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Substance use disorders have been associated with alterations in the oxytocinergic system, but few studies have investigated both the peptide and epigenetic mechanisms potentially implicated in the regulation of oxytocin receptor. In this study, we compared plasma oxytocin and blood DNA methylation in the OXTR gene between people with and without cocaine use disorder (CUD). We measured the oxytocin levels of 51 people with CUD during acute abstinence and of 30 healthy controls using an enzyme immunoassay. The levels of DNA methylation in four CpG sites at exon III of the OXTR gene were evaluated in a subsample using pyrosequencing. The Addiction Severity Index was used to assess clinical characteristics. We found higher oxytocin levels in men with CUD (56.5 pg/mL; 95% CI: 48.2-64.7) than in control men (33.6 pg/mL; 95% CI: 20.7-46.5), while no differences between women with and without CUD were detected. With a moderate effect size, the interaction effect between group and sex remained significant when controlling for height, weight and age data. A positive correlation in the CUD sample was found between oxytocin levels and days of psychological suffering prior to treatment enrollment. No group differences were observed regarding DNA methylation data. This suggests that CUD is associated with higher peripheral oxytocin levels in men during acute abstinence. This finding may be considered in future studies that aim at using exogenous oxytocin as a potential treatment for cocaine addiction.

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Although it has been previously demonstrated that oxytocin (OXT) receptor stimulation can control skeletal muscle mass in vivo, the intracellular mechanisms that mediate this effect are still poorly understood. Thus, rat oxidative skeletal muscles were isolated and incubated with OXT or WAY-267,464, a non-peptide selective OXT receptor (OXTR) agonist, in the presence or absence of atosiban (ATB), an OXTR antagonist, and overall proteolysis was evaluated. The results indicated that both OXT and WAY-267,464 suppressed muscle proteolysis, and this effect was blocked by the addition of ATB. Furthermore, the WAY-induced anti-catabolic action on protein metabolism did not involve the coupling between OXTR and Gαi since it was insensitive to pertussis toxin (PTX). The decrease in overall proteolysis induced by WAY was probably due to the inhibition of the autophagic/lysosomal system, as estimated by the decrease in LC3 (an autophagic/lysosomal marker), and was accompanied by an increase in the content of Ca2+-dependent protein kinase (PKC)-phosphorylated substrates, pSer473-Akt, and pSer256-FoxO1. Most of these effects were blocked by the inhibition of inositol triphosphate receptors (IP3R), which mediate Ca2+ release from the sarcoplasmic reticulum to the cytoplasm, and triciribine, an Akt inhibitor. Taken together, these findings indicate that the stimulation of OXTR directly induces skeletal muscle protein-sparing effects through a Gαq/IP3R/Ca2+-dependent pathway and crosstalk with Akt/FoxO1 signaling, which consequently decreases the expression of genes related to atrophy, such as LC3, as well as muscle proteolysis.

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Introduction: The amygdala is a limbic region of high value for understanding anxiety and its treatment. Dopamine D2 receptors (D2Rs) and oxytocin receptors (OXTRs) have both been shown to participate in modulating anxiety involving effects in the amygdala. The goal is to understand if D2R-OXTR heterocomplexes exist in the central amygdala and if, through enhancing allosteric receptor-receptor interactions, may enhance anxiolytic actions. Methods: The methods used involve the shock-probe burying test, the in situ proximity ligation assay (PLA), image acquisition and analysis, and the BRET2 assay. Bilateral cannulas were introduced into the amygdala, and the effects of the coadministration of oxytocin and the D2R-like agonist quinpirole into the amygdala were studied. Results: The combination treatment enhanced the anxiolytic effects compared to the single treatment. The D2R/D3R antagonist raclopride blocked the effects of the combination treatment of oxytocin and the D2R agonist, although oxytocin is regarded as a distinct modulator of fear-mediating anxiolytic effects. In situ PLA results indicate the existence of D2R-OXTR heteroreceptor complexes and/or the co-location of OXTR and D2R within the same cell membrane nanodomains in the central amygdala. With BRET2, evidence is given for the existence of D2R-OXTR heteromers in HEK293 cells upon co-transfection. Discussion: The enhanced behavioral effects observed upon co-treatment with OXTR and D2R agonists may reflect the existence of improved positive receptor-receptor interactions in the putative D2R-OXTR heterocomplexes in certain neuronal populations of the basolateral and central amygdala. The D2R-OXTR heterocomplex, especially upon agonist co-activation in the central amygdala, may open a new pharmacological venue for the treatment of anxiety.

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Polybrominated diphenyl ethers (PBDEs), used as flame retardants are persistent organic pollutants exerting important health effects. PBDEs with >5 bromide substitutions were considered less harmful and therefore extensively used commercially. DE-79 was a widely used PBDE mixture of hexa-, hepta-, octa- and nona-brominated compounds that increases vasopressin (AVP) production. AVP and oxytocin (OT) are both produced in neurons of the supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei projecting to the neurohypophysis and to brain regions involved in copulatory behavior. OT plays an important role in male copulation. Since DE-79 alters AVP expression in the SON and PVN, it might also modify OT content and alter male sexual behavior. We analyzed if repeated DE-79 exposure of adult male rats affected OT content and OT receptor (OTR) density in the SON, PVN, medial preoptic area (mPOA), ventral tegmental area, nucleus accumbens, and amygdala, and if male copulatory behavior was affected. We show that DE-79 exposure produces a generalized decrease in brain OT immunoreactivity, increases OTR density in all brain regions analyzed but the mPOA, and reduces the ejaculatory threshold after a first ejaculation. The documented ejaculation-induced OT release might participate in this last effect. Thus, one-week DE-79 exposure alters the OT-OTR system and modifies male rat sexual performance. Based on the literature it could be speculated that these effects are related to the putative endocrine disrupting actions of DE-79, ultimately altering brain OT levels and OTR expression that might affect copulation and other important OT-mediated brain functions.

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Introduction: Vasopressin (AVP) and oxytocin (OXT) are neuropeptides produced by magnocellular neurons (MCNs) of the hypothalamus and secreted through neurohypophysis to defend mammals against dehydration. It was recently demonstrated that MCNs also project to limbic structures, modulating several behavioral responses. Methods and Results: We found that 24 h of water deprivation (WD) or salt loading (SL) did not change exploration or anxiety-like behaviors in the elevated plus maze (EPM) test. However, rats deprived of water for 48 h showed reduced exploration of open field and the closed arms of EPM, indicating hypoactivity during night time. We evaluated mRNA expression of glutamate decarboxylase 1 (Gad1), vesicular glutamate transporter 2 (Slc17a6), AVP (Avpr1a) and OXT (Oxtr) receptors in the lateral habenula (LHb), basolateral (BLA) and central (CeA) amygdala after 48 h of WD or SL. WD, but not SL, increased Oxtr mRNA expression in the CeA. Bilateral pharmacological inhibition of OXTR function in the CeA with the OXTR antagonist L-371,257 was performed to evaluate its possible role in regulating the EPM exploration or water intake induced by WD. The blockade of OXTR in the CeA did not reverse the hypoactivity response in the EPM, nor did it change water intake induced in 48-h water-deprived rats. Discussion: We found that WD modulates exploratory activity in rats, but this response is not mediated by oxytocin receptor signaling to the CeA, despite the upregulated Oxtr mRNA expression in that structure after WD for 48 h.

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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.

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ABSTRACT Recent research has shown that genetic variations in the oxytocin receptor (OXTR) may be related to variations in subtypes of obsessive-compulsive disorder (OCD). We aimed to explore the relationship between different subtypes of OCD and the genetic variation between rs1316193 and rs4686301 of the OXTR. In this case-control study, 92 OCD patients and 92 healthy controls were included in the OCD and control groups, respectively. The Y-BOCS scale was used to assess the severity of the OCD symptoms. The fasting peripheral blood samples were collected to extract DNA. rs4686301 and rs13316193 were genotyped using restriction fragment length polymorphism analysis techniques. Whether the gene frequency of the locus and the distribution of allele frequency were related to OCD were further study by TaqMan allele typing. The rs4686301 locus differed significantly between behavior and control groups. The genotype frequency and allele frequency at the rs4686301 locus were statistically significant between behavior and control groups (P<0.05). There was significant difference in the genotype frequency at the rs13316193 locus between behavior and control groups (P<0.05). The rs4686301 polymorphism of the OXTR may affect the clinical subtype of OCD. The rs13316193 polymorphism of the OXTR may be a risk factor for obsessive-compulsive behavior.

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Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder characterized by impairments in social behaviors and communication. Oxytocin and its signaling pathway are related to a range of human behaviors, from facial expression recognition to aggressive behaviors, and have been suggested as involved in the etiology of ASD. Our aim was to evaluate the influence of two polymorphisms (rs1042778, rs53576) at the oxytocin receptor gene (OXTR) on ASD diagnosis and on specific ASD-related clinical symptoms (seizures, panic, and aggressive behaviors). We also assessed if these SNPs could be related to changes in OXTR availability and functionality using a bioinformatic approach. The sample was composed by 209 probands with ASD and their biological parents. Family-based approach and logistic regression models were used to investigated the outcomes. We observed that panic and aggressive behaviors were nominally associated with presence of rs1042778 T allele (P = 0.019/Pcorr = 0.114; P = 0.046/Pcorr = 0.276 respectively). Also, in the family-based analysis, a trend towards association with ASD susceptibility was observed for rs1042778 (G allele) (P = 0.066). In a bioinformatic approach, we demonstrated that rs1042778 G allele is determinant for the binding of the transcription factor MAZ, suggesting that when the T allele is present, the absence of MAZ binding might be associated with lower transcription levels of the OXTR gene. The overall findings suggest that the OXTR gene may play a role in ASD diagnosis and some of its clinical phenotypes, supported by previous animal and clinical studies. Further investigations are necessary to replicate our findings and fully understand the effects of the oxytocin pathway on ASD.

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BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic neurodevelopmental disorder that affects up to 3% of the general population. Although epigenetic mechanisms play a role in neurodevelopment disorders, epigenetic pathways associated with OCD have rarely been investigated. Oxytocin is a neuropeptide involved in neurobehavioral functions. Oxytocin has been shown to be associated with the regulation of complex socio-cognitive processes such as attachment, social exploration, and social recognition, as well as anxiety and other stress-related behaviors. Oxytocin has also been linked to the pathophysiology of OCD, albeit inconsistently. The aim of this study was to investigate methylation in two targets sequences located in the exon III of the oxytocin receptor gene (OXTR), in OCD patients and healthy controls. We used bisulfite sequencing to quantify DNA methylation in peripheral blood samples collected from 42 OCD patients and 31 healthy controls. RESULTS: We found that the level of methylation of the cytosine-phosphate-guanine sites in two targets sequences analyzed was greater in the OCD patients than in the controls. The higher methylation in the OCD patients correlated with OCD severity. We measured DNA methylation in the peripheral blood, which prevented us from drawing any conclusions about processes in the central nervous system. CONCLUSION: To our knowledge, this is the first study investigating DNA methylation of the OXTR in OCD. Further studies are needed to evaluate the roles that DNA methylation and oxytocin play in OCD.

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In order to survive after birth, mammalian infants need a caretaker, usually the mother. Several behavioral strategies have evolved to guarantee the transition from a period of intense caregiving to offspring independence. Here, we examine a selection of literature on the genetic, epigenetic, physiological, and behavioral factors relating to development and mother-infant interactions. We intend to show the utility of comparisons between rodent and human models for deepening knowledge regarding this key relationship. Particular attention is paid to the following factors: the distinct developmental stages of the mother-pup relationship as relating to behavior; examples of key genetic components of mammalian mother-infant interactions, specifically those coding for the hormones oxytocin and vasopressin; and the possible functions of gene imprinting in mediating interactions between genetics and environment in the mother-infant relationship. As early mother-infant attachment seems to establish the basic parameters for later social interactions, ongoing investigations in this area are essential. We propose the importance of interdisciplinary collaboration in order to better understand the network of genes, gene regulation, neuropeptide action, physiological processes, and feedback loops essential to understand the complex behaviors of mother-infant interaction.