation induction regiments utilized today in in vitro fertilization (IVF) could be affecting the receptivity/quality of the implanting endometrium. [ABSTRACT FROM AUTHOR]

Aims: To study the effects of oxytocin on isolated rabbit distal colon and the regulation of ovarian steroids by its action. Methods: Muscle strips parallel to either the circular or the longitudinal fibres were excised and suspended in tissue chambers containing 5 mL Krebs solution (37 °C) and bubbled continuously with 95% O2 and 5% CO2. The effects of oxytocin on isometric spontaneous contractile responses were recorded. The effects of atosiban, tetrodotoxin, Mg2+, progesterone and oestradiol on the oxytocin-induced response were also examined. Results: Oxytocin (1, 10 and 100 nmol L−1) dose dependently decreased the area under the contraction curve of distal colonic smooth muscle strips. The oxytocin receptor antagonist atosiban blocked the oxytocin (10 nmol L−1)-caused responses in a dose-dependent manner. Tetrodotoxin (10 μmol L−1) had no effect on the oxytocin-induced response. Mg2+-free Krebs solution attenuated the oxytocin-induced response, but oestradiol (0.1 μmol L−1) or progesterone (0.1 μmol L−1) increased the oxytocin-induced response. Conclusion: These results suggest that oxytocin inhibits the contractile motility of the distal colon, which is regulated by Mg2+ and ovarian steroids. [ABSTRACT FROM AUTHOR]

Relaxin decreases oxytocin-stimulated rat myometrial contractions in vitro. This study used pregnant relaxin-deficient (Rlx-/-) mice to investigate the interaction between relaxin, oxytocin receptor (OTR), and estrogen receptor (ER) expression in the myometrium. Myometrial OTRs were significantly decreased on gestation day 18.5 in Rlx-/- mice than in Rlx+/+ mice. An increase in ER in Rlx+/+ mice at term was correlated with a decrease in ER, which was not observed in Rlx-/- mice. Treatment of Rlx-/- mice with relaxin had no effect on OTR, LGR7, or ER expression, but it caused a significant decrease in ERs. [ABSTRACT FROM AUTHOR]

Conducting basic scientific research on a complex psychiatric disorder, such as autism, is a challenging prospect. It is difficult to dissociate the fundamental neurological and psychological processes that are disturbed in autism and, therefore, it is a challenge to discover accurate and reliable animal models of the disease. Because of their role in animal models of social processing and social bonding, the neuropeptides oxytocin and vasopressin are strong candidates for dysregulation in autism. In this review, we discuss the current animal models which have investigated oxytocin and vasopressin systems in the brain and their effects on social behavior. For example, mice lacking the oxytocin gene have profound deficits in social processing and social recognition, as do rats lacking vasopressin or mice lacking the vasopressin V1a receptor (V1aR). In another rodent model, monogamous prairie voles are highly social and form strong pair bonds with their mates. Pair bonds can be facilitated or disrupted by perturbing the oxytocin and vasopressin systems. Non-monogamous vole species that do not pair bond have different oxytocin and V1aR distribution patterns in the brain than monogamous vole species. Potential ties from these rodent models to the human autistic condition are then discussed. Given the hallmark disturbances in social function, the study of animal models of social behavior may provide novel therapeutic targets for the treatment of autism. [Copyright &y& Elsevier]

The oxytocin receptor is an important contractile-associated protein, up-regulated at term in the myometrium in many mammalian species. We conducted studies in a novel animal model to challenge the general view that gonadal steroids are a major regulatory factor of uterine oxytocin receptors. Female marsupials have separate uteri and, in monovular species such as the tammar wallaby, the conceptus is present in one uterus whereas the contralateral uterus is empty. A marked increase in myometrial oxytocin receptors occurs only in the gravid uterus. Fetectomy experiments demonstrated that local embryo-derived factors stimulate this gravid uterus-specific increase in oxytocin receptors, and that uterine distension is probably not a key component in this regulatory pathway. Unilateral ovariectomy has no significant effect on uterine oxytocin receptors, emphasizing the impact of the conceptus on oxytocin receptor regulation and the minimal influence of gonadal steroids on parturition in this species. Our data highlight that regulation of uterine oxytocin receptor expression is multifactorial, and does not necessarily rely on gonadal steroids. [ABSTRACT FROM AUTHOR]

Using two different coimmunoprecipitation strategies as well as bioluminescence resonance energy transfer (BRET) techniques, we determined that the human oxytocin receptor forms dimeric and oligomeric complexes in vivo in intact living cells, and that these complexes exist at the cell surface level. Using a BRET-based assay, we found that oligomers can form between oxytocin receptors themselves (homo-oligomers) as well as, with a reduced affinity, between the oxytocin receptor and related members of the vasopressin receptor family (V1a and V2 receptors), but not with the more remotely related bradykinin receptor. The existence of oxytocin receptor oligomers at the level of the cell surface was demonstrated by a coimmunoprecipitation approach involving direct antibody exposure of intact living cells. Furthermore, this approach demonstrated that cell surface oxytocin receptor oligomerization is ligand independent. However, agonist addition led to an apparent rapid decrease in receptor oligomerization, as assessed by the coimmunoprecipitation approach, indicating that agonist exposure may modulate the oligomerization status. It remains to be determined to what extent oxytocin receptor oligomerization impacts on signal transduction. [ABSTRACT FROM AUTHOR]

Abstract In sheep, central oxytocin release at parturition induces maternal behaviour which is thought to be mediated by changes in the expression of central oxytocin receptors. The distribution, effects of parturition, previous maternal experience and hormonal status on the distribution of an oxytocin receptor was investigated using immunocytochemistry and in situ hybridization. In ewes with no previous maternal experience, parturition induced significant increases in oxytocin receptor mRNA expression in the anterior olfactory nucleus, medial preoptic area, ventromedial hypothalamus, lateral septum, medial amygdala, bed nucleus of the stria terminalis and diagonal band of Broca. In maternally experienced ewes, parturition induced additional increases in two areas, the paraventricular nucleus and the Islands of Calleja. The changes in progesterone and oestrogen that occur during late pregnancy and parturition appear to contribute to increases in expression in the anterior olfactory nucleus, Islands of Calleja, medial preoptic area, ventromedial hypothalamus, bed nucleus of the stria terminalis and diagonal band of Broca, but not in the paraventricular nucleus, lateral septum and medial amygdala. These results demonstrate that progesterone and oestrogen priming enhance oxytocin receptor mRNA expression in a number of regions in the olfactory system, hypothalamus and limbic brain. These effects appear to be independent of maternal experience. Parturition increases oxytocin receptor mRNA expression in all the areas influenced by hormonal priming and the lateral septum, medial amygdala and paraventricular nucleus. Maternal experience also enhances expression of oxytocin receptor mRNA in the paraventricular nucleus and the Islands of Calleja. Because the paraventricular nucleus is the main source of oxytocin release in the brain, this upgrading of autoreceptors as a result of maternal experience may serve to enhance release of this peptide in projection sites regulating maternal behaviour. [ABSTRACT FROM AUTHOR]

Oxytocin (OT) effects on brain function and behavior are mediated by the oxytocin receptor (OXTR). The distribution of OXTR in the brain can profoundly influence social behavior. Emerging evidence suggests that DNA methylation of OXTR influences OXTR expression. Previously, we conducted a pharmaco‐functional Magnetic Resonance Imaging (fMRI) study in which healthy subjects were randomized to 24 IU intranasal OT or placebo and imaged with fMRI while playing a dyadic social interaction task known as the iterated Prisoner's Dilemma (PD) game with same‐sex partners. Here, we investigate whether DNA methylation of OXTR modulates the effect of intranasal OT on the neural response to positive and negative social interactions in the PD game. OXTR methylation did not modulate OT effects within brain regions where we previously reported OT effects in response to reciprocated (caudate nucleus) and unreciprocated cooperation (amygdala and anterior insula). However, OXTR methylation did modulate OT effects on the response to both reciprocated and unreciprocated cooperation in other brain regions such as the precuneus and visual cortex. Further restricting the analysis to OXTR rs53576 GG individuals revealed that OXTR methylation modulated OT effects on the precuneus response to reciprocated cooperation in men, the lateral septum response to reciprocated cooperation in women, and the visual cortex response to unreciprocated cooperation in men. These results suggest that OXTR methylation status may influence OT effects on mentalizing, attention and reward processing during social interactions. OXTR methylation may be important to consider if exogenous OT is used to treat social behavioral disorders in the future. [ABSTRACT FROM AUTHOR]

Oxytocin (OT) often regulates social behaviours in sex‐specific ways, and this may be a result of sex differences in the brain OT system. Adult male rats show higher OT receptor (OTR) binding in the posterior bed nucleus of the stria terminalis (pBNST) than adult female rats. In the present study, we investigated the mechanisms that lead to this sex difference. First, we found that male rats have higher OTR mRNA expression in the pBNST than females at postnatal day (P) 35 and P60, which demonstrates the presence of the sex difference in OTR binding density at message level. Second, the sex difference in OTR binding density in the pBNST was absent at P0 and P3, but was present by P5. Third, systemic administration of the oestrogen receptor (ER) antagonist fulvestrant at P0 and P1 dose‐dependently reduced OTR binding density in the pBNST of 5‐week‐old male rats, but did not eliminate the sex difference in OTR binding density. Fourth, pBNST‐OTR binding density was lower in androgen receptor (AR) deficient genetic male rats compared to wild‐type males, but higher compared to wild‐type females. Finally, systemic administration of the histone deacetylase inhibitor valproic acid at P0 and P1 did not alter pBNST‐OTR binding density in 5‐week‐old male and female rats. Interestingly, neonatal ER antagonism, AR deficiency, and neonatal valproic acid treatment each eliminated the sex difference in pBNST size. Overall, we demonstrate a role for neonatal ER and AR activation in setting up the sex difference in OTR binding density in the pBNST, which may underlie sexual differentiation of the pBNST and social behaviour. [ABSTRACT FROM AUTHOR]

To investigate relationships between the polymorphisms and social functioning of children with Attention Deficit/Hyperactivity Disorder (ADHD), according to the polymorphism of three oxytocin receptor (OXTR) genes (rs53576, rs13316193, and and rs2268493). A total of 198 children-studying in the same primary and secondary school and matched in terms of age and gender (99 ADHD, 99 control)-were included in this study. The Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version was administered to establish the clinical diagnosis. The Social Reciprocity Scale (SRS) was applied to evaluate social functioning. The total genomic DNA was isolated from buccal mucosa samples. No significant differences were determined between the ADHD and control groups in terms of rs2268493, rs13316193, and rs53576 genotype distribution (P = 0.078, P = 0.330, and P = 0.149, respectively). However, the control group T allele frequency in the OXTR Single Nucleotide Polymorphism (SNP) rs2268493 was significantly higher than the ADHD group (P = 0.024). Compared to the control group, the ADHD group had a higher score on the SRS scale (SRS total; Z = -21,135, P < 0.001). No significant difference existed in the SRS scale scores between the children with the T/T genotype and the C allele in the ADHD group (SRS total; Z = -0.543, P = 0.587). The allele distribution of the OXTR gene SNP rs2268493 was significantly different in the ADHD group, compared to the control group. This observation is important in understanding the underlying biological infrastructure in ADHD and developing treatment modalities., (© 2015 Wiley Periodicals, Inc.)