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A pronounced decrease of oxytocin and increase of oxytocin receptor binding sites were recently reported in male alcohol dependent rats and male alcohol dependent patients. Here we comment on this and emphasize that in female alcohol dependent rats and humans no changes occur in the oxytocin system. We therefore suggest specific intervention with oxytocin only in male subjects., (© 2020 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

New Findings: What is the central question of this study? We hypothesized that potential anti-tumour effects of exercise training might be mediated by oxytocin and explored the underlying mechanisms in a mouse model of breast cancer. What is the main finding and its importance? Interval exercise training, by inducing oxytocin secretion, may reduce the activity of the PI3K/Akt and ERK pathways, and consequently, results in a smaller tumour volume in a mouse model of breast cancer. Exercise training can affect the growth of breast tumours. We hypothesized that exercise training might reduce breast tumour growth by inducing oxytocin (OT) secretion and its related signalling pathways, such as PI3K/Akt and ERK. Therefore, 56 BALB/c mice were equally divided into seven groups to study the effects of OT and atosiban (an oxytocin receptor antagonist) together with interval exercise training on mammary tumour growth, as well as tumour-related signalling pathways, including PI3K/Akt and ERK. Animal weight, OT plasma concentration, tumour weight and volume were measured at the end of the study. PI3K/Akt and ERK were evaluated by Western blot and qPCR assays. The results showed that OT plasma concentration was significantly increased in trained animals. The volume and weight of tumours were decreased significantly after both exercise training and OT administration. The expression of genes involved in tumour cell proliferation, such as PI3KR2, Akt and mTOR, was notably lower in the exercise-trained and OT-treated groups. Furthermore, the expression of genes involved in cell apoptosis, such as caspase-3 and Bax, was significantly increased in the tumour tissues. In addition, Western blot results showed that phosphorylated Akt and ERK were significantly decreased in the exercise training and OT groups compared with the tumour group. Interestingly, atosiban reversed these effects. These results indicated that interval exercise training, acting via OT secretion, may reduce PI3K/Akt and ERK axis activities, and consequently, decrease tumour volume and weight in a mouse model of breast cancer., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') use results in distinctive mood changes of a prosocial nature, most likely through its enhancement of serotonin (5HT) neurotransmission. Activation of 5HT-1A postsynaptic receptors has been shown to stimulate the release of oxytocin in the central nervous system where it regulates aspects of mood and behavior. Using a drug discrimination paradigm, we examined whether modulation of oxytocin receptor activity would affect conditioned behavioral responses to MDMA. Male and female Sprague Dawley rats (n=24) were trained to reliably differentiate between MDMA and a related stimulant, amphetamine (AMP), and saline using a three-lever drug discrimination paradigm. The extent to which substitution with carbetocin (an oxytocin analog) or co-administration with atosiban (an oxytocin receptor antagonist) affected drug-appropriate responding was evaluated. The tricyclic antidepressant imipramine was included as a negative control. The results supported the hypotheses that substitution with an oxytocin analog (carbetocin) would partially generalize to the MDMA training cue, whereas blocking oxytocin receptors with atosiban would result in a selective disruption of MDMA--but not AMP-appropriate responding. These findings were specific to the oxytocin receptor ligands as imipramine pre-treatment did not affect drug-appropriate responding. The results of this study implicate oxytocin receptor activation as a key MDMA-specific interoceptive cue in male and female rats and support the conclusion that this is one of the features of MDMA's subjective effects that distinguishes it from AMP., (© 2010 The Authors, Addiction Biology © 2010 Society for the Study of Addiction.)

Aim: pulmonary hypertension (PH) in the rat leads to right ventricular (RV) hypertrophy, inflammation and increased natriuretic peptide (NP) levels in plasma and RV. Because the release of nitric oxide (NO) and atrial natriuretic peptide (ANP) is a function of the oxytocin receptor (OTR), we examined the effect of PH on gene and protein expression of OTR, NP (A, atrial; B, brain) and receptors (NPRs), nitric oxide synthases (NOS), interleukin (IL)-1β, IL-6 and tumour necrosis factor-α in the hypertrophied RV in a model of PH., Methods: RV hypertrophy was induced in male Sprague-Dawley rats with monocrotaline (MCT; 60 mg kg(-1) ) and was confirmed by the presence of an increased RV weight and RV-to-[left ventricle (LV) and septum] ratio., Results: in the RV of MCT-treated rats, a approximately 40% reduction in OTR mRNA and protein was observed compared with the RV of control rats. This reduction was associated with increased transcripts of ANP and BNP in both ventricles and a corresponding increase in NP receptor mRNA expression for receptors A, B and C. Protein expression of inducible NOS was increased in the RV, whereas endothelial NOS transcripts were increased only in the LV of MCT-treated rats. In the RV of MCT-treated rats, downregulation of OTR was also associated with increased mRNA expression of IL-1β and IL-6., Conclusion: our results show that downregulation of the OTR in the RV of MCT-treated rats is associated with increased expression of NP and their receptors as well as IL-1β and IL-6. This reduction in OTR in RV myocardium may have an impact on cardiac function in the MCT-induced model of PH.

1. Diabetes is one of the most frequent complications of gestation, affecting approximately 7% of pregnancies. However, little is known about its effects on electrically and pharmacologically stimulated myometrial contractility. The aim of the present study was to investigate the consequences of streptozotocin (STZ)-induced diabetes on: (i) electrical field stimulation (EFS)-evoked contraction of isolated uterine rings as a function of gestational age; and (ii) the uterotonic and tocolytic actions of α- and β-adrenoceptor stimulation, respectively. The effects of oxytocin in late pregnancy were also investigated. 2. During pregnancy, EFS-evoked contractions of isolated uterine rings from intact rats declined, whereas isolated uterine rings from diabetic rats exhibited continuously low sensitivity to EFS. 3. In non-pregnant rats, diabetes resulted in increased noradrenaline-mediated contractility and a decreased relaxation response to terbutaline. At the mRNA level, diabetes enhanced the expression of α1B-adrenoceptors in non-pregnant rats from 14.65 to 18.39 μg/mL (P < 0.05), whereas the expression of α1D-adrenoceptors decreased (from 42.87 to 35.67 μg/mL; P < 0.05). During pregnancy, the responses to these sympathomimetics did not differ between diabetic and intact rats. 4. In late pregnancy (on Days 15 and 21), oxytocin caused greater maximum contractility of uterine rings from diabetic rats without affecting the EC(50). In addition, on Day 15 of pregnancy, the expression of oxytocin receptors in the myometrium of diabetic rats was higher than that in intact rats. 5. The results of the present study indicate that experimental diabetes facilitates gestation-induced denervation and increases myometrial sensitivity to oxytocin in late pregnancy. If similar mechanisms operate in humans, this could contribute to a tendency to premature uterine contractions in diabetes-complicated pregnancies.

1. Antagonists of the V(2) vasopressin (AVP) receptor are aquaretic agents, inhibiting water resorption without stimulating electrolyte excretion. In this set of experiments, a novel V(2) receptor antagonist, RWJ-351647, was characterized in vitro and in vivo. 2. RWJ-351647 displaced (3)H-AVP binding from cloned human V(2) and V(1A) receptors with Ki values of 1 nmol/L and 24 nmol/L. In assays using transfected HEK293 cells expressing either human or rat V(2) receptors, RWJ-351647 inhibited AVP-induced cAMP accumulation with Ki values of 3 nmol/L and 6 nmol/L, respectively. 3. RWJ-351647 was very selective in binding assays and showed only weak functional antagonist activity at either the cloned human V(1B) and oxytocin receptors or the human platelet V(1A) receptor. No agonist activity was seen with the compound at any receptor. 4. Pharmacokinetic studies in rats showed RWJ-351647 to be 41.9% bioavailable after a single oral administration. After repeated daily dosing over 5 days, the oral bioavailability remained at 43.9% with no change in the compound peak plasma levels or clearance rate. 5. In efficacy studies, RWJ-351647 increased urine output and decreased urine osmolality with oral doses as low as 0.1 mg/kg and 1.0 mg/kg in rats and cynomolgus monkeys, respectively. In a multiple dose study in primates, RWJ-351647 maintained a consistent aquaretic effect over 10 days without increasing sodium or potassium excretion. 6. In summary, RWJ-351647 was shown to be a selective and potent V(2) receptor antagonist with sustainable aquaretic activity in both rats and primates. The preclinical data suggest that RWJ-351647 is a potent and effective aquaretic agent with potential for use in diseases characterized by water retention.

Objective: To determine the effect of the progesterone metabolite 5 beta-dihydroprogesterone on human oxytocin receptor binding in myometrial membranes and on whole-cell calcium current in single myometrial cells., Design: Receptor binding studies in human myometrial membranes prepared from biopsies taken before or after the onset of labour and in Chinese hamster ovary cells expressing the human oxytocin receptor. Whole cell patch-clamp experiments were undertaken on isolated myometrial cells., Setting: University research laboratories and University hospital.Patients undergoing caesarean section at term either prior to or following onset of labour., Methods: Myometrial biopsies were taken from women undergoing caesarean section. The binding affinities of oxytocin, 5 beta-dihydroprogesterone and atosiban were determined in myometrial membranes and Chinese hamster ovary cells expressing the human oxytocin receptor. The effect of 5 beta-dihydroprogesterone on inward current was also determined in isolated myometrial cells. Receptor binding affinity and electrophysiological inward current., Results: 5 beta-Dihydroprogesterone did not reduce oxytocin receptor binding in myometrial membranes or Chinese hamster ovary cells expressing the human oxytocin receptor. Nor did it influence calcium current under whole-cell patch conditions in single myometrial cells. In contrast, atosiban inhibited binding in myometrial membranes prepared from samples taken either prior to or following labour (K(i) = 112 and 108 nM, respectively). The affinity of atosiban for the oxytocin receptor was much lower than oxytocin (K(i) = 5 and 6 nM in samples taken before or after labour, respectively) in myometrial membranes and in Chinese hamster ovary cells expressing the human oxytocin receptor (K(i) = 63 M and 1 nM for atosiban and oxytocin, respectively)., Conclusions: We conclude that 5 beta-dihydroprogesterone is unlikely to regulate myometrial activity as a result of a direct effect on oxytocin receptor binding or inward calcium current.

The oxytocin receptor (OTR) is part of an ancient hormone system expressed in diverse phyla in relation to acute reproductive smooth muscle responses, such as egg-laying, birth, or milk letdown. The regulation of the OTR gene, while correlating with steroid levels in vivo, remains elusive. There appear to be both inhibitory and stimulatory influences acting upon a constitutive pattern of basal expression. We have found no evidence, however, for an effect of the sex steroids either directly on gene transcription, or on the receptor itself at the protein level. In the prostatic carcinoma cell line Du145, we have shown that up-regulation of the OTR gene transcription can be effected by cAMP. In an attempt to characterize the expression of the OTR protein in vivo, we have shown, using ligand-blotting, that the OTR can be expressed at different sizes in transfected cells and in myometrium. Also, in the myometrium at term, immunohistochemistry suggests that there is both an increase in OTR protein per cell, as well as in the number of smooth muscle cells expressing OTR, emphasizing that perinatal changes are the results of both individual gene activation events and gross cellular differentiation. The OTR is a valuable model system reflecting molecular changes in the perinatal period. When we understand how this important molecule is regulated, we will also be a long way towards understanding the mechanisms controlling myometrial contractility at birth. Experimental Physiology (2001) 86.2, 289-296.

Problem: Little is known regarding the regulation of the timing of parturition. Recent evidence suggests an interaction between the immune system and uterine contractility in late gestation., Method: Pregnant rats were treated with LPS in vivo in attempts to establish a model of premature parturition induced by the pro-inflammatory response. Uterine explants were incubated in vitro to determine the effects of IL-6 on uterine synthesis of oxytocin (OT) and its receptor (OTR)., Results: LPS injection was quite toxic to pregnant rats and gave extremely variable results. In animals that delivered, there was a marked increase in the uterine concentrations of OTR and OTR mRNA. There was no consistent effect regarding the timing of parturition. IL-6 caused a significant increase in the concentration of OTR mRNA in uterine explants from pregnant rats but not in tissues from non-pregnant animals., Conclusion: Rat uterine concentrations of OTR are regulated by IL-6. Pro-inflammatory cytokines may stimulate uterine contractility in late gestation rat uterine tissues through a mechanism involving stimulation of OTR.

In this report, a series of four experiments was performed to evaluate the relationship between the olfactory bulb norepinephrine system and intra-olfactory bulb infusion of oxytocin in the preservation of social memory responses. The present data indicate that oxytocin exerts this preservation of social recognition through a specific, receptor-mediated mechanism within the olfactory bulb (experiment 1). The involvement of the olfactory bulb norepinephrine system is revealed by the demonstration that retrodialysis of oxytocin into the olfactory bulb increases norepinephrine release (experiment 4). Our data suggest that the increased output of olfactory bulb norepinephrine resulting from oxytocin appears to activate alpha-adrenoceptors to produce this preservation in recognition because infusions of clonidine into the olfactory bulb preserve recognition responses in a manner similar to that observed with oxytocin (experiment 2). In addition, a co-infusion of oxytocin with phentolamine abolishes recognition responses (experiment 3). Accordingly, this model affords the opportunity to study neuropeptide-catecholamine interactions, link these interactions with a specific behavioural outcome and identify a novel function/site of action for oxytocin in the male.

Oxytocin binding sites were detected by autoradiography on films and emulsion-coated sections in the spinal cord of adult and postnatal rats from C8 to L2, using a highly selective 125I-labelled oxytocin antagonist. Oxytocin binding sites were detected on all transverse sections in the dorsal horn, where labelling was scattered over laminae I and II. The autonomic areas, i.e. the intermediolateral cell column, the central grey (lamina X) and the nucleus intercalatus were labelled. Binding in the intermediolateral cell column was most frequently observed on sections from T9 to T11 in adult and T7 to T8 in postnatal rats. In this location, oxytocin binding sites were highly concentrated on cell bodies of putative sympathetic preganglionic neurons; however, not all of these cells were labelled. Diffuse labelling occurred on the dorsal part of the central grey, mainly between T8 and L2. Isolated labelled cells belonging to the nucleus intercalatus were scattered between the central canal and the intermediolateral cell column. In addition, oxytocin binding sites were found on some motoneurons of the lateral group of T12-T13, but only in postnatal rats. The distribution of oxytocin binding sites in the rat spinal cord coincides with that of the oxytocin innervation and strongly suggests a modulatory role of this peptide in sensory and autonomic functions.