oxytocin and Disease-Models--Animal

Dysmenorrhea is a prevalent gynecological disease among women at reproductive age. It is classified as the primary dysmenorrhea and the secondary dysmenorrhea according to the etiology. The primary dysmenorrhea is caused by uterine hypercontraction without any identifiable pelvic lesions, while the secondary dysmenorrhea is incurred by gynecological disorder with pelvic organic lesions. However, the underlying mechanism of dysmenorrhea is not completely clear. Animal models of dysmenorrhea, especially mouse and rat model, are helpful to explore the pathophysiological mechanism of dysmenorrhea, clarify the therapeutic effect of compounds, and guide clinical treatment. The murine model of primary dysmenorrhea is commonly induced by oxytocin or prostaglandin F

Topics: Animals; Dinoprost; Disease Models, Animal; Dysmenorrhea; Female; Humans; Mice; Oxytocin; Rats; Uterus

Finding a cure for Alzheimer's disease (AD) has been notoriously challenging for many decades. Therefore, the current focus is mainly on prevention, timely intervention, and slowing the progression in the earliest stages. A better understanding of underlying mechanisms at the beginning of the disease could aid in early diagnosis and intervention, including alleviating symptoms or slowing down the disease progression. Changes in social cognition and progressive parvalbumin (PV) interneuron dysfunction are among the earliest observable effects of AD. Various AD rodent models mimic these early alterations, but only a narrow field of study has considered their mutual relationship. In this review, we discuss current knowledge about PV interneuron dysfunction in AD and emphasize their importance in social cognition and memory. Next, we propose oxytocin (OT) as a potent modulator of PV interneurons and as a promising treatment for managing some of the early symptoms. We further discuss the supporting evidence on its beneficial effects on AD-related pathology. Clinical trials have employed the use of OT in various neuropsychiatric diseases with promising results, but little is known about its prospective impacts on AD. On the other hand, the modulatory effects of OT in specific structures and local circuits need to be clarified in future studies. This review highlights the connection between PV interneurons and social cognition impairment in the early stages of AD and considers OT as a promising therapeutic agent for addressing these early deficits.

Topics: Alzheimer Disease; Animals; Cognition; Disease Models, Animal; Hippocampus; Humans; Interneurons; Mice, Transgenic; Oxytocin; Parvalbumins; Prospective Studies; Social Cognition

Over the past 70 years, the understanding of Autism Spectrum Disorder (ASD) improved greatly and is characterized as a heterogeneous neuropsychiatric syndrome. ASD is characterized by difficulties in social communication, restricted and repetitive behavior, interests, or activities. And it is often described as a combination of genetic predisposition and environmental factors. There are many treatments and approaches to ASD, including pharmacological therapies with antipsychotics, antidepressants, mood regulators, stimulants, and behavioral ones. However, no treatment is capable of reverting ASD. This review provides an overview of animal models of autism. We summarized genetic and environmental models and then valproic acid treatment as a useful model for ASD. As well as the main therapies and approaches used in the treatment, relating them to the neurochemical pathways altered in ASD, emphasizing the pharmacological potential of peptides and bioinspired compounds found in animal venoms as a possible future treatment for ASD.

Topics: Animals; Antipsychotic Agents; Autism Spectrum Disorder; Disease Models, Animal; Humans; Mice; Oxytocin; Peptides; Valproic Acid

Post-traumatic stress disorder (PTSD) has a high lifetime prevalence and is one of the more serious challenges in mental health care. Fear-conditioned learning involving the amygdala has been thought to be one of the main causative factors; however, recent studies have reported abnormalities in the thalamus of PTSD patients, which may explain the mechanism of interventions such as eye movement desensitization and reprocessing (EMDR). Therefore, I conducted a miniature literature review on the potential contribution of the thalamus to the pathogenesis of PTSD and the validation of therapeutic approaches. As a result, we noticed the importance of the retinotectal pathway (superior colliculus-pulvinar-amygdala connection) and discussed therapeutic indicators.

Topics: Amygdala; Animals; Conditioning, Psychological; Connectome; Diffusion Tensor Imaging; Disease Models, Animal; Eye Movement Desensitization Reprocessing; Fear; Humans; Hyperbaric Oxygenation; Oxytocin; Pulvinar; Retina; Stress Disorders, Post-Traumatic; Superior Colliculi; Treatment Outcome; Visual Pathways

Breast cancer is making up one-quarter of all new female cancer cases diagnosed worldwide. Breast cancer surgeries, radiation therapies, cytotoxic chemotherapies and targeted therapies have made significant progress and play a dominant role in breast cancer patient management. However, many challenges remain, including resistance to systemic therapies, tumour recurrence and metastasis. The cyclic neuropeptide oxytocin (OT) elicits a plethora of biological responses via the oxytocin receptor (OTR) in both the central and peripheral nervous system, including social bonding, stress, maternal behaviour, sexual activity, uterus contraction, milk ejection and cancer. As a typical member of the G protein-coupled receptor family, OTR represents also an intriguing target for cancer therapy. There is emerging evidence that OTR plays a role in breast cancer development and progression, and several breast cancer cell lines express OTR. However, despite supporting evidence that OT lowers breast cancer risks, its mechanistic role in breast cancer development and the related signalling pathways are not fully understood. Here, we review the current knowledge of the OT/OTR signalling system in healthy breast tissue as well as in breast cancer, and discuss OTR as a potential therapeutic target for breast cancer management.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Transformation, Neoplastic; Chemoprevention; Disease Management; Disease Models, Animal; Disease Susceptibility; Drug Evaluation, Preclinical; Female; Gene Expression Regulation, Neoplastic; Humans; Ligands; Molecular Targeted Therapy; Oxytocin; Receptors, Estrogen; Receptors, Oxytocin; Signal Transduction

Despite its relatively well-understood role as a reproductive and pro-social peptide, oxytocin (OT) tells a more convoluted story in terms of its modulation of fear and anxiety. This nuanced story has been obscured by a great deal of research into the therapeutic applications of exogenous OT, driving more than 400 ongoing clinical trials. Drawing from animal models and human studies, we review the complex evidence concerning OT's role in fear learning and anxiety, clarifying the existing confusion about modulation of fear versus anxiety. We discuss animal models and human studies demonstrating the prevailing role of OT in strengthening fear memory to a discrete signal or cue, which allows accurate and rapid threat detection that facilitates survival. We also review ostensibly contrasting behavioral studies that nonetheless provide compelling evidence of OT attenuating sustained contextual fear and anxiety-like behavior, arguing that these OT effects on the modulation of fear vs. anxiety are not mutually exclusive. To disambiguate how endogenous OT modulates fear and anxiety, an understudied area compared to exogenous OT, we survey behavioral studies utilizing OT receptor (OTR) antagonists. Based on emerging evidence about the role of OTR in rat dorsolateral bed nucleus of stria terminalis (BNST) and elsewhere, we postulate that OT plays a critical role in facilitating accurate discrimination between stimuli representing threat and safety. Supported by human studies, we demonstrate that OT uniquely facilitates adaptive fear but reduces maladaptive anxiety. Last, we explore the limited literature on endogenous OT and its interaction with corticotropin-releasing factor (CRF) with a special emphasis on the dorsolateral BNST, which may hold the key to the neurobiology of phasic fear and sustained anxiety.

Topics: Animals; Anxiety; Corticotropin-Releasing Hormone; Disease Models, Animal; Fear; Humans; Oxytocin; Septal Nuclei

The effects of oxytocin on social cognition and behavior have recently attracted considerable attention. In particular, oxytocin has been proposed as a novel therapeutic for psychiatric disorders with social deficits such as autism spectrum disorders. This review provides a brief overview of behavioral and neural responses to oxytocin manipulations in humans and animal models. Although the differences in findings between human and animal studies should be interpreted carefully, shared behavioral phenotypes have been recognized, such as social bonding, social responses, and recognition and usage of social cues. Previous literature suggests that the neural effects of oxytocin in humans and animals overlap in the prefrontal, limbic, and paralimbic cortices. Oxytocin-induced alterations in these regions may indicate a fundamental basis for how oxytocin modulates social behaviors and facilitate the discovery of new pharmaceutical targets for treating social deficits.

Topics: Animals; Attention; Autism Spectrum Disorder; Behavior, Animal; Cerebral Cortex; Disease Models, Animal; Humans; Oxytocin; Prefrontal Cortex; Social Behavior

Oxytocin is associated mainly with modulating reproductive function. However, studies suggest that oxytocin also plays a role in endocrine pancreatic function. In the present study, islet expression of oxytocin and its related receptor was confirmed in mouse islets as well as cultured rodent and human beta-cells. Oxytocin significantly stimulated glucose-induced insulin secretion from isolated mouse islets. Similar insulinotropic actions were also observed in rodent BRIN BD11 and human 1.1B4 beta-cells. Positive effects of oxytocin on insulin secretion were almost fully annulled by the oxytocin receptor antagonist, atosiban. In terms of mechanism of insulin secretory action, oxytocin had no effect on beta-cell membrane potential or cAMP generation, but did augment intracellular calcium concentrations. In vivo administration of oxytocin to mice significantly reduced overall blood glucose levels and increased plasma insulin concentrations in response to a glucose challenge. Oxytocin also had a modest, but significant, appetite suppressive effect. As expected, streptozotocin diabetic mice had marked loss of beta-cell area accompanied by increases in alpha-cell area, whilst hydrocortisone treatment increased beta-cell and overall islet areas. Both mouse models of diabetes presented with dramatically decreased percentage islet oxytocin co-localisation with insulin and increased co-localisation with glucagon. More detailed studies in cultured beta-cell lines revealed direct positive effects of oxytocin on beta-cell proliferation and protection against apoptosis. Together, these data highlight a potentially important role of islet-derived oxytocin and related receptor signalling pathways on the modulation of beta-cell function and survival.

Topics: Animals; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose; Humans; Insulin; Insulin-Secreting Cells; Mice; Oxytocin; Signal Transduction

Nonapeptides and their respective receptors have been conserved throughout evolution and display astonishing similarities among the animal kingdom. They can be found in worms, birds, fish, amphibians, reptiles and mammals, including rodents, non-human primates and humans. In particular, the neuropeptide oxytocin (OT) has attracted the attention of scientists due to its profound effects on social behavior. However, although both the neuropeptide and its receptor are identical in rodents and primates, the effects of OT vary greatly in the two species. Here, we provide a brief overview about OT's role in the evolution of mammals and provide reasons for the manifold effects of OT within the brain with a particular focus on the discrepancy of OT's effects in rodents and primates. In addition, we suggest new approaches towards improvement of translatability of scientific studies and highlight the most recent advances in animal models for autism spectrum disorder, a disease, in which the normal function of the OT system seems to be impaired.

Topics: Animals; Autism Spectrum Disorder; Brain; Disease Models, Animal; Humans; Mice; Neuropeptides; Oxytocin

The nonapeptides oxytocin (OXT) and arginine vasopressin (AVP) are two key mediators in regulating various aspects of mammalian social behaviours. There are several lines of evidence that genetic variants of the OXT/AVP system exist in autism spectrum disorder (ASD) and that this system is dysfunctional at least in some ASD entities. These findings have stimulated the interest to perform studies testing the potential therapeutic application of OXT/AVP in ASD. In this respect animal models are critical for investigating the pathophysiology and for compound screening leading to new therapeutic approaches. Based on findings in animal models that show alterations of the OXT/AVP system, it has been hypothesised that single- or multiple-dose administration or the stimulation of endogenous release can improve several social deficits. Here we comprehensively review the role of the OXT/AVP system in social recognition, social interaction and maternal behaviour in the light of different ASD animal models and patient studies. We further discuss implications for OXT/AVP-related pharmacological interventions to alleviate social deficits in ASD in the future.

Topics: Animals; Arginine Vasopressin; Autism Spectrum Disorder; Disease Models, Animal; Humans; Interpersonal Relations; Oxytocin; Social Behavior

Autism spectrum disorder is a behavioral disorder characterized by impairments in social interaction and communication together with the presence of stereotyped behaviors and restricted interests. Although highly genetic, its etiology is complex which correlates with the extensive heterogeneity found in its clinical manifestation, adding to the challenge of understanding its pathophysiology and develop targeted pharmacotherapies. The neuropeptide oxytocin is part of a highly conserved system involved in the regulation of social behavior, and both animal and human research have shown that variation in the oxytocin system accounts for interindividual differences in the expression of social behaviors in mammals. In autism, recent studies in human patients and animal models are starting to reveal that alterations in the oxytocin system are more common than previously anticipated. Genetic variation in the key players involved in the system (i.e., oxytocin receptor, oxytocin, and CD38) has been found associated with autism in humans, and animal models of the disorder converge in an altered oxytocin system and/or dysfunction in oxytocin related biological processes. Furthermore, oxytocin administration exerts a behavioral and neurobiological response, and thus, the oxytocin system has become a promising potential therapeutical target for autism. Animal models represent a valuable tool to aid in the research into the potential therapeutic use of oxytocin. In this review, I aim to discuss the main findings related to oxytocin research in autism with a focus on findings in animal models. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 202-213, 2017.

Topics: Animals; Autism Spectrum Disorder; Disease Models, Animal; Humans; Oxytocin; Social Behavior

Schizophrenia is a disabling, heterogeneous disorder with clinical features that can be parsed into three domains: positive symptoms, negative symptoms, and cognitive deficits. Current antipsychotic drugs produce fairly robust clinical benefit against positive symptoms but typically have minimal therapeutic effects on negative symptoms and cognitive deficits. Oxytocin (OT) is a nonapeptide that, in addition to its role as a hormone regulating peripheral reproductive-relevant functions, acts as a neurotransmitter in the brain. Several lines of preclinical and clinical research suggest that the OT system may play a role in regulating the expression of schizophrenia spectrum disorders and that targeting the central OT system may yield novel treatments to address these symptoms. In this review, we summarize the extant preclinical and clinical evidence relevant to the role of OT in schizophrenia with particular emphasis on its putative therapeutic effects on each of the three above-mentioned clinical domains.

Topics: Animals; Brain; Cognition; Cognition Disorders; Disease Models, Animal; Humans; Oxytocin; Schizophrenia; Schizophrenic Psychology

Over the years the effect of the neuropeptide oxytocin and its possible utilization for pain management has been increasingly more investigated and discussed. Initial results emphasized the effects of oxytocin with respect to labor and breastfeeding. Diverse animals studies were also able to demonstrate the effectiveness of the peptide in attachment behavior and pain perception; however, it is still unclear how oxytocin affects pain perception in humans. The potential therapeutic effectiveness of oxytocin could be particularly important for primary and secondary treatment of pain patients because chronification of pain can occur more frequently in this area.. For this review the databases PubMed, Medline und PsycINFO were searched using the terms oxytocin, pain, human and analgesic. The search resulted in a total of 89 original articles after excluding articles regarding labor pain, breastfeeding and animal studies. Only those studies were included which were carried out between 1994 and 2015. A total of 17 articles remained for inclusion in this review and included 13 studies on the exogenous application of oxytocin and 4 on measurement of oxytocin levels in plasma.. This review article gives a summary of the current state of research on oxytocin and its direct and indirect association with human pain perception and emphasizes its relevance for the multimodal management of pain.

Topics: Affect; Animals; Brain; Breast Feeding; Chronic Pain; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Labor Pain; Mice; Nociceptors; Oxytocin; Pain Management; Pain Perception; Pain Threshold; Pregnancy; Randomized Controlled Trials as Topic; Rats; Receptors, Oxytocin

Oxytocin (OXT), which is a well-known neurohypophysial hormone that is synthesized in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus, is secreted from the posterior pituitary (PP) into the systemic circulation, where it plays an essential role in reproduction, especially during and after childbirth. Many recent studies have shown that OXT contributes to the modulation of several functions, such as social recognition, trust building, anti-nociception, anti-inflammation, stress relief and suppression of feeding. However, little is known about the neuronal networks responsible for OXT effects. Endogenious OXT has two regulations: the 1st regulation is humoral regulation, in which OXT is delivered to target organs from PP via the bloodstream; the 2nd regulation is nerve regulations, in which OXT from parvocellular neurosecretory neurons in the PVN directly project to the central nerve system (CNS). OXT binding sites, as well as OXT receptor expression, are located in various regions of the CNS, including the dorsal horn of spinal cord in rats, where it plays an important role in nociception. We examined the response to acute and chronic nociception/-inflammation in rat models using OXT-monomeric red fluorescent protein 1 (mRFP1) transgenic rats. We used formalin test as acute nociceptive/-inflammatory rat models and adjuvant arthritis as chronic nociceptive/-inflammatory rat models. We studied the effects of acute and chronic nociception/-inflammation on OXT-mRFP1 expression in the hypothalamus, posterior pituitary and spinal cord, and examined the role that OXT plays in acute and chronic nociceptive responses in rats. This review focuses on pain modulation and anti-inflammation by OXT according to previous clinical and animal research.

Topics: Animals; Brain; Disease Models, Animal; Humans; Inflammation; Oxytocin; Pain; Pain Management

Topics: Animals; Child Development Disorders, Pervasive; Disease Models, Animal; Eukaryotic Initiation Factors; Fragile X Mental Retardation Protein; Mice; Nerve Tissue Proteins; Neurofibromin 1; Oxytocin; PTEN Phosphohydrolase; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

The recent involvement of oxytocin in social behavior of animals and humans has motivated the study of its effects on the social behavior of individuals with autism spectrum disorders (ASD).. To review the current state of oxytocin studies concerning its therapeutic potential in treating social deficits of the ASD population, and to establish likely future directions to be taken by the studies in this field.. Some studies have linked oxytocin to the pathophysiology of autistic disorders. Most studies that have administered oxytocin (mainly with intranasal administration of 24 IU) to ASD subjects have shown significant improvements in their social performance with acceptable safety parameters. However, there is controversial data as the outcome measures are widely dispersed, the samples are reduced and heterogeneous, and the treatment durations are different. The limitations related to the lack of understanding of the oxytocin's action mechanisms and the symptomatic heterogeneity of ASD are hampering progress towards the establishment of oxytocin as a treatment of ASD patients. Recent studies suggest the investigation of the combination of the oxytocin treatment with social skills training, and the enhancement of endogenous secretion of oxytocin.. The effects of oxytocin are promising regarding the treatment of social deficits in ASD individuals. Future studies should aim to facilitate understanding of the oxytocin's ways of action and to establish the optimal treatment regime.. La oxitocina en el tratamiento de los deficits sociales asociados a los trastornos del espectro autista.. Introduccion. La implicacion de la oxitocina en la conducta social de animales y humanos ha llevado a estudiar los efectos de su administracion en el comportamiento y cognicion social de pacientes con trastornos del espectro autista (TEA). Objetivos. Revisar la investigacion sobre el potencial terapeutico de la oxitocina en el tratamiento de los deficits sociales de la poblacion con TEA y discutir las probables direcciones futuras de los estudios en este campo. Desarrollo. Diversos trabajos han relacionado la oxitocina con la fisiopatologia de los TEA. La mayoria de los estudios que han administrado oxitocina, generalmente por via intranasal (24 UI), ha observado mejoras significativas en el rendimiento social, sin detectar efectos secundarios destacables. No obstante, existen datos contradictorios debido a la heterogeneidad de las variables analizadas por los diferentes estudios, al uso de muestras heterogeneas y pequeñas o a la diferente duracion de los tratamientos. Las limitaciones relacionadas con la falta de comprension de los mecanismos de accion de la oxitocina y la diversidad sintomatologica de los TEA dificultan el establecimiento de este peptido como tratamiento de los pacientes autistas. Estudios recientes destacan la conveniencia de explorar el efecto de la combinacion del tratamiento de oxitocina con programas conductuales de intervencion en habilidades sociales, asi como la potenciacion de la secrecion endogena de oxitocina. Conclusiones. Los efectos de la administracion de oxitocina resultan prometedores en relacion con el tratamiento de los deficits sociales en individuos con TEA. Estudios futuros deberian facilitar la comprension de las vias de accion de la oxitocina y el establecimiento de pautas optimas de tratamiento.

Topics: Adolescent; Adult; Animals; Autism Spectrum Disorder; Disease Models, Animal; Dose-Response Relationship, Drug; Emotions; Female; Gene Knockdown Techniques; Humans; Male; Oxytocin; Receptors, Oxytocin; Sex Characteristics; Social Behavior Disorders

A review of the literature was conducted to assess the association between oxytocin (OT) and pain.. PsychInfo, PubMed, and Medline (EBSCO) research databases were searched for peer-reviewed articles written between 1950 and 2012. Of a total of 1166 articles returned, 50 (9 human, 33 animal, and 8 spinal cord samples) met full inclusion criteria and were included in the review.. OT had a reliable effect as defined by increasing pain tolerance in 29 of 33 animal studies reviewed. This effect persisted across central and peripheral modes of administration and type of noxious stimulus used (eg, heat, electric). The results suggest that OT acts as an analgesic for acute pain in animals. Preliminary research with humans offers consistent evidence to suggest that OT decreases pain sensitivity, though the reliability and stability of such effects cannot yet be determined. Although the findings are encouraging, there is a need for methodologically rigorous work in humans where OT is administered centrally.. Further research seems to be warranted as the existence of biologically and psychologically plausible mechanisms linking OT and pain have been well supported using animal models with limited but encouraging human research. Implications and recommendations are discussed. Findings from this research may inform therapeutic methods for the management of pain.

Topics: Analgesics; Animals; Databases, Factual; Disease Models, Animal; Humans; Oxytocin; Pain; Spinal Cord

We have demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin (OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in Cd38 knockout mice. We investigated single nucleotide polymorphisms (SNPs) in the human CD38 gene in autism spectrum disorder (ASD) patients. The SNP rs3796863 (A>C) was associated with high-functioning autism (HFA) in American samples. Although this finding was partially confirmed in low-functioning autism subjects in Israel, it has not been replicated in Japanese HFA subjects. The second SNP of interest, rs1800561 (4693C>T), leads to the substitution of an arginine (R) at codon 140 by tryptophan (W;R140W) in CD38. This mutation was found in 4 probands of ASD and in family members of 3 pedigrees with variable levels of ASD or ASD traits. The plasma levels of OXT in ASD subjects with the R140W allele were lower than those in ASD subjects lacking this allele. One proband with the R140W allele receiving intranasal OXT for approximately 3 years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and aggression. Five other ASD subjects with mental deficits received nasal OXT for various periods;three subjects showed improved symptoms, while 2 showed little or no effect. These results suggest that SNPs in CD38 may be risk factors for ASD by abrogating the OXT function, and that some ASD subjects can be treated with OXT in preliminary clinical trials.

Topics: ADP-ribosyl Cyclase 1; Animals; Child Development Disorders, Pervasive; Disease Models, Animal; Humans; Oxytocin; Polymorphism, Single Nucleotide; Social Behavior

Traditionally associated with female reproduction, oxytocin (OT) was revisited recently and was revealed to have several new roles in the cardiovascular system. Functional OT receptors have been discovered in the rat and human heart, as well as in vascular beds. The cardiovascular activities of OT include: (i) lowering blood pressure; (ii) negative cardiac inotropy and chronotropy; (iii) parasympathetic neuromodulation; (iv) vasodilatation; (v) anti-inflammatory; (vi) antioxidative; and (vii) metabolic effects. These outcomes are mediated, at least in part, by stimulating cardioprotective mediators, such as nitric oxide and atrial natriuretic peptide. OT and its extended form OT-Gly-Lys-Arg have been shown to be abundant in the foetal mouse heart. OT has the capacity to generate cardiomyocytes from various types of stem cells, including the cardiac side population. Mesenchymal cells transfected with OT-Gly-Lys-Arg, or preconditioned with OT, are resistant to apoptosis and express endothelial cell markers. OT increases glucose uptake in cultured cardiomyocytes from newborn and adult rats, in normal, hypoxic and even insulin resistance conditions. In rats with experimentally-induced myocardial infarction, continuous in vivo OT delivery improves the cardiac healing process, as well as cardiac work, reduces inflammation and stimulates angiogenesis. Therefore, in pathological conditions, OT exerts anti-inflammatory and cardioprotective properties, and improves vascular and metabolic functions. Thus, OT has potential for therapeutic use.

Topics: Animals; Atrial Natriuretic Factor; Cardiovascular System; Cell Differentiation; Disease Models, Animal; Humans; Models, Biological; Myocardial Infarction; Myocytes, Cardiac; Oxytocin; Receptors, Oxytocin

Animal models and behavioral paradigms are critical for elucidating the neural mechanism involved in complex behaviors, including social cognition. Both genotype and phenotype based models have implicated the neuropeptide oxytocin (OT) in the regulation of social behavior. Based on the findings in animal models, alteration of the OT system has been hypothesized to play a role in the social deficits associated with autism and other neuropsychiatric disorders. While the evidence linking the peptide to the etiology of the disorder is not yet conclusive, evidence from multiple animal models suggest modulation of the OT system may be a viable strategy for the pharmacological treatment of social deficits. In this review, we will discuss how animal models have been utilized to understand the role of OT in social cognition and how those findings can be applied to the conceptualization and treatment of the social impairments in ASD. Animal models with genetic alterations of the OT system, like the OT, OT receptor and CD38 knock-out mice, and those with phenotypic variation in social behavior, like BTBR inbred mice and prairie voles, coupled with behavioral paradigms with face and construct validity may prove to have predictive validity for identifying the most efficacious methods of stimulating the OT system to enhance social cognition in humans. The widespread use of strong animal models of social cognition has the potential yield pharmacological, interventions for the treatment social impairments psychiatric disorders. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Topics: Administration, Intranasal; Animals; Anxiety; Arvicolinae; Autistic Disorder; Behavior Therapy; Cystinyl Aminopeptidase; Disease Models, Animal; Drug Discovery; Genotype; Humans; Mice; Models, Psychological; Oxytocin; Phenotype; Receptors, Oxytocin; Recognition, Psychology; Social Behavior

We have demonstrated that entire oxytocin (OT) system is synthesized in the rat and human heart and this hormone is implicated in several cardiac functions including stem cells differentiation into cardiomyocytes. These observations led us to the invention of OT as an inducer of cardiomyogenesis (US20060205636A1). We also proposed the use of OT, its functional derivatives, and/or physiological precursors as well as nucleic acids capable of encoding OT as cell-differentiating and useful agents for treating or preventing diseases, such as heart diseases associated with loss of cardiomyocytes. The invention is relevant to the use of OT or OT-related compounds. OT is claimed as an inducer that promotes the differentiation of non-cardiomyocytes (e.g. stem/progenitor cells) in situ, which can be used to repair, restore or fortify damaged cardiac tissue or in cell culture in order to provide material for cell or tissue grafting in the heart. Recent reports documented the significant progress in the research on the role of OT in cardiovascular regulation. Most of the results are consistent with the postulated cardioprotective role of OT. In this review, new data are discussed in the context of the main points presented in the invention.

Topics: Animals; Cardiac Surgical Procedures; Cardiotonic Agents; Cell Differentiation; Disease Models, Animal; Humans; Models, Cardiovascular; Muscle Development; Myocardial Ischemia; Myocytes, Cardiac; Oxytocin; Regeneration; Signal Transduction; Stem Cell Transplantation; Stem Cells

Currently, there is not an effective pharmacotherapy for the core symptoms of the autism spectrum disorders (ASD), which include aberrant social behavior, delayed communication and repetitive behavior and/or restricted interests. There are several drugs that treat the symptoms associated with autism including irritability, aggressiveness and hyperactivity. Current drug research is based on the ongoing genetic, animal model and neuropathologic research. Two areas in particular, the glutamate and oxytocin systems, provide exciting new avenues for drug discovery.. This review examines what approaches have been used for the drugs that are currently being used to treat people with ASD. For the most part, drugs that treat other neuropsychiatric disorders have been examined to treat the people with ASD, unfortunately with little effect on the core symptoms.. Until recently, there was not a plethora of knowledge about the neurobiological substrates of social behavior, pragmatic language usage and repetitive and/or restricted behaviors. Therefore, drug discovery has used the tools available for other neuropsychiatric disorders. Now that more biological information is available, there are many avenues for research for drug targets for ASD.

Topics: Adolescent; Adolescent Behavior; Animals; Antipsychotic Agents; Aripiprazole; Brain; Central Nervous System Stimulants; Child; Child Behavior; Child Development Disorders, Pervasive; Child, Preschool; Disease Models, Animal; Dopamine Antagonists; Dopamine Uptake Inhibitors; Drug Discovery; GluK2 Kainate Receptor; Glutamic Acid; Humans; Methylphenidate; Mice; Mice, Inbred C57BL; Oxytocin; Piperazines; Quinolones; Rats; Receptors, Kainic Acid; Risperidone; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists

We offer a neurobiologic theory based on animal work that helps account for the conspicuous male predominance in autism spectrum disorders (ASD). In young male animals, testosterone (TST) binds to androgen receptors (AR) in brainstem neurons responsible for enhancing brain arousal. As a consequence, arousal-related neurotransmitters bombard the amygdala hypersensitized by TST acting though AR. Arousal-related inputs are known to prime amygdaloid mechanisms for fear and anxiety, with resultant social avoidance. We hypothesize that similar mechanisms contribute to autism's male predominance and to its defining impaired social skills. The theory rests on two key interacting factors: the molecular effects of TST in genetically vulnerable boys in combination with environmental stresses they experienced in utero, neonatally, or during the first years. We postulate that higher TST levels and, therefore, higher amounts of arousal-related inputs to the amygdala sensitize these genetically vulnerable male infants to very early stresses. In sharp contrast to boys, girls not only do not have high levels of TST-facilitated arousal-causing inputs to the amygdala but they also enjoy the protection afforded by estrogenic hormones, oxytocin, and the oxytocin receptor. This theory suggests that novel technologies applied to the molecular endocrinology of TST's actions through AR will offer new avenues of enquiry into ASD. Since the high male preponderance in autism is important yet understudied, we offer our theory, which is based on detailed neurobehavioral research with animals, to stimulate basic and clinical research in animals and humans and hopefully help develop novel more effective medical treatments for autism.

Topics: Adolescent; Amygdala; Animals; Arousal; Autistic Disorder; Brain; Brain Stem; Child; Child, Preschool; Cross-Sectional Studies; Disease Models, Animal; Estrogens; Female; Genetic Predisposition to Disease; Humans; Infant; Infant, Newborn; Male; Neurotransmitter Agents; Oxytocin; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Antigen; Receptors, Oxytocin; Sex Factors; Social Behavior; Testosterone

Oxytocin (OXT) in the hypothalamus is the biological basis of social recognition, trust, and bonding. We showed that CD38, a leukaemia cell marker, plays an important role in the hypothalamus in the process of OXT release in adult mice. Disruption of Cd38 (Cd38(-/-)) produced impairment of maternal behavior and male social recognition in mice, similar to the behavior observed in Oxt and OXT receptor (Oxtr) gene knockout (Oxt(-/-) and Oxtr(-/-), respectively) mice. Locomotor activity induced by separation from the dam was higher and the number of ultrasonic vocalization (USV) calls was lower in Cd38(-/-) than Cd38(+/+) pups. These phenotypes seemed to be caused by the high plasma OXT levels during development from neonates 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 differentiating plasma OXT. Contribution by breastfeeding was an important exogenous source for regulating plasma OXT before weaning by the presence of OXT in milk and the dam's mammary glands. The dissimilarity of Cd38(-/-) infant behaviour to Oxt(-/-) or Oxtr(-/-) mice can be explained partly by this exogenous source of OXT. These results suggest that secretion of OXT into the brain in a CD38-dependent manner may play an important role in the development of social behavior, and mice with OXT signalling deficiency, including Cd38(-/-), Oxt(-/-) and Oxtr(-/-) mice are good animal models for developmental disorders, such as autism.

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Animals; Autistic Disorder; Disease Models, Animal; Mice; Mice, Knockout; Oxytocin

In recent years, studies have advocated neuropeptide systems as modulators for the behavioral states found in mood disorders such as depression and anxiety disorders. Neuropeptides have been tested in traditional animal models and screening procedures that have been validated by known antidepressants and anxiolytics. However, it has become clear that although these tests are very useful, neuropeptides have distinct behavioral effects and dose-dependent characteristics, and therefore, use of these tests with neuropeptides must be done with an understanding of their unique characteristics. This review will focus on the behavioral actions of neuropeptides and their synthetic analogs, particularly in studies utilizing various preclinical tests of depression and anxiety. Specifically, the following neuropeptide systems will be reviewed: corticotropin-releasing factor (CRF), urocortin (Ucn), teneurin C-terminal associated peptide (TCAP), neuropeptide Y (NPY), arginine vasopressin (AVP), oxytocin, the Tyr-MIF-1 family, cholecystokinin (CCK), galanin, and substance P. These neuropeptide systems each have a unique role in the regulation of stress-like behavior, and therefore provide intriguing therapeutic targets for mood disorder treatment.

Topics: Animals; Anxiety; Arginine Vasopressin; Behavior, Animal; Cholecystokinin; Corticotropin-Releasing Hormone; Depression; Disease Models, Animal; Galanin; Humans; MSH Release-Inhibiting Hormone; Neuropeptide Y; Neuropeptides; Neuropsychological Tests; Oxytocin; Social Behavior; Urocortins

Autism is a developmental disorder characterized by three core symptom domains: speech and communication abnormalities, social functioning impairments and repetitive behaviours and restricted interests. Oxytocin (OXT) is a nine-amino-acid peptide that is synthesized in the paraventricular and supraoptic nucleus of the hypothalamus and released into the bloodstream by axon terminals in the posterior pituitary where it plays an important role in facilitating uterine contractions during parturition and in milk let-down. In addition, OXT and the structurally similar peptide arginine vasopressin (AVP) are released within the brain where they play a key role in regulating affiliative behaviours, including sexual behaviour, mother-infant and adult-adult pair-bond formation and social memory/recognition. Finally, OXT has been implicated in repetitive behaviours and stress reactivity. Given that OXT is involved in the regulation of repetitive and affiliative behaviours, and that these are key features of autism, it is believed that OXT may play a role in autism and that OXT may be an effective treatment for these two core symptom domains. In this chapter we review evidence to date supporting a relationship between OXT and autism; we then discuss research looking at the functional role of OXT in autism, as well as a pilot study investigating the therapeutic efficacy of OXT in treating core autism symptom domains. Finally, we conclude with a discussion of directions for future research.

Topics: Affect; Animals; Autistic Disorder; Cognition; Communication; Cumulative Trauma Disorders; Disease Models, Animal; Female; Humans; Mother-Child Relations; Obsessive-Compulsive Disorder; Oxytocin; Paraventricular Hypothalamic Nucleus; Parturition; Pregnancy; Social Behavior; Speech Disorders; Supraoptic Nucleus; Uterine Contraction

Selective serotonin reuptake inhibitors (SSRIs) differ in the severity of induced ejaculation delay. Various studies indicate that oxytocin is involved in sexual behavior.. To review and evaluate the involvement of oxytocin in SSRI-induced ejaculation delay.. Oxytocine release, 5-hydroxytryptamine (5-HT) neurotransmission, and desensitization of 5-HT(1A) receptors.. A review and critical analysis of animal studies investigating the interaction of serotonergic and oxytocinergic neurotransmission in relation to the ejaculation process.. Although acute treatment with the SSRIs fluoxetine and paroxetine immediately causes increased serotonin levels, delayed ejaculation does not occur. The increased serotonin levels induce oxytocin release via activation of 5-HT(1A) receptors, and this might compensate for the inhibitory actions of serotonin on sexual behavior. Chronic treatment with fluoxetine and paroxetine desensitizes 5-HT(1A) receptors on oxytocin neurons, and that might in part determine the onset of delayed ejaculation. Desensitization of 5-HT(1A) receptors is less strong following chronic treatment with the SSRIs fluvoxamine or citalopram, which may attenuate the degree of delayed ejaculation.. Preliminary data suggest that the severity of chronic SSRI treatment-induced delayed ejaculation and the differences between the various SSRIs in inducing ejaculation delay is related to gradual desensitization of 5-HT(1A) receptors on oxytocin neurons.

Topics: Animals; Disease Models, Animal; Drug Administration Schedule; Ejaculation; Erectile Dysfunction; Male; Oxytocin; Rats; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Sexual Behavior, Animal

A thorough presentation of the influence of thyroliberin (TRH) on vasopressin and oxytocin release from the hypothalamo-neurohypophysial system is presented. Thyroliberin affects in different ways both neurohormone secretion in females during lactation according to the water-electrolyte metabolism in the course of the circadian rhythm of vasopressin and oxytocin release as well as during in vitro incubation of isolated neurointermediate lobe or hypothalamo-neurohypohysial explants. The results showed that: TRH acts as a stimulator of oxytocin release into the blood by equilibrated water-electrolyte metabolism, TRH acts in the central nervous system as an inhibitory neuromodulator of vasopressin and oxytocin release from the hypothalamo-neurohypophysial system under in vitro conditions, by osmotic stimulation, as well as in females during lactation, TRH inhibits AVP release in acute bleeding-provoked hypovolemia and alters the circadian rhythm of vasopressin and oxytocin release. It is assumed that this neuropeptide can interact with the mechanisms engaged in vasopressin and oxytocin release and can disturb these mechanisms, especially under conditions of augmented demand of the organism for these neurohormones.

Topics: Animals; Dehydration; Disease Models, Animal; Dogs; Female; Humans; Hypothalamo-Hypophyseal System; Lactation; Male; Oxytocin; Pituitary-Adrenal System; Pregnancy; Rats; Thyrotropin-Releasing Hormone; Thyroxine; Vasopressins; Water; Water Deprivation

Topics: Amygdala; Animals; Arginine Vasopressin; Arvicolinae; Brain Chemistry; Disease Models, Animal; Female; Genes, fos; Humans; Male; Mice; Mice, Knockout; Mice, Transgenic; Neuropeptides; Olfactory Pathways; Oxytocin; Pair Bond; Prosopagnosia; Receptors, Vasopressin; Recognition, Psychology; Social Behavior

This article documents and quantitatively assesses the capacity of estrogen, phytoestrogens, and antiestrogens to affect biphasic dose-response relationships in animal/human models and across a broad range of cell types, affecting multiple endpoints. The range of endpoints displaying such biphasic dose responses includes plasminogen activation, oxytocin secretion, angiogenesis, cell proliferation, bone growth, monocyte chemotaxis, secretion of various cytokines, and other effects. The quantitative features of the dose response relationships revealed that the magnitude of the stimulatory responses was typically less than twofold, whereas the stimulatory responses were markedly variable ranging from about 5- to 10(6)-fold. Mechanistic explanations of the biphasic responses are addressed.

Topics: Animals; Bone Development; Cell Division; Chemotaxis; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Estrogen Receptor Modulators; Estrogens; Estrogens, Non-Steroidal; Homeostasis; Humans; Isoflavones; Monocytes; Neovascularization, Physiologic; Oxytocin; Phytoestrogens; Plant Preparations; Plasminogen Activators

1. Studies of the regulation of neurosecretory cell gene expression suffer from the lack of suitable cell lines. Two approaches have been used to overcome this deficit: transfection of neuropeptide genes into heterologous cell lines and generation of transgenic animals. 2. Studies with heterologous cell lines have revealed the potential involvement of nuclear hormone receptors, POU proteins, and fos/jun/ATF family members in the regulation of the vasopressin and oxytocin genes. Although limited in their scope, these studies have contributed greatly to the dissection of basic properties of elements in the vasopressin and oxytocin gene promoters. 3. Transgenic mice, and more recently rats, have been used to elucidate genomic regions governing cell specificity and physiological regulation of neurosecretory gene expression. The genes encoding the neuropeptides vasopressin and oxytocin have been used in many transgenic studies, due to the well-defined expression patterns and physiology of the endogenous neuropeptides. Cell-specific and physiologically regulated expression of these transgenes has been achieved, demonstrating the action of putative repressor elements and regulation of the expression of one gene by sequences present in the other gene. 4. Appropriate expression and translation of transgenes have resulted in the production of several useful systems. Expression of oncogene sequences in gonadotropin-releasing hormone neurons has allowed the development of cell lines from the resulting tumors, overproduction of corticotropin-releasing factor has produced animal models of anxiety and obesity, and directed ectopic expression of growth hormone has generated a potentially useful rat model of dwarfism. These and other animal models of human disease will provide important avenues for the development of therapeutic strategies.

Topics: Animals; Animals, Genetically Modified; Cell Line; Disease Models, Animal; Gene Expression Regulation; Humans; Neurosecretory Systems; Oxytocin; Transcription, Genetic; Vasopressins

It has been demonstrated through the use of new techniques that the action of vasopressin on the kidneys is not limited to changing the water permeability of distal tubules and collecting ducts. However, it has yet to be established whether these additional actions, such as lowering Kf (possibly by contracting mesangial cells), or increasing postglomerular vascular resistance, are important factors in the control of GFR and renal blood flow. The use of animals with diabetes insipidus, particularly the Brattleboro homozygous (DI) rat, may help to circumvent a number of methodological problems and provide a useful model for assessing the role of vasopressin in the control of renal hemodynamics. Although that role may be exerted through a direct effect on the vascular tone, it may be an indirect effect in which the antidiuretic action of vasopressin alters fluid balance and elicits secondary changes in other vasoactive hormones. The complexity of this latter possibility suggests that other methodological problems (in the measurement and/or control of the related variables) may complicate the final resolution of this issue for some time to come.

Topics: Animals; Arginine Vasopressin; Diabetes Insipidus; Disease Models, Animal; Diuresis; Glomerular Filtration Rate; Hemodynamics; Kidney; Oxytocin; Rats; Rats, Brattleboro; Rats, Mutant Strains; Renal Circulation; Vascular Resistance; Vasopressins

This study aims to longitudinally assess the effect of oxytocin on bone and bone fat masses using micro-CT, in vivo magnetic resonance spectroscopy (MRS), and histopathological adipocyte quantification. Early in vivo oxytocin (OT) treatment to the osteoporosis (OP) rabbit model may reliably inhibit bone degeneration and reduce bone marrow fat accumulation by decreasing marrow adipocyte size and density.. This study aims to longitudinally assess the effect of early OT treatment on bone and bone fat masses in a rabbit OP model by comparing the results of MRS and micro-CT with histopathological findings.. Sixty 20-week-old female rabbits were randomly assigned into three groups. The control and OP groups were subjected to either sham surgery or bilateral ovariectomy (OVX). The OT group was subcutaneously injected with OT daily from the second week after OVX for 8 weeks. The left proximal femurs of the rabbits were evaluated through MRS, micro-CT, and histopathological examination at 0, 4, 8, 10, and 12 weeks after operation. Differences in fat fraction (FF) values, micro-CT parameters, and calculated pathological marrow adipocytes among three groups were analyzed.. The FF values of the OP group significantly increased (p = 0.019), but the tissue mineral density (TMD) decreased (p = 0.037) from eighth week compared with those of the control group. The FF values of the OT group significantly decreased (p = 0.044), but the TMD values increased (p = 0.042) from eighth week compared with those of the OP group. The adypocyte diameter of the OT group significantly decreased (p = 0.041) from eighth week and then adypocyte density did so too from tenth week, compared with those of the OP group at the same time point. No difference in adypocyte calculation was found between the OT and control groups until the 12th week after operation.. Early in vivo OT treatment slowed down bone deterioration and reduced bone marrow adiposity accumulation in a rabbit OP model, which is consistent with pathologic findings. OT treatment is a promising preventive OP therapy.

Topics: Adipocytes; Animals; Bone and Bones; Bone Marrow; Disease Models, Animal; Female; Longitudinal Studies; Magnetic Resonance Spectroscopy; Oxytocics; Oxytocin; Rabbits; X-Ray Microtomography

Topics: Acoustic Stimulation; Animals; Antidepressive Agents; Anxiety; Arginine Vasopressin; Cross-Sectional Studies; Disease Models, Animal; Double-Blind Method; Electroshock; Female; Humans; Male; Oxytocin; Predictive Value of Tests; Septal Nuclei

Topics: Animals; Autistic Disorder; Disease Models, Animal; Habenula; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Oxytocin; Septal Nuclei; Social Behavior

A neurodevelopmental disease, autism spectrum disorder (ASD) occurs in males three times more commonly than girls. Higher prenatal testosterone exposure may result in autistic-like behaviour in boys, according to earlier research. It is unclear how fetal testosterone affects the development of autism. In this study, we tested the hypothesis that prenatal testosterone exposure in an animal model may result in autistic behaviours by modifying serotonin, dopamine, IGF-1 and oxytocin levels.. Group 1 (control, n = 6) and Group 2 (testosterone undecanoate, n = 6) of female rats were randomly assigned. For 2-3 days during the oestrus cycle, female rats were housed with a reproductive male (three females/one male). On the 10th day of gestation, rats in Group 1 received 1 ml/kg% 0.9 NaCl saline, whereas rats in Group 2 received 250 mg/kg testosterone undecanoate. Until weaning on postnatal day 21 (P21), the mothers were permitted to care for their pups. On P21, 40 littermates-10 male and female for control and 10 male and female from mothers that exposed to testosterone-were arbitrarily split up and housed. On P50, these mature rats were tested for their behaviour. The rats were then sacrificed. The brain tissue was subjected to histological examinations as well as biochemical tests for homovanillic acid (HVA), 5-Hydroxyindoleacetic acid (5-HIAA), oxytocin and insulin-like growth factor-1 (IGF-1).. The groups differed significantly in the behavioural examinations (three-chamber social test, passive avoidance learning analysis, open field test), with the testosterone-exposed groups exhibiting autistic symptoms to a higher extent. When compared with the control groups, testosterone exposure caused significant histological changes in the hippocampus CA1 and CA3 areas, including gliosis and cell death of neurons. In the testosterone-exposed groups, HVA, 5-HIAA and IGF-1 tissue expressions in the brain elevated, whereas oxytocin levels reduced. These findings point to a potential connection between neurodevelopmental disorders like ASD and exposure to testosterone during gestation.. Overall, we revealed that prenatal testosterone exposure led to autistic traits by elevating serotonin, dopamine and IGF-1 levels while lowering oxytocin levels.

Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Disease Models, Animal; Dopamine; Female; Humans; Hydroxyindoleacetic Acid; Insulin-Like Growth Factor I; Male; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Serotonin; Testosterone

Early non-motor features including anxiety, depression and altered social cognition are present in Huntington's disease (HD). The underlying neurobiological mechanisms are not known. Oxytocin (OXT) is involved in the regulation of emotion, social cognition and metabolism, and our previous work showed that the OXT system is affected early in HD. The aim of the study was to investigate the potential causal relationship between the selective expression of mutant huntingtin (mHTT) in OXT neurons and the development of non-motor features and neuropathology.. To express mHTT only in OXT neurons, we used a novel flex-switch adeno-associated viral vector design to selectively express either mHTT or wild-type HTT in the paraventricular nucleus of the hypothalamus using OXT-Cre-recombinase mice. We also performed a mirror experiment to selectively delete mHTT in OXT neurons using the BACHD mouse model. Mice underwent a battery of behavioural tests to assess psychiatric and social behaviours 3 months post-injection or at 2 months of age, respectively. Post-mortem analyses were performed to assess the effects on the OXT system.. Our results show that selective expression of mHTT in OXT neurons was associated with the formation of mHTT inclusions and a 26% reduction of OXT-immunopositive neurons as well as increased anxiety-like behaviours compared with uninjected mice. However, selective deletion of mHTT from OXT neurons alone was not sufficient to alter the metabolic and psychiatric phenotype of the BACHD mice at this early time point.. Our results indicate that mHTT expression can exert cell-autonomous toxic effects on OXT neurons without affecting the non-motor phenotype at early time points in mice.

Topics: Animals; Disease Models, Animal; Huntingtin Protein; Huntington Disease; Mice; Mice, Transgenic; Neurons; Oxytocin; Phenotype

Obstructive sleep apnea is a prevalent and poorly treated cardiovascular disease that leads to hypertension and autonomic imbalance. Recent studies that restore cardiac parasympathetic tone using selective activation of hypothalamic oxytocin neurons have shown beneficial cardiovascular outcomes in animal models of cardiovascular disease. This study aimed to determine if chemogenetic activation of hypothalamic oxytocin neurons in animals with existing obstructive sleep apnea-induced hypertension would reverse or blunt the progression of autonomic and cardiovascular dysfunction.. Two groups of rats were exposed to chronic intermittent hypoxia (CIH), a model of obstructive sleep apnea, for 4 weeks to induce hypertension. During an additional 4 weeks of exposure to CIH, 1 group was treated with selective activation of hypothalamic oxytocin neurons while the other group was untreated.. Hypertensive animals exposed to CIH and treated with daily hypothalamic oxytocin neuron activation had lower blood pressure, faster heart rate recovery times after exercise, and improved indices of cardiac function compared with untreated hypertensive animals. Microarray analysis suggested that, compared with treated animals, untreated animals had gene expression profiles associated with cellular stress response activation, hypoxia-inducible factor stabilization, and myocardial extracellular matrix remodeling and fibrosis.. In animals already presenting with CIH-induced hypertension, chronic activation of hypothalamic oxytocin neurons blunted the progression of hypertension and conferred cardioprotection after an additional 4 weeks of CIH exposure. These results have significant clinical translation for the treatment of cardiovascular disease in patients with obstructive sleep apnea.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Heart Diseases; Hypertension; Hypoxia; Neurons; Oxytocin; Rats; Rats, Sprague-Dawley; Sleep Apnea, Obstructive

Traumatic brain injury (TBI) is a major risk factor to develop epilepsy and cognitive impairments. Neuropeptide oxytocin has been previously evidenced to produce antiepileptic effects. However, the involvement of central oxytocin in TBI-induced epileptic status and cognitive dysfunctions is not fully elucidated. In this study, we aim to investigate the role of oxytocin on a TBI model followed by seizure induction to clarify whether the epilepsy and cognitive deficits could be mitigated by oxytocin. TBI was established by weight drop and epileptic behaviors were induced by pentylenetetrazole (PTZ) injection in mice. Moreover, oxytocin was microinjected into the medial prefrontal cortex (mPFC) to observe the effects on the epilepsy and cognition. The blood-brain barrier (BBB) function and the neuroinflammation were measured by Evans Blue staining and enzyme-linked immunosorbent assays, respectively. Mice exposed to TBI demonstrate increased vulnerability to PTZ-mediated seizures and cognitive disturbances with a decrease in peripheral and brain oxytocin levels. Additionally, TBI reduces oxytocin, disrupts the BBB permeability and triggers neuroinflammation in mPFC in PTZ-treated mice. Intra-mPFC oxytocin simultaneously mitigates epilepsy and cognitive impairments. Finally, oxytocin restores BBB integrity and reduces mPFC inflammation in PTZ-treated TBI mice. These findings showed that intra-mPFC oxytocin suppressed the seizure vulnerability and cognitive deficits in TBI mice. The normalization of BBB integrity and inhibition of neuroinflammation may be involved in the antiepileptic and cognition-improved effects of oxytocin, suggesting that targeting inflammatory procedure in mPFC may decrease the risk to develop epilepsy and cognitive impairments in individuals previously experienced TBI.

Topics: Animals; Anticonvulsants; Brain Injuries, Traumatic; Cognitive Dysfunction; Disease Models, Animal; Epilepsy; Mice; Neuroinflammatory Diseases; Oxytocin; Pentylenetetrazole; Prefrontal Cortex; Seizures

Increasing evidence shows that higher physical activity such as running and swimming exercises is associated with decreased depression-related symptoms. However, underlying mechanisms are not fully understood. This study aimed to investigate whether oxytocinergic system can mediate the antidepressant effect of swimming exercises in mice. First, male NMRI mice were subjected to swimming training for eight weeks, then animals intraperitoneally received oxytocin antagonist (L-368899) 1 h before behavioral tests. We assessed anhedonia and social behavior and behavioral despair using the sucrose preference test, social interaction test, and tail suspension test. Oxytocin levels in the brain and serum were also measured. The results showed that swimming training decreased anhedonia and behavioral despair, whereas it increased social behavior and oxytocin levels in male mice. On the other hand, a subthreshold dose of oxytocin antagonist treatment in exercised mice prevented the antidepressant effect of swimming exercise via increased anhedonia and behavioral despair and decreased social behavior compared to the swimming training group. However, the blockade of oxytocin receptors did not affect oxytocin levels in exercised mice. Overall, these findings suggest that oxytocinergic system can play a role in mediating the antidepressant-like effect of swimming training in mice.

Topics: Anhedonia; Animals; Antidepressive Agents; Depression; Disease Models, Animal; Male; Mice; Motor Activity; Oxytocin; Swimming

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

Topics: Animals; Brain-Gut Axis; Depression; Disease Models, Animal; Female; Hippocampus; Ketamine; Mice; Oxidative Stress; Oxytocin; Receptors, Oxytocin; Stress, Psychological

Current treatment options for Alzheimer's disease (AD) are limited, inefficient, and often have serious side effects. Oxytocin is a neuropeptide implicated in a variety of central processes, such as social and reproductive behaviors. Among others, it has garnered attention in various domains of psychiatric research, while its role in the development and course of neurodegenerative disorders like AD is rather unknown.. This study aimed to investigate the role of exogenous oxytocin administration on memory, specifically in view of AD, as a potential novel treatment option.. We describe a novel treatment approach by using a relatively low dose of long-term intranasal oxytocin treatment, to restore memory deficits in female APPswePS1dE9 mice.. Female APPswePS1dE9 mice treated with oxytocin showed increased spatial memory performance in the object location task and improved working memory in the Y-Maze, while indicating decreased sociability.. These results indicate that oxytocin is able to reverse acquired cognitive deficits in female APPswePS1dE9 mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Female; Maze Learning; Memory Disorders; Memory, Short-Term; Mice; Mice, Transgenic; Oxytocin; Presenilin-1

Rett syndrome (RTT) is characterized by dysfunction in neuronal excitation/inhibition (E/I) balance, potentially impacting seizure susceptibility via deficits in K+/Cl- cotransporter 2 (KCC2) function. Mice lacking the Methyl-CpG binding protein 2 (MeCP2) recapitulate many symptoms of RTT, and recombinant human insulin-like growth factor-1 (rhIGF-1) restores KCC2 expression and E/I balance in MeCP2 KO mice. However, clinical trial outcomes of rhIGF-1 in RTT have been variable, and increasing its therapeutic efficacy is highly desirable. To this end, the neuropeptide oxytocin (OXT) is promising, as it also critically modulates KCC2 function during early postnatal development. We measured basal KCC2 expression levels in MeCP2 KO mice and identified 3 key frontal brain regions showing KCC2 alterations in young adult mice, but not in postnatal P10 animals. We hypothesized that deficits in an IGF-1/OXT signaling crosstalk modulating KCC2 may occur in RTT during postnatal development. Consistently, we detected alterations of IGF-1 receptor and OXT receptor levels in those brain areas. rhIGF-1 and OXT treatments in KO mice rescued KCC2 expression in a region-specific and complementary manner. These results suggest that region-selective combinatorial pharmacotherapeutic strategies could be most effective at normalizing E/I balance in key brain regions subtending the RTT pathophysiology.

Topics: Animals; Disease Models, Animal; Insulin-Like Growth Factor I; Methyl-CpG-Binding Protein 2; Mice; Oxytocin; Rett Syndrome; Symporters

Adverse early life experiences influence behavioral and physiological functions and increase vulnerability to neuropsychiatric disorders. Maternal separation (MS) is an established animal model that reproduces the features of chronic stress or adverse experiences during early life. Previous studies have been shown that MS may lead to impairments of social behaviors. Here, we investigated the effects of MS on mutual reward preferences in a double T-maze prosocial choice task. Since enriched environment (EE) and intranasal oxytocin (OT) administration have beneficial effects on cognition and social behaviors, in the present study we tested whether these treatments, alone or in combination, would affect prosocial behavior of rats which underwent MS during infancy. Rat pups underwent MS paradigm for 180 min/day from postnatal day (PND) 1-21. From PND 22-34, rats were exposed to an EE and/or received intranasal OT (2 μg/μl, 7 days). Hence, the 8 groups consisted of control (CTRL), MS, CTRL+EE, CTRL+OT and the saline groups. Assessment of prosocial choice behavior was started in adolescence. MS impaired prosocial choice behavior and reduced mutual reward preferences. Getting exposed to EE and intranasal OT administration could overcome MS-induced deficits and promoted mutual reward preferences of MS rats. Combination of short-term EE and OT strengthened prosocial behavior. Obtained results showed that EE and OT may be considered as profitable therapeutic approaches for promoting some aspects of social behavior.

Topics: Administration, Intranasal; Altruism; Animals; Behavior, Animal; Choice Behavior; Cognition; Disease Models, Animal; Female; Housing, Animal; Male; Maternal Deprivation; Oxytocin; Rats; Rats, Wistar; Reward; Social Behavior

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by specific social symptoms, restricted interests, stereotyped repetitive behaviors, and delayed language development. The 3q29 microdeletion (3q29del), a recurrent copy number variant, confers a high risk for ASD and schizophrenia, and serves as an important pathological model for investigating the molecular pathogenesis of a large number of neurodevelopmental and psychiatric conditions. Recently, mouse models carrying a deletion of the chromosomal region corresponding to the human 3q29 region (Df/+ mice) were generated and demonstrated neurodevelopmental and psychiatric conditions associated behavioral abnormalities, pointing to the relevance of Df/+ mice as a model for these conditions with high construct and face validity. Currently, the molecular pathogenesis of these behavioral phenotypes in Df/+ mice remains unclear. The oxytocin (OXT) system plays a central role in social behavior across species and has a potential role in ASD. In this study, to elucidate the molecular mechanisms behind impaired social behavior in Df/+ mice, we investigated the possible involvement of OXT signaling in impaired social behavior in Df/+ mice. We demonstrated that OXT administration restored the impaired social behavior in Df/+ mice. We also demonstrated that the number of OXT-positive cells in the paraventricular nucleus (PVN) was significantly lower in Df/+ mice than in wild-type (WT) littermates. Consistent with this, the level of OXT peptide in the cerebral cortex of Df/+ mice was lower than in WT littermates. Our study may provide important insights into the molecular pathophysiological basis of neurodevelopmental and psychiatric conditions, including ASD.

Topics: Animals; Autism Spectrum Disorder; Brain; Chromosome Deletion; Chromosomes, Human, Pair 3; Developmental Disabilities; Disease Models, Animal; Intellectual Disability; Mice; Oxytocin; Social Behavior

Although initially showing great potential, oxytocin treatment has encountered a translational hurdle in its promise of treating the social deficits of autism. Some debate surrounds the ability of oxytocin to successfully enter the brain, and therefore modify neuroanatomy. Moreover, given the heterogeneous nature of autism, treatment will only amerliorate symptoms in a subset of patients. Therefore, to determine whether oxytocin changes brain circuitry, and whether it does so variably, depending on genotype, we implemented a large randomized, blinded, placebo-controlled, preclinical study on chronic intranasal oxytocin treatment in three different mouse models related to autism with a focus on using neuroanatomical phenotypes to assess and subset treatment response. Intranasal oxytocin (0.6IU) was administered daily, for 28 days, starting at 5 weeks of age to the 16p11.2 deletion, Shank3 (exon 4-9) knockout, and Fmr1 knockout mouse models. Given the sensitivity of structural magnetic resonance imaging (MRI) to the neurological effects of interventions like drugs, along with many other advantages, the mice underwent in vivo longitudinal and high-resolution ex vivo imaging with MRI. The scans included three in vivo T1weighted, 90 um isotropic resolution scans and a T2-weighted, 3D fast spin echo with 40um isotropic resolution ex vivo scan to assess the changes in neuroanatomy using established automated image registration and deformation based morphometry approaches in response to oxytocin treatment. The behavior of the mice was assessed in multiple domains, including social behaviours and repetitive behaviours, among others. Treatment effect on the neuroanatomy did not reach significance, although the pattern of trending effects was promising. No significant effect of treatment was found on social behavior in any of the strains, although a significant effect of treatment was found in the Fmr1 mouse, with treatment normalizing a grooming deficit. No other treatment effect on behavior was observed that survived multiple comparisons correction. Overall, chronic treatment with oxytocin had limited effects on the three mouse models related to autism, and no promising pattern of response susceptibility emerged.

Topics: Administration, Intranasal; Animals; Autism Spectrum Disorder; Autistic Disorder; Disease Models, Animal; Fragile X Mental Retardation Protein; Humans; Mice; Microfilament Proteins; Nerve Tissue Proteins; Neuroanatomy; Oxytocin; Random Allocation; Social Behavior

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Inflammation; Mice; Mice, Transgenic; Nanogels; Oxytocin

Oxytocin is a neuropeptide hormone that plays an important role in social bonding and behavior. Recent studies indicate that oxytocin could be involved in the regulation of neurological disorders. However, its role in modulating cognition in Alzheimer's disease (AD) has never been explored. Hence, the present study aims to investigate the potential of chronic intranasal oxytocin in halting memory impairment & AD pathology in aluminum chloride-induced AD in female rats. Morris water maze was used to assess cognitive dysfunction in two-time points throughout the treatment period. In addition, neuroprotective effects of oxytocin were examined by assessing hippocampal acetylcholinesterase activity, β-amyloid 1-42 protein, and Tau levels. In addition, ERK1/2, GSK3β, and caspase-3 levels were assessed as chief neurobiochemical mediators in AD. Hippocampi histopathological changes were also evaluated. These findings were compared to the standard drug galantamine alone and combined with oxytocin. Results showed that oxytocin restored cognitive functions and improved animals' behavior in the Morris test. This was accompanied by a significant decline in acetylcholinesterase activity, 1-42 β-amyloid and Tau proteins levels. Hippocampal ERK1/2 and GSK3β were also reduced, exceeding galantamine effects, thus attenuating AD pathological hallmarks formation. Determination of caspase-3 revealed low cytoplasmic positivity, indicating the ceasing of neuronal death. Histopathological examination confirmed these findings, showing restored hippocampal cells structure. Combined galantamine and oxytocin treatment showed even better biochemical and histopathological profiles. It can be thus concluded that oxytocin possesses promising neuroprotective potential in AD mediated via restoring cognition and suppressing β-amyloid, Tau accumulation, and neuronal death.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Caspase 3; Cognitive Dysfunction; Disease Models, Animal; Female; Galantamine; Glycogen Synthase Kinase 3 beta; MAP Kinase Signaling System; Oxytocin; Rats; tau Proteins

Primary dysmenorrhea is one of the most common reasons for gynecologic visits, but due to the lack of suitable animal models, the pathologic mechanisms and related drug development are limited. Herein, we establish a new mouse model which can mimic the periodic occurrence of primary dysmenorrhea to solve this problem. Non-pregnant female mice were pretreated with estradiol benzoate for 3 consecutive days. After that, mice were injected with oxytocin to simulate menstrual pain on the 4th, 8th, 12th, and 16th days (four estrus cycles). Assessment of the cumulative writhing score, uterine tissue morphology, and uterine artery blood flow and biochemical analysis were performed at each time point. Oxytocin injection induced an equally severe writhing reaction and increased PGF

Topics: Animals; Cyclooxygenase 2; Disease Models, Animal; Dysmenorrhea; Female; Humans; Mice; Oxytocin; Uterus

Pentylenetetrazole (PTZ)-induced kindling is an animal model for studying human temporal lobe epilepsy (TLE), which is characterized by alterations of hippocampal neurons and memory. Although the intranasal (IN) administration of oxytocin (OT) has limited efficiency, nanoparticles (NPs) are a promising candidate to deliver OT to the brain. However, there are very limited data on epilepsy research about oxytocin-loaded nanoparticles (NP-OTs). The aim of this study is to investigate the effects of IN administration of chronic NP-OTs on the hippocampus of PTZ-induced male epileptic rats in terms of seizure severity, memory, neurogenesis, and neuronal damage. Saline/OT/NP-OTs were administrated to both control (Ctrl) and PTZ groups intranasally. Consequently, saline and PTZ were injected, respectively, 25 times every 48 h. Then, seizure severity (score and latency) was calculated for the PTZ groups. A spatial working memory evaluation test (SWMET) was performed after the last injection. Hippocampus histopathology, neurogenesis, and apoptosis were demonstrated. Serum total antioxidant status (TAS) and total oxidant status (TOS) levels and the oxidative stress index (OSI) were measured. We showed that OTs and NP-OTs prevented the kindling development and had positive effects on seizure severity. SWMET-related behaviors were also recovered in the PTZ + NP-OT group. A significant increase of neurogenesis and decrease of apoptosis in the hippocampus of the PTZ + NP-OT group were observed, while OTs and NP-OTs had protective effects against PTZ-induced damage to hippocampal neurons. Our results indicate that the chronic administration of NP-OTs may have positive effects on hippocampal damage via increasing neurogenesis and decreasing apoptosis and seizure severity.

Topics: Animals; Disease Models, Animal; Epilepsy; Hippocampus; Male; Nanoparticles; Neurogenesis; Neurons; Oxytocin; Pentylenetetrazole; Rats; Seizures

Chronic stress and glucocorticoid exposure are risk factors for depression. Oxytocin (OT) has been shown to have antistress and antidepressant-like effects in male rodents. However, depression is twice as common in women than in men, and it remains unclear whether OT exerts antidepressant-like effects in women with depression. Therefore, in this study, we investigated the therapeutic effect of chronic OT administration in a female mouse model of dexamethasone (DEX)-induced depression.. Female C57BL/6J mice were administered saline (vehicle, s.c.), DEX (s.c.), or OT (i.p.) + DEX (s.c.) daily for 8 weeks, and then assessed for anxiety- and depression-like behaviors. We also examined the hippocampal levels of phosphorylated cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF), which are important mediators of the response to antidepressants.. Simultaneous OT treatment blocked the adverse effects of DEX on emotional behaviors. Furthermore, it upregulated p-CREB and BDNF in the hippocampus.. OT may exert antidepressant-like effects by activating hippocampal CREB-BDNF signaling in a female mouse model of depression.

Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Cyclic AMP Response Element-Binding Protein; Depression; Dexamethasone; Disease Models, Animal; Female; Glucocorticoids; Hippocampus; Humans; Male; Mice; Mice, Inbred C57BL; Oxytocin

The effects of Piper malacophyllum (C. Pesl) C. DC extracts and its isolated compounds were analysed in a mouse model of primary dysmenorrhoea (PD). Female Swiss mice (6-8 weeks old) on proestrus were intraperitoneally treated with estradiol benzoate for 3 days, to induce PD. Twenty-four hours later, animals were treated 24 h later with vehicle, plant extract, gibbilimbol B, 4,6-dimethoxy-5-E-phenylbutenolide, mixture of 4,6-dimethoxy-5-E-phenylbutenolide and 4,6-dimethoxy-5-Z-phenylbutenolide, or ibuprofen. One hour later, oxytocin was injected and the numbers of abdominal writhing were counted. Then, mice were euthanized and uteri were collected for morphometrical and histological analyses. The effects of P. malacophyllum in inflammation were investigated in mouse peritoneal neutrophils culture stimulated with LPS or fMLP (chemotaxis and mediator release). Finally, uterus contractile and relaxing responses were assessed. Similar to ibuprofen, P. malacophyllum extract and isolated compounds reduced abdominal writhing in mice with PD. Histology indicated a marked neutrophil and mast cell infiltrate in the uterus of PD animals which was attenuated by the extract. The compounds and the extract reduced neutrophil chemotaxis and inflammatory mediator release by these cells. Reduced TNF levels were also observed in uteri of PD mice treated with P. malacophyllum. The extract did not affect spontaneous uterine contractions nor those induced by carbachol or KCl. However, it caused relaxation of oxytocin-induced uterine contraction, an effect blunted by H1 receptor antagonist. Overall the results indicate that P. malacophyllum may represent interesting natural tools for reliving PD symptoms, reducing the triad of pain, inflammation and spasmodic uterus behaviour.

Topics: Animals; Disease Models, Animal; Dysmenorrhea; Female; Ibuprofen; Inflammation; Mast Cells; Mice; Neutrophils; Oxytocin; Piper; Plant Extracts

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by deficits in social behaviour, increased repetitive behaviour, anxiety and gastrointestinal symptoms. The aetiology of ASD is complex and involves an interplay of genetic and environmental factors. Emerging pre-clinical and clinical studies have documented a potential role for the gut microbiome in ASD, and consequently, the microbiota represents a potential target in the development of novel therapeutics for this neurodevelopmental disorder. In this study, we investigate the efficacy of the live biotherapeutic strain, Blautia stercoris MRx0006, in attenuating some of the behavioural deficits in the autism-relevant, genetic mouse model, BTBR T+ Itpr3tf/J (BTBR). We demonstrate that daily oral administration with MRx0006 attenuates social deficits while also decreasing repetitive and anxiety-like behaviour. MRx0006 administration increases the gene expression of oxytocin and its receptor in hypothalamic cells in vitro and increases the expression of hypothalamic arginine vasopressin and oxytocin mRNA in BTBR mice. Additionally at the microbiome level, we observed that MRx0006 administration decreases the abundance of Alistipes putredinis, and modulates the faecal microbial metabolite profile. This alteration in the metabolite profile possibly underlies the observed increase in expression of oxytocin, arginine vasopressin and its receptors, and the consequent improvements in behavioural outcomes. Taken together, these findings suggest that the live biotherapeutic MRx0006 may represent a viable and efficacious treatment option for the management of physiological and behavioural deficits associated with ASD.

Topics: Animals; Anxiety; Arginine Vasopressin; Autism Spectrum Disorder; Autistic Disorder; Clostridiales; Disease Models, Animal; Mice; Mice, Inbred Strains; Oxytocin; RNA, Messenger

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia, obesity, developmental delay and intellectual disability. Studies suggest dysfunctional signaling of the neuropeptide oxytocin as one of the key mechanisms in PWS, and administration of oxytocin via intranasal or systemic routes yielded promising results in both humans and mouse models. However, a detailed assessment of the oxytocin system in mouse models of PWS such as the Magel2-deficient Magel2

Topics: Animals; Astrocytes; Disease Models, Animal; Female; Hypothalamus; Male; Mice; Neuropeptides; Oxytocin; Prader-Willi Syndrome; Receptors, Oxytocin

The gut-microbiota-brain axis plays an important role in stress-related disorders, and dysfunction of this complex bidirectional system is associated with Alzheimer's disease. This study aimed to assess the idea that whether gut microbiota depletion from early adolescence can alter anxiety- and depression-related behaviours in adult mice with or without Alzheimer-like disease. Male C57BL/6 mice were treated with an antibiotic cocktail from weaning to adulthood. Adult mice received an intracerebroventricular injection of amyloid-beta (Aβ)1-42, and were subjected to anxiety and depression tests. We measured, brain malondialdehyde and glutathione following anxiety tests, and assessed brain oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis function by measuring adrenocorticotrophic hormone (ACTH) and corticosterone following depression tests. Healthy antibiotic-treated mice displayed significant decreases in anxiety-like behaviours, whereas they did not show any alterations in depression-like behaviours and HPA axis function. Antibiotic treatment from early adolescence prevented the development of anxiety- and depression-related behaviours, oxidative stress and HPA axis dysregulation in Alzheimer-induced mice. Antibiotic treatment increased oxytocin in the brain of healthy but not Alzheimer-induced mice. Taken together, these findings suggest that gut microbiota depletion following antibiotic treatment from early adolescence might profoundly affect anxiety- and depression-related behaviours, and HPA axis function in adult mice with Alzheimer-like disease.

Topics: Adrenocorticotropic Hormone; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Bacterial Agents; Anxiety; Behavior, Animal; Brain-Gut Axis; Depression; Disease Models, Animal; Dysbiosis; Gastrointestinal Microbiome; Hypothalamo-Hypophyseal System; Male; Mice, Inbred C57BL; Oxidative Stress; Oxytocin; Peptide Fragments

Hyponatremia due to elevated arginine vasopressin (AVP) secretion increases mortality in liver failure patients. No previous studies have addressed sex differences in hyponatremia in liver failure animal models.. This study addressed this gap in our understanding of the potential sex differences in hyponatremia associated with increased AVP secretion.. This study tested the role of sex in the development of hyponatremia using adult male, female, and ovariectomized (OVX) female bile duct-ligated (BDL) rats.. All BDL rats had significantly increased liver to body weight ratios compared to sham controls. Male BDL rats had hyponatremia with significant increases in plasma copeptin and FosB expression in supraoptic AVP neurons compared to male shams (all p < 0.05; 5-7). Female BDL rats did not become hyponatremic or demonstrate increased supraoptic AVP neuron activation and copeptin secretion compared to female shams. Plasma oxytocin was significantly higher in female BDL rats compared to female sham (p < 0.05; 6-10). This increase was not observed in male BDL rats. Ovariectomy significantly decreased plasma estradiol in sham rats compared to intact female sham (p < 0.05; 6-10). However, circulating estradiol was significantly elevated in OVX BDL rats compared to the OVX and female shams (p < 0.05; 6-10). Adrenal estradiol, testosterone, and dehydroepiandrosterone (DHEA) were measured to identify a possible source of circulating estradiol in OVX BDL rats. The OVX BDL rats had significantly increased adrenal estradiol along with significantly decreased adrenal testosterone and DHEA compared to OVX shams (all p < 0.05; 6-7). Plasma osmolality, hematocrit, copeptin, and AVP neuron activation were not significantly different between OVX BDL and OVX shams. Plasma oxytocin was significantly higher in OVX BDL rats compared to OVX sham.. Our results show that unlike male BDL rats, female and OVX BDL rats did not develop hyponatremia, supraoptic AVP neuron activation, or increased copeptin secretion compared to female shams. Adrenal estradiol might have compensated for the lack of ovarian estrogens in OVX BDL rats.

Topics: Animals; Arginine Vasopressin; Bile Ducts; Dehydroepiandrosterone; Disease Models, Animal; Estradiol; Female; Glycopeptides; Hyponatremia; Ligation; Male; Ovariectomy; Oxytocin; Rats; Rats, Sprague-Dawley; Sex Characteristics; Sex Factors; Supraoptic Nucleus; Testosterone

Previous studies have shown that, oxytocin has anticonvulsant and neuroprotective effects. One of the most important complications of Hypercapnic-hypoxia is drug resistance epilepsy. Effects of chronic intraperitoneal oxytocin treatment on gliosis, neuroinflammation and seizure activity was investigated in a model in which rats were exposed to hypoxia on postnatal day 1 and later challenged to the seizure-inducing pentylenetetrazol Forty pups were included in the study on their first day of birth. 16 pups were exposed to 100% CO

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Brain; Disease Models, Animal; GABAergic Neurons; Gliosis; Hippocampus; Humans; Hypoxia; Inflammation; Neuroprotective Agents; Oxytocin; Rats; Respiratory Distress Syndrome, Newborn; Respiratory Insufficiency

Ovarian hyperstimulation syndrome (OHSS) is a life-threatening complication of ovarian stimulation in reproductive medicine. Here, we aimed to investigate the role of oxytocin (OT) and cabergoline in the prevention and alleviation of the OHSS in an animal model.. Thirty-five female immature Wistar rats were randomly assigned to five groups. The control group (n = 7) received saline only for five consecutive days. Remaining twenty-eight rats received 10 IU of pregnant mare serum gonadotropin (PMSG) followed by 30 IU of human chorionic gonadotropin (hCG) to induce OHSS. Group 2 (n = 7) was managed with no additional intervention after the induction of OHSS. Group 3 (n = 7) received 100 μg/kg cabergoline 2 h before the PMSG injection for four consecutive days and 2 h before the hCG injection on the fifth day. Group 4 (n = 7) and group 5 (n = 7) received 80 μg/kg and 160 μg/kg OT after induction of OHSS, respectively. Oxytocin was administered 2 h before the PMSG injection for four consecutive days and 2 h before the hCG injection on the fifth day. Body and ovary weight, vascular permeability (VP), VEGF expression in the ovaries, and levels of VEGF in the peritoneal fluids were examined in all animals.. Cabergoline and OT reduced body weight, ovary weight, and VP compared to that of the OHSS group (p < 0.05). VEGF expressions in ovaries and peritoneal VEGF levels were decreased in cabergoline and OT groups compared to that of the OHSS groups (p < 0.001 for cabergoline and OT-80 μg/kg; p < 0.00001 for OT-160 μg/kg). However, there was no statistically significant difference in these parameters between the OT and cabergoline groups.. Both OT and cabergoline were active in the alleviation of OHSS through suppression of VEGF and VP. Overall, we conclude that OT is effective for downregulation for VEGF and improvement in vascular permeability in OHSS.

Topics: Animals; Cabergoline; Disease Models, Animal; Female; Ovarian Hyperstimulation Syndrome; Oxytocics; Oxytocin; Rats; Rats, Sprague-Dawley; Rats, Wistar; Vascular Endothelial Growth Factor A

Akebiae Fructus, a Tujia minority folk medicine and a well-known traditional Chinese medicine for soothing the liver, regulating Qi, promoting blood circulation and relieving pain, is widely used in the treatment of primary dysmenorrhea. However, little is known about its underlying mechanism.. To explore the effect of Akebiae Fructus on primary dysmenorrhea model induced by estradiol benzoate and oxytocin, and to provide better understanding of the mechanism of Akebiae Fructus for primary dysmenorrhea treatment.. The primary dysmenorrhea mouse model was used in this study. Except for the control group and the normal administration group, the mice of other groups were subcutaneously injected with estradiol benzoate (10 mg/kg/d) for 10 consecutive days. From the 5th day of the ten-day model period, the positive control groups were given 0.075 g/kg ibuprofen and 7.5 g/kg Leonurus granule, the drug groups were given 0.2 g/kg, 0.4 g/kg, 0.8 g/kg Akebiae Fructus extract, the normal administration group was given 0.8 g/kg Akebiae Fructus extract, and the same volume saline was given in the control group. On the tenth day, oxytocin (10 U/kg) was peritoneally injected after estradiol benzoate injected 1 h. After the oxytocin injection, writhing behavior was observed for 30 min. Then the uterine tissue was collected to measure the level of PGF. Akebiae Fructus inhibited the writhing, decreased the PGF. Akebiae Fructus could effectively alleviate the symptoms of primary dysmenorrhea, regulate metabolic disorders, and control the related gene expression in primary dysmenorrhea. The study may provide clues for further study of Akebiae Fructus treatment on primary dysmenorrhea.

Topics: Animals; Benzoates; Biomarkers; Dinoprost; Dinoprostone; Disease Models, Animal; Drugs, Chinese Herbal; Dysmenorrhea; Female; Gene Expression Regulation; Inflammation; Medicine, Chinese Traditional; Metabolic Networks and Pathways; Metabolome; Mice, Inbred ICR; Oxytocin; Pain; Ranunculales; Transcriptome; Uterine Contraction; Uterus

Sepsis promotes an inflammatory state in the central nervous system (CNS) that may cause autonomic, cognitive, and endocrine changes. Microglia, a resident immune cell of the CNS, is activated in several brain regions during sepsis, suggesting its participation in the central alterations observed in this disease. In this study, we aimed to investigate the role of microglial activation in the neuroendocrine system functions during systemic inflammation. Wistar rats received an intracerebroventricular injection of the microglial activation inhibitor minocycline (100 μg/animal), shortly before sepsis induction by cecal ligation and puncture. At 6 and 24 h after surgery, hormonal parameters, central and peripheral inflammation, and markers of apoptosis and synaptic function in the hypothalamus were analyzed. The administration of minocycline decreased the production of inflammatory mediators and the expression of cell death markers, especially in the late phase of sepsis (24 h). With respect to the endocrine parameters, microglial inhibition caused a decrease in oxytocin and an increase in corticosterone and vasopressin plasma levels in the early phase of sepsis (6 h), while in the late phase, we observed decreased oxytocin and increased ACTH and corticosterone levels compared to septic animals that did not receive minocycline. Prolactin levels were not affected by minocycline administration. The results indicate that microglial activation differentially modulates the secretion of several hormones and that this process is associated with inflammatory mediators produced both centrally and peripherally.

Topics: Animals; Brain; Corticosterone; Disease Models, Animal; Male; Microglia; Minocycline; Neurons; Neurosecretory Systems; Oxytocin; Rats; Rats, Wistar; Sepsis; Vasopressins

Previous studies indicate that oxytocin (OT) administration reduces body weight in high-fat diet (HFD)-induced obese (DIO) rodents through both reductions in food intake and increases in energy expenditure. We recently demonstrated that chronic hindbrain [fourth ventricular (4V)] infusions of OT evoke weight loss in DIO rats. Based on these findings, we hypothesized that chronic 4V OT would elicit weight loss in DIO mice. We assessed the effects of 4V infusions of OT (16 nmol/day) or vehicle over 28 days on body weight, food intake, and body composition. OT reduced body weight by approximately 4.5% ± 1.4% in DIO mice relative to OT pretreatment body weight (

Topics: Adipocytes, Brown; Adipocytes, White; Adiposity; Animals; Anti-Obesity Agents; Diet, High-Fat; Disease Models, Animal; Eating; Energy Intake; Infusions, Intraventricular; Leptin; Male; Mice, Inbred C57BL; Obesity; Oxytocin; Rhombencephalon; Thermogenesis; Uncoupling Protein 1; Weight Loss

Environmental Enrichment (EE) has been suggested as a possible therapeutic intervention for neurodevelopmental disorders such as autism. Although the benefits of this therapeutic method have been reported in some animal models and human studies, the unknown pathophysiology of autism as well as number of conflicting results, urge for further examination of the therapeutic potential of EE in autism. Therefore, the aim of this study was to examine the effects of environmental enrichment on autism-related behaviors which were induced in the maternal separation (MS) animal model.. Maternally separated (post-natal day (PND) 1-14, 3h/day) and control male rats were at weaning (PND21) age equally divided into rats housed in enriched environment and normal environment. At adolescence (PND42-50), the four groups were behaviorally tested for direct social interaction, sociability, repetitive behaviors, anxiety behavior, and locomotion. Following completion of the behavioral tests, the blood and brain tissue samples were harvested in order to assess plasma level of brain derived neurotrophic factor (BDNF) and structural plasticity of brain using ELISA and stereological methods respectively.. We found that environmental enrichment reduced repetitive behaviors but failed to improve the impaired sociability and anxiety behaviors which were induced by maternal separation. Indeed, EE exacerbated anxiety and social behaviors deficits in association with increased plasma BDNF level, larger volume of the hippocampus and infra-limbic region and higher number of neurons in the infra-limbic area (

Topics: Animals; Animals, Newborn; Anxiety; Autistic Disorder; Behavior, Animal; Biomarkers; Brain; Brain-Derived Neurotrophic Factor; Combined Modality Therapy; Disease Management; Disease Models, Animal; Male; Maternal Deprivation; Oxytocin; Rats; Social Behavior

Neonatal hypoxic-ischemic encephalopathy (NHIE) is one of the most prevalent causes of death during the perinatal period. The lack of exposure to oxytocin is associated with NHIE-mediated severe brain injury. However, the underlying mechanism is not fully understood. This study combined immunohistochemistry with electrophysiological recordings of hippocampal CA1 neurons to investigate the role of oxytocin in an in vitro model of hypoxic-ischemic (HI) injury (oxygen and glucose deprivation, OGD) in postnatal day 7-10 rats. Immunohistochemical analysis showed that oxytocin largely reduced the relative intensity of TOPRO-3 staining following OGD in the hippocampal CA1 region. Whole-cell patch-clamp recording revealed that the OGD-induced onset time of anoxic depolarization (AD) was significantly delayed by oxytocin. This protective effect of oxytocin was blocked by pretreatment with [d(CH2)51, Tyr (Me)2, Thr4, Orn8, des-Gly-NH29] vasotocin (dVOT, an oxytocin receptor antagonist) or bicuculline (a GABA

Topics: Animals; Animals, Newborn; CA1 Region, Hippocampal; Cell Death; Disease Models, Animal; Excitatory Postsynaptic Potentials; Hypoxia-Ischemia, Brain; Inhibitory Postsynaptic Potentials; Neurons; Neuroprotective Agents; Oxytocics; Oxytocin; Patch-Clamp Techniques; Rats; Receptors, GABA-A; Receptors, Oxytocin

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that is associated with immune dysfunction. Recent studies have indicated that the neurosecretory hormone oxytocin (OXT) has been proven to alleviate experimental colitis.. We investigated the role of OXT/OXT receptor (OXTR) signalling in dendritic cells (DCs) using mice with specific OXTR deletion in CD11c+ cells (OXTRflox/flox×CD11c-cre mice) and a dextran sulfate sodium (DSS)-induced colitis model.. The level of OXT was abnormal in the serum or colon tissue of DSS-induced colitis mice or the plasma of UC patients. Both bone marrow-derived DCs (BMDCs) and lamina propria DCs (LPDCs) express OXTR. Knocking out OXTR in DCs exacerbated DSS-induced acute and chronic colitis in mice. In contrast, the injection of OXT-pretreated DCs significantly ameliorated colitis. Mechanistically, OXT prevented DC maturation through the phosphatidylinositol 4,5-bisphosphate 3-kinase (Pi3K)/AKT pathway and promoted phagocytosis, adhesion and cytokine modulation in DCs. Furthermore, OXT pre-treated DCs prevent CD4+ T cells differentiation to T helper 1 (Th1) and Th17.. Our results suggest that OXT-induced tolerogenic DCs efficiently protect against experimental colitis via Pi3K/AKT pathway. Our work provides evidence that the nervous system participates in the immune regulation of colitis by modulating DCs. Our findings suggest that generating ex vivo DCs pretreated with OXT opens new therapeutic perspectives for the treatment of UC in humans.

Topics: Adult; Aged; Aged, 80 and over; Animals; Colitis; Colitis, Ulcerative; Dendritic Cells; Dextran Sulfate; Disease Models, Animal; Female; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Oxytocin; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Oxytocin; Signal Transduction

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZ

Topics: Administration, Intranasal; Animals; Autism Spectrum Disorder; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Humans; Mice; Mutation, Missense; Nerve Tissue Proteins; Neurons; Oxytocin; Point Mutation; Promoter Regions, Genetic; Protein Binding; Receptors, Oxytocin; Receptors, Vasopressin; Social Behavior; Transcription, Genetic; Transposases

Various molecular mechanisms are activated in neurons during ischemic stroke. Extracellular glutamate secretion into brain tissue causes neurotoxicity and brain damage. Excitatory amino acid transporter 3 (EAAT3) could remove the extracellular glutamate. Neuroprotective activity of oxytocin (OT) in ischemia of various tissues has been reported. This study investigates the neuroprotective effect of OT in an animal model of middle cerebral artery occlusion (MCAO) and the possible role of EAAT3. Transient MCAO was performed as a model of ischemic stroke in male rats and then OT was administrated intra-nasally. Infarct volume was measured by 2, 3, 5-triphenyl tetrazolium chloride staining. Nissl staining method was performed for the evaluation of neuronal cell morphology. Immunohistochemistry assay was performed to analyze the EAAT3 expression in the ischemic region. OT significantly reduced the infarct volume in the cerebral cortex and striatum after ischemia (

Topics: Animals; Brain Ischemia; Disease Models, Animal; Excitatory Amino Acid Transporter 3; Glutamates; Infarction, Middle Cerebral Artery; Ischemic Stroke; Male; Oxytocin; Rats; Stroke

Gestational stress can increase postpartum depression in women. To treat maternal depression, fluoxetine (FLX) is most commonly prescribed. While FLX may be effective for the mother, at high doses it may have adverse effects on the fetus. As environmental enrichment (EE) can reduce maternal stress effects, we hypothesized that a subthreshold dose of FLX increases the impact of EE to reduce anxiety and depression-like behavior in postpartum dams exposed to gestational stress. We evaluated this hypothesis in mice and to assess underlying mechanisms we additionally measured hypothalamic-pituitary-adrenal (HPA) axis function and brain levels of the hormone oxytocin, which are thought to be implicated in postpartum depression. Gestational stress increased anxiety- and depression-like behavior in postpartum dams. This was accompanied by an increase in HPA axis function and a decrease in whole-brain oxytocin levels in dams. A combination of FLX and EE remediated the behavioral, HPA axis and oxytocin changes induced by gestational stress. Central administration of an oxytocin receptor antagonist prevented the remediating effect of FLX + EE, indicating that brain oxytocin contributes to the effect of FLX + EE. These findings suggest that oxytocin is causally involved in FLX + EE mediated remediation of postpartum stress-related behaviors, and HPA axis function in postpartum dams.

Topics: Animals; Anxiety; Anxiety Disorders; Brain; Depression, Postpartum; Disease Models, Animal; Female; Fluoxetine; Hypothalamo-Hypophyseal System; Male; Maternal Behavior; Mice; Oxytocin; Pituitary-Adrenal System; Postpartum Period; Pregnancy; Receptors, Oxytocin; Stress, Psychological

Intranasal treatment with oxytocin showed beneficial effects in post-traumatic stress disorder and autism spectrum disorders; however, it was not investigated as much in depression. Keeping in mind the favorable effects of oxytocin on animal models of anxiety and depression, we postulated that synergy between prescribed first choice drugs, selective serotonin reuptake inhibitors (SSRIs) and oxytocin could improve the treatment outcome compared with SSRI monotherapy. Our previous in vitro genome-wide transcriptomic study on human lymphoblastoid cell lines exposed to paroxetine resulted in increase of integrin β3 (ITGB3) gene expression, and further, ITGB3/CHL1 expression ratio was hypothesized to influence the sensitivity to SSRIs. The aim of this report was to explore molecular mechanisms behind the antidepressant-like oxytocin effect, alone and in synergy with citalopram, on behavioral and molecular level in corticosterone treated rats, a paradigm used to model anxiety and depression in animals. Oxytocin treatment (1) ameliorated corticosterone-induced reduction of neurogenesis and number of parvalbumin-positive interneurons in the hippocampal CA1 region, (2) enhanced anxiolytic- and antidepressant-like effects of citalopram in the open field test, and (3) the SSRI/oxytocin synergy persisted in reversing the reduction of the Itgb3 gene expression and increased Itgb3/Chl1 ratio in the prefrontal cortices. These results support the existence of synergy between citalopram and oxytocin in reversing the molecular and behavioral changes induced by corticosterone treatment and point to possible molecular mechanisms behind antidepressant-like effect of oxytocin.

Topics: Animals; Antidepressive Agents; Anxiety; Cell Adhesion Molecules; Citalopram; Corticosterone; Depression; Disease Models, Animal; Drug Synergism; Integrin beta3; Interneurons; Male; Neurogenesis; Oxytocin; Prefrontal Cortex; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors

The Wistar audiogenic rat (WAR) strain is used as an animal model of epilepsy, which when submitted to acute acoustic stimulus presents tonic-clonic seizures, mainly dependent on brainstem (mesencephalic) structures. However, when WARs are exposed to chronic acoustic stimuli (audiogenic kindling-AK), they usually present tonic-clonic seizures, followed by limbic seizures, after recruitment of forebrain structures such as the cortex, hippocampus and amygdala. Although some studies have reported that hypothalamic-hypophysis function is also altered in WAR through modulating vasopressin (AVP) and oxytocin (OXT) secretion, the role of these neuropeptides in epilepsy still is controversial. We analyzed the impact of AK and consequent activation of mesencephalic neurocircuits and the recruitment of forebrain limbic (LiR) sites on the hypothalamic-neurohypophysial system and expression of Avpr1a and Oxtr in these structures. At the end of the AK protocol, nine out of 18 WARs presented LiR. Increases in both plasma vasopressin and oxytocin levels were observed in WAR when compared to Wistar rats. These results were correlated with an increase in the expressions of heteronuclear (hn) and messenger (m) RNA for Oxt in the paraventricular nucleus (PVN) in WARs submitted to AK that presented LiR. In the paraventricular nucleus, the hnAvp and mAvp expressions increased in WARs with and without LiR, respectively. There were no significant differences in Avp and Oxt expression in supraoptic nuclei (SON). Also, there was a reduction in the Avpr1a expression in the central nucleus of the amygdala and frontal lobe in the WAR strain. In the inferior colliculus, Avpr1a expression was lower in WARs after AK, especially those without LiR. Our results indicate that both AK and LiR in WARs lead to changes in the hypothalamic-neurohypophysial system and its receptors, providing a new molecular basis to better understaind epilepsy.

Topics: Acoustic Stimulation; Animals; Disease Models, Animal; Epilepsy, Reflex; Gene Expression Regulation; Hippocampus; Hypothalamus; Kindling, Neurologic; Male; Neurosecretory Systems; Oxytocin; Pituitary Gland, Posterior; Rats; Rats, Wistar; Seizures; Vasopressins

Kamikihito (KKT) is a Kampo medicine that is prescribed in Japan for the treatment of anemia, insomnia and mental anxiety in Japan. However, its precise mechanism of action remains unclear.. This study aimed to evaluate the possible antistress effect of KKT in rats with acute stress and the contribution of oxytocin to the process.. Acute immobilization stress (AIS; for 90 min) was used to assess the effect of KKT on acute stress. Male Wistar rats were orally treated with KKT. Parameters of stress were evaluated, and concentrations of oxytocin in plasma and cerebrospinal fluid (CSF) were measured.. AIS-induced defecation and fecal weight were significantly decreased because of treatment with KKT. The plasma levels of stress-related hormones following AIS were investigated. The pre-administration of KKT significantly increased adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) levels following AIS. Conversely, there was no significant change in the plasma oxytocin level. Microdialysis and hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) were used to monitor the oxytocin secretion in CSF. Oxytocin level increased during AIS following the treatment of KKT. At 30 min after AIS, the level remained higher than before AIS. Furthermore, using an open field test, the locomotion (exploratory behavior) immediately after AIS was examined. The total traveled distance decreased after AIS; however, the decrease was significantly inhibited by the treatment of KKT. However, the effect of KKT was obstructed by the pre-administration of the oxytocin receptor antagonist.. These results suggest that KKT has antistress activity and increased oxytocin secretion may be a mechanism underlying this phenomenon.

Topics: Administration, Oral; Adrenocorticotropic Hormone; Animals; Behavior, Animal; Corticosterone; Defecation; Disease Models, Animal; Drugs, Chinese Herbal; Locomotion; Male; Medicine, Kampo; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats, Wistar; Restraint, Physical; Stress, Physiological

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by communication disability with no curative treatment. Maternal separation-induced ultrasonic vocalisation (USV) was widely used to assess communication disability between pups and dams. Particularly, USV calls in many genetically modified ASD model mice were altered. Previously, we demonstrated that mice pups exposed to valproic acid in utero (VPA pups) showed decreased number of USV calls on postnatal day 11 and were rescued by subcutaneous injection of oxytocin. However, the qualitative change of USV calls by oxytocin has not been evaluated in VPA pups. In the present study, we examined the duration of oxytocin effect and analysed the altered pattern of USV calls using VPA pups. The oxytocin administration increased the total number of USV calls and the effect persisted up to 120 min in VPA pups. The pattern analysis revealed that the increase in the number of complex calls also persisted up to 120 min. These results suggested that oxytocin had a prolonged effect on USV calls, mainly on complex calls, in VPA pup, showing that oxytocin could recover their social modality to respond to maternal separation.

Topics: Animals; Autism Spectrum Disorder; Communication; Disease Models, Animal; Female; Humans; Male; Maternal Deprivation; Maternal Exposure; Mice; Oxytocin; Pregnancy; Social Interaction; Ultrasonic Waves; Valproic Acid; Vocalization, Animal

Several studies have shown that oxytocin (OXT) modulates social behavior. Similarly, monoamines such as dopamine (DA) play a role in regulating social behavior. Previous studies have demonstrated that the soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) protein syntaxin 1A (STX1A) regulates the secretion of OXT and monoamines, and that STX1A gene knockout (STX1A KO) mice exhibit atypical social behavior, such as deficient social recognition, due to reduced OXT release. In this study, we analyzed the neural mechanism regulating social behavior by OXT and/or DA using STX1A KO mice as a model animal. We found that OXT directly induced DA release from cultured DA neurons through OXT and V1a receptors. In STX1A KO mice, the atypical social behavior was partially improved by OXT administration, which was inhibited by D1 receptor blockade. In addition, the atypical social behavior in STX1A KO mice was partially improved by facilitation of DAergic signaling with the DA reuptake inhibitor GBR12909. Moreover, the amelioration by GBR12909 was inhibited by OXTR blockade. These results suggest that the reciprocal interaction between the DAergic and OXTergic neuronal systems in the CNS may be important in regulating social behavior.

Topics: Animals; Behavioral Symptoms; Cells, Cultured; Central Nervous System; Chemotactic Factors; Disease Models, Animal; Dopamine; Dopamine Antagonists; Dopaminergic Neurons; Mice; Mice, Knockout; Oxytocin; Piperazines; Receptors, Dopamine D1; Receptors, Oxytocin; Social Behavior; Syntaxin 1

Induction and augmentation of labor is one of the most common obstetrical interventions. However, this intervention is not free of risks and could cause adverse events, such as hyperactive uterine contraction, uterine rupture, and amniotic-fluid embolism. Our previous study using a new animal model showed that labor induced with high-dose oxytocin (OXT) in pregnant mice resulted in massive cell death in selective brain regions, specifically in male offspring. The affected brain regions included the prefrontal cortex (PFC), but a detailed study in the PFC subregions has not been performed. In this study, we induced labor in mice using high-dose OXT and investigated neonatal brain damage in detail in the PFC using light and electron microscopy. We found that TUNEL-positive or pyknotic nuclei and Iba-1-positive microglial cells were detected more abundantly in infralimbic (IL) and prelimbic (PL) cortex of the ventromedial PFC (vmPFC) in male pups delivered by OXT-induced labor than in the control male pups. These Iba-1-positive microglial cells were engulfing dying cells. Additionally, we also noticed that in the forceps minor (FMI) of the corpus callosum (CC), the number of TUNEL-positive or pyknotic nuclei and Iba-1-positive microglial cells were largely increased and Iba-1-positive microglial cells phagocytosed massive dying cells in male pups delivered by high-dose OXT-induced labor. In conclusion, IL and PL of the vmPFC and FMI of the CC, were susceptible to brain damage in male neonates after high-dose OXT-induced labor.

Topics: Animals; Animals, Newborn; Calcium-Binding Proteins; Cell Death; Corpus Callosum; Disease Models, Animal; Female; Labor, Induced; Limbic System; Male; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Oxytocin; Phagocytosis; Prefrontal Cortex; Pregnancy; Reproducibility of Results

Oxytocin (OT) and dopamine (DA) are two important elements that are closely related to mental and reward processes in the brain. OT controlled DA functional regulation contributes to various behaviours such as social reward, social cognition and emotion-related behaviours. Previous studies indicated that diminished dopaminergic transmission in the medial prefrontal cortex (mPFC) is correlated with the pathophysiology of depression. However, the interaction of OT and DA and their roles in antidepressant effects still require further exploration. Here, we investigated the antidepressant effect of OT through local mPFC administration, and further explored the underlying mechanisms that indicated that OT could strengthen dopaminergic synaptic transmission with OT receptor (OTR) activation dependent in the mPFC. Our results showed that local administration of OT in the mPFC exerts antidepressant (-like) effects in both naïve and social defeat stress (SDS) depressive animal model. Mechanism study suggested that OT enhances DA level with OTR activation dependent, and elevated mPFC DA levels might further enhance excitatory synaptic transmission by activating the D1/PKA/DARPP32 intracellular signalling pathway in the mPFC. Hence, our study revealed that the activation of OTR strengthens excitatory synaptic transmission via the potentiation of dopaminergic synaptic transmission, especially via D1R activation dependent, in the mPFC, which may be the underlying mechanism of antidepressant (-like) effects mediated by OT. With specifically activation of the D1/PKA/DAPRR32 signalling pathway, our results may augment the important role of OT in reward circuits in the central nervous system.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Cyclic AMP-Dependent Protein Kinases; Depression; Disease Models, Animal; Dopamine; Dopamine and cAMP-Regulated Phosphoprotein 32; Excitatory Postsynaptic Potentials; Male; Mice; Open Field Test; Oxytocin; Prefrontal Cortex; Pyramidal Cells; Receptors, Dopamine D1; Receptors, Oxytocin; Signal Transduction; Social Defeat; Stress, Psychological; Synaptic Transmission

Learning and memory impairment manifests years before the onset of motor impairments in Huntington's disease (HD). Oxytocin (OXT), as a neurohypophyseal neuropeptide has a key role in both learning and memory. Hence, we investigated possible protective effect of OXT on instrumental fear conditioning memory impairment by 3-Nitropropionic acid (3-NP) induced HD, considering sex and prenatal stress effects. Pregnant Wistar rats were exposed to restraint stress for 45 min three times a day, from the gestational day 8 to parturition. 3-NP was injected intraperitoneally (20 mg/kg) for 5-7 days after OXT (10 μg/μl. icv) injection in the male and female offspring rats respectively. One day after the last 3-NP injection, the rotarod and passive avoidance task were conducted. As the key molecular determinants in metabolism and memory processes, we measured the activity of acetylcholinesterase (AChE) and the amount of receptor interacting protein3 (RIP3) in the hippocampus, prefrontal cortex, striatum and amygdala using spectrophotometry and western blotting respectively. Besides, the activity of glutamate dehydrogenase was measured (GDH) as a chain between metabolism and memory formation. The results indicated that OXT improved learning and memory impairment caused by 3-NP or prenatal stress in both sexes. It was along with a significant decrease in the level of RIP3, AChE and GDH activities. However, in the presence of prenatal stress, the OXT could improve 3-NP induced learning and memory impairments just in female rats. So it could be suggested as an effective neurotherapeutic agent in diseases such as HD, but its sex and context dependency should be considered carefully.

Topics: Animals; Behavior, Animal; Brain; Cognitive Dysfunction; Conditioning, Operant; Disease Models, Animal; Fear; Female; Huntington Disease; Male; Neurotoxins; Nitro Compounds; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Propionates; Rats; Rats, Wistar; Receptor-Interacting Protein Serine-Threonine Kinases; Sex Characteristics; Stress, Psychological

Consolation is a type of empathy-like behavior that has recently been observed in some socially living rodents. Despite the growing body of literature suggesting that stress affects empathy, the relationship between stress and consolation remains understudied at the preclinical level. Here, we examined the effects of chronic emotional stress or physical stress exposure on consolation and emotional behaviors by using the socially monogamous mandarin vole (Microtus mandarinus) in both males and females.. Physical stress voles were exposed to 14-day social defeat stress, whereas emotional stress voles vicariously experienced the defeat of their partners. We found that physical stress, but not emotional stress, voles showed reduced grooming toward their defeated partners and increased anxiety- and despair-like behaviors. Meanwhile, physical stress voles exhibited decreased neural activity in the anterior cingulate cortex, which is centrally involved in empathy. The densities of oxytocin receptors, dopamine D2 receptors, and serotonin 1A-receptors within the anterior cingulate cortex were significantly decreased in the physical stress group compared with controls. All the behavioral and physiological changes were similar between the sexes. Finally, we found that the reduced consolation behavior and some anxiety-like syndromes in physical stress voles could be alleviated by pretreatment with an oxytocin receptor, D2 receptors, or serotonin 1A-receptor agonist within the anterior cingulate cortex, whereas injections of corresponding receptor antagonists to the control voles decreased the consolation behavior and increased some anxiety-like behaviors.. Our results indicated that chronic physical stress exposure impaired consolation and induced anxiety-like behaviors in mandarin voles and oxytocin receptors, 5-HT1A receptors, and D2 receptors within the anterior cingulate cortex may play important roles in these processes.

Topics: Aggression; Animals; Arvicolinae; Behavior, Animal; Disease Models, Animal; Empathy; Female; Gyrus Cinguli; Housing, Animal; Male; Neurotransmitter Agents; Oxytocin; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Signal Transduction; Social Defeat; Stress, Psychological; Time Factors

Oxytocin (OT) is critical for the expression of social behavior across a wide array of species; however, the role of this system in the encoding of socially relevant information is not well understood. In the present study, we show that chemogenetic activation of OT neurons within the paraventricular nucleus of the hypothalamus (PVH) of male mice (OT-Ires-Cre) enhanced social investigation during a social choice test, while chemogenetic inhibition of these neurons abolished typical social preferences. These data suggest that activation of the OT system is necessary to direct behavior preferentially toward social stimuli. To determine whether the presence of a social stimulus is sufficient to induce activation of PVH-OT neurons, we performed the first definitive recording of OT neurons in awake mice using two-photon calcium imaging. These recordings demonstrate that social stimuli activate PVH-OT neurons and that these neurons differentially encode social and nonsocial stimuli, suggesting that PVH-OT neurons may act to convey social salience of environmental stimuli. Finally, an attenuation of social salience is associated with social disorders, such as autism. We therefore also examined possible OT system dysfunction in a mouse model of autism,

Topics: Action Potentials; Animals; Appetitive Behavior; Autistic Disorder; Benzodiazepines; Calcium Signaling; Clozapine; Disease Models, Animal; Exploratory Behavior; Genes, Reporter; Male; Mice; Mice, Knockout; Microfilament Proteins; Nerve Tissue Proteins; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Patch-Clamp Techniques; Pyrazoles; Receptors, Oxytocin; Social Behavior; Wakefulness

Recent evidence indicates that reactivated memories are malleable and can integrate new information upon their reactivation. We injected rats with oxytocin to investigate whether the delivery of a drug which dampens anxiety and fear before the reactivation of trauma memory decreases the emotional load of the original representation and durably alleviates PTSD-like symptoms. Rats exposed to the single prolonged stress (SPS) model of PTSD were classified 15 and 17 days later as either resilient or vulnerable to trauma on the basis of their anxiety and arousal scores. Following 2 other weeks, they received an intracerebral infusion of oxytocin (0.1 µg/1 µL) or saline 40 min before their trauma memory was reactivated by exposure to SPS reminders. PTSD-like symptoms and reactivity to PTSD-related cues were examined 3-14 days after oxytocin treatment. Results showed that vulnerable rats treated with saline exhibited a robust PTSD syndrome including increased anxiety and decreased arousal, as well as intense fear reactions to SPS sensory and contextual cues. Exposure to a combination of those cues resulted in c-fos hypo-activation and dendritic arbor retraction in prefrontal cortex and amygdala neurons, relative to resilient rats. Remarkably, 83% of vulnerable rats subjected to oxytocin-based emotional remodeling exhibited a resilient phenotype, and SPS-induced morphological alterations in prelimbic cortex and basolateral amygdala were eliminated. Our findings emphasize the translational potential of the present oxytocin-based emotional remodeling protocol which, when administered even long after the trauma, produces deep re-processing of traumatic memories and durable attenuation of the PTSD symptomatology.

Topics: Animals; Disease Models, Animal; Fear; Oxytocin; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic

Social dysfunction is among the core symptoms of schizophrenia. The neuropeptides oxytocin (OXT) and vasopressin (VP) are involved in the regulation of social behaviour and social cognition. There are indications that both of these neurotransmitter systems are altered in schizophrenia. Prenatal (embryonic day 17) exposure to the neurotoxin methylazoxymethanol acetate (MAM; 22 mg/kg) leads to a schizophrenia-like phenotype in rats and has been used as a model of schizophrenia symptoms. Here, we examined the social phenotype of MAM-exposed female and male rats and measured concentrations of OXT, VP and their specific receptors in various brain areas involved in the control of social behaviour. We report decreases in social behaviour and ultrasonic vocalisations (USVs) in the MAM rats during social encounters. Specifically, the duration of social interactions and number of corresponding USVs were reduced in this group. In the MAM rats, "positive" 50-kHz USVs were flatter, i.e., displayed lower bandwidth, a greater percentage of "short" calls and lower percentage of frequency-modulated calls. The MAM animals exhibited diminished interest towards social stimuli in olfactory preference tests. In the resident-intruder test, MAM exposure reduced dominance behaviour only in the males. We also report cognitive impairments, including reduced novel object recognition and cognitive inflexibility in the attentional set shifting test, and decreased OXT and OXT receptor concentrations in the prefrontal cortex and hypothalamus and VP and VP receptors in the hypothalamus in the MAM rats. Deficits in central OXT and VP systems may underlie abnormalities present in the MAM model of schizophrenia.

Topics: Animals; Disease Models, Animal; Female; Male; Methylazoxymethanol Acetate; Neurotoxins; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Schizophrenia; Schizophrenic Psychology; Social Behavior; Vocalization, Animal

To explore the proteomic changes in the hypothalamus of rats treated with Mongolian medical warm acupuncture for insomnia therapy based proteomics.. We used an iTRAQ-based quantitative proteomic approach to identify proteins that potential molecular mechanisms involved in the treatment of insomnia by Mongolian medical warm acupuncture.. In total, 7477 proteins were identified, of which 36 proteins showed increased levels and 45 proteins showed decreased levels in insomnia model group (M) compared with healthy control group (C), 72 proteins showed increased levels and 44 proteins showed decreased levels from the warm acupuncture treated insomnia group (W) compared with healthy controls (C), 28 proteins showed increased levels and 17 proteins showed decreased levels from the warm acupuncture-treated insomnia group (W) compared with insomnia model group (M). Compared with healthy control groups, warm acupuncture-treated insomnia group showed obvious recovered. Bioinformatics analysis indicated that up-regulation of neuroactive ligand-receptor interaction and oxytocin signaling was the most significantly elevated regulate process of Mongolian medical warm acupuncture treatment for insomnia. Proteins showed that increased/decreased expression in the warm acupuncture-treated insomnia group included Prolargin (PRELP), NMDA receptor synaptonuclear-signaling and neuronal migration factor (NSMF), Transmembrane protein 41B (TMEM41B) and Microtubule-associated protein 1B (MAP1B) to adjust insomnia.. A combination of findings in the present study suggest that warm acupuncture treatment is efficacious in improving sleep by regulating the protein expression process in an experimental rat model and may be of potential benefit in treating insomnia patients with the added advantage with no adverse effects.

Topics: Acupuncture Therapy; Animals; Disease Models, Animal; Extracellular Matrix Proteins; Fenclonine; Humans; Hypothalamus; Male; Medicine, Mongolian Traditional; Microtubule-Associated Proteins; Nerve Tissue Proteins; Oxytocin; Proteomics; Rats; Sleep Initiation and Maintenance Disorders; Up-Regulation

Estradiol derived from neural aromatization of testosterone plays a key role in the organization and activation of neural structures underlying male behaviors. This study evaluated the contribution of the estrogen receptor (ER) β in estradiol-induced modulation of social and mood-related behaviors by using mice lacking the ERβ gene in the nervous system. Mutant males exhibited reduced social interaction with same-sex congeners and impaired aggressive behavior. They also displayed increased locomotor activity, and reduced or unaffected anxiety-state level in three paradigms. However, when mice were exposed to unescapable stress in the forced swim and tail suspension tests, they spent more time immobile and a reduced time in swimming and climbing. These behavioral alterations were associated with unaffected circadian and restraint stress-induced corticosterone levels, and unchanged number of tryptophan hydroxylase 2-immunoreactive neurons in the dorsal raphe. By contrast, reduced mRNA levels of oxytocin and arginine-vasopressin were observed in the bed nucleus of stria terminalis, whereas no changes were detected in the hypothalamic paraventricular nucleus. The neural ERβ is thus involved to different extent levels in social and mood-related behaviors, with a particular action on oxytocin and arginine-vasopressin signaling pathways of the bed nucleus of stria terminalis, yet the involvement of other brain areas cannot be excluded.

Topics: Affect; Aggression; Animals; Anxiety; Arginine Vasopressin; Behavior, Animal; Disease Models, Animal; Estradiol; Estrogen Receptor beta; Humans; Locomotion; Male; Mice; Mice, Knockout; Mutation; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Septal Nuclei; Signal Transduction; Testosterone

Autism spectrum disorder (ASD) is a neurodevelopmental disorder estimated by the World Health Organization to occur in one of 160 children worldwide. No pharmaceutical treatments are available to improve the deficits in social communication that are common symptoms of ASD. Recent clinical trials have focused on the nasal application of oxytocin, a neuronal peptide known to regulate a variety of social behaviours. However, the effect of oxytocin on this deficit is inconclusive. By contrast, evidence from ASD animal model studies indicates that when animals are treated with oxytocin during early development, improvements in social deficits are observed in adulthood. Thus, it is necessary to examine the effect of therapeutic target medication prescribed in early development. Mice prenatally exposed to valproic acid (VPA) are widely used as an animal model of ASD. However, many behavioural studies have been conducted during adulthood rather than early development. To establish a screening system to identify therapeutic drugs that are effective when delivered during the early postnatal period, it is important to examine the early developmental changes in their communicative behaviours. In the present study, we examined the ultrasonic vocalisation (USV) of VPA-exposed mice pups during their early postnatal developmental days. USV rates were comparable to those of the controls until the first week of their life but declined more on postnatal day 11. We checked the expression of oxytocin system in the hypothalamus and found the down-regulation of oxytocin and CD38, and up-regulation of oxytocin receptor in the VPA pups. Acute administration of oxytocin on postnatal day 11 increased the call rate of VPA pups. Taken together, we have demonstrated there was a deficiency in the oxytocinergic signalling in the VPA pups and also shown the existence of time periods that are effective with respect to screening the therapeutic drugs.

Topics: ADP-ribosyl Cyclase 1; Animals; Autism Spectrum Disorder; Disease Models, Animal; Female; Maternal Deprivation; Mice; Mice, Inbred ICR; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Oxytocin; Social Behavior; Valproic Acid; Vocalization, Animal

Oxytocin (OT) has shown a cardioprotective effect on myocardial ischemia/reperfusion injury (MIRI). This study aimed to investigate whether the cardioprotective effect of OT is associated with the inhibition of mast cell degranulation and inflammation.. The left anterior descending coronary artery of rats was ligated for 30 min and reperfused for 120 min to establish an ischemia and reperfusion (I/R) injury model. A preliminary experiment was conducted to evaluate the optimal dose of OT (0.01, 0.1, 1 μg/kg via intraperitoneal). The mast cell secretagogue compound 48/80 (C48/80) was used to promote the degranulation of mast cells with or without I/R injury, while rats were pretreated with OT to determine whether this compound suppresses mast cell degranulation. The expression of the inflammatory factors HMGB1 and NF-κB p65 was evaluated. A cell experiment was performed for verification.. C48/80 (0.5 mg/kg, intravenous) increased mast cell degranulation and tryptase release compared with I/R-treated alone (27.12 ± 3.52 % vs. 16.57 ± 2.23 %; 8.34 ± 1.66 ng/mL vs. 3.63 ± 0.63 ng/mL), but these effects could be decreased by OT (0.1 μg/kg, intraperitoneal) preconditioning (19.29 ± 0.74 %; 5.37 ± 0.73 ng/mL). Besides that, hemodynamic disorders, arrhythmias, cardiac edema, infarct size, histopathological damage, and the levels of cTnI, HMGB1 and NF-κB p65 were significantly increased in I/R-treated group compared with corresponding observations in the control group, and C48/80 exacerbated these injuries, but pretreatment with OT could ameliorate these effects. Furthermore, C48/80 (10 μg/mL) inhibited the viability and promoted the apoptosis of H9C2(2-1) and RBL-2H3 cells, and increased the release of cTnI and tryptase, all of which were reversed by prophylactic OT (0.01 ng/mL) treatment.. We concluded that OT pretreatment inhibits the degranulation of cardiac mast cells induced by I/R injury and downregulates the expression of the inflammatory factors HMGB1 and NF-κB p65.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cell Degranulation; Cell Line; Disease Models, Animal; HMGB1 Protein; Inflammation Mediators; Male; Mast Cells; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Oxytocin; Rats, Sprague-Dawley; Transcription Factor RelA; Troponin I

Oxytocin (OT) is a critical molecule for social recognition and memory that mediates social and emotional behaviours. In addition, OT acts as an anxiolytic factor and is released during stress. Based on the activity of CD38 as an enzyme that produces the calcium-mobilizing second messenger cyclic ADP-ribose (cADPR), CD157, a sister protein of CD38, has been considered a candidate mediator for the production and release of OT and its social engagement and anti-anxiety functions. However, the limited expression of CD157 in the adult mouse brain undermined confidence that CD157 is an authentic and/or actionable molecular participant in OT-dependent social behaviour. Here, we show that CD157 knockout mice have low levels of circulating OT in cerebrospinal fluid, which can be corrected by the oral administration of nicotinamide riboside, a recently discovered vitamin precursor of nicotinamide adenine dinucleotide (NAD). NAD is the substrate for the CD157- and CD38-dependent production of cADPR. Nicotinamide riboside corrects social deficits and fearful and anxiety-like behaviours in CD157 knockout males. These results suggest that elevating NAD levels with nicotinamide riboside may allow animals with cADPR- and OT-forming deficits to overcome these deficits and function more normally.

Topics: ADP-ribosyl Cyclase; Animals; Antigens, CD; Anxiety; Autism Spectrum Disorder; Dietary Supplements; Disease Models, Animal; Female; GPI-Linked Proteins; Male; Mice; Mice, Mutant Strains; Niacinamide; Oxytocin; Pyridinium Compounds; Social Behavior

Neuropsychiatric disturbances with altered social cognition, depression and anxiety are among the most debilitating early features in the fatal neurodegenerative disorder Huntington disease (HD) which is caused by an expanded CAG repeat in the huntingtin gene. The underlying neurobiological mechanisms are not known. Neuropathological analyses of postmortem human HD hypothalamic tissue have demonstrated loss of the neuropeptides oxytocin and vasopressin. The dynamic interplay between these neuropeptides is crucial for modulating emotional and social behavior but its role in HD is unclear. In the present study, we have investigated the effect of expressing the mutant huntingtin gene on the development of behavioral changes using the transgenic BACHD mouse model at different ages. We show for the first time that BACHD mice exhibit deficits in social behavior with parallel aberrations in the balance of the oxytocin-vasopressin system. Importantly, our data also show that restoration of the interplay within the system with an acute dose of intranasal oxytocin immediately prior to behavioral testing can rescue the depressive-like phenotype but not anxiety-like behavior in this transgenic model. These findings demonstrate that imbalances in the oxytocin-vasopressin interplay contribute to the neuropsychiatric component of HD and suggest that interventions aimed at restoring the blunted levels of oxytocin may confer therapeutic benefits for this disease.

Topics: Administration, Intranasal; Animals; Animals, Newborn; Anxiety; Behavior, Animal; Disease Models, Animal; Female; Huntingtin Protein; Huntington Disease; Male; Mice; Mice, Transgenic; Oxytocin; Phenotype; Signal Transduction; Social Behavior; Vasopressins

Oxytocin has been suggested as a potential therapeutic agent in autism and other neuropsychiatric conditions. Although, the link between the deficit in "SH3 domain and ankyrin repeat containing protein 3" (SHANK3) and autism spectrum disorders is highly studied topic, developmental mechanisms are still poorly understood. In this study, we clearly confirm that SHANK3 deficiency is accompanied with abnormalities in neurite number and length, which are reversed by oxytocin treatment (1 μM, 48h) in primary hippocampal neurons. Transient silencing for the SHANK3 gene (siSHANK3) in neuron-like cell line (SH-SY5Y) revealed a significant decrease in the expression levels of Neurexins 1α, 1β, 2α and 2β. Oxytocin treatment compensated reduced levels of Synapsin I, PSD95 and Neuroligin 3 in siSHANK3 cells suggesting a marked potential of oxytocin to ameliorate defects present in conditions of SHANK3 deficiency. Further analysis of hippocampal tissue revealed that oxytocin application (0.1 μg/μl, s.c. at P2 and P3 day) affects levels of synaptic proteins and GTPases in both WT and SHANK3 deficient mice on day P5. Oxytocin stimulated the mRNA expression of RhoB and Rac1 in both WT and SHANK3 deficient mice. Our data suggest that autism relevant synaptic pathologies could be reversed by oxytocin treatment.

Topics: Animals; Animals, Newborn; Autistic Disorder; Cells, Cultured; Disease Models, Animal; Female; Gene Expression; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Nerve Tissue Proteins; Neurites; Neurons; Neuroprotection; Oxytocin; Receptors, Neurotransmitter

To evaluate the potential effect of Ankaferd Blood Stopper (ABS) and oxytocin (OT) in an experimental endometriosis model, 18 female Sprague Dawley rats were used in this study. The animals were divided randomly into three groups after surgical induction of endometriosis: group 1: control group (isotonic NaCl, 1 mL/kg/day, intramuscular, n=6); group 2: OT group (OT, 80 U/kg/day, intramuscular, n=6); group 3: ABS group (ABS, 1.5 mL/kg/day, intraperitoneal, n=6). Each group was treated for four weeks (two times per week). Volumes of endometriotic explants were measured in biopsy samples for histopathological analysis. Vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1), and tumour necrosis factor (TNF-α) levels were measured in plasma and peritoneal fluid. Endometriotic explant volumes were significantly decreased after OT administration (P<0.0001). The epithelial score was significantly decreased in both treatment groups compared to the control group (P<0.05). TUNEL immunohistochemistry showed more apoptotic changes in the endometriosis foci (gland epithelium and surrounding tissue) in the OT group than in the control group (P<0.05). The levels of VEGF, MCP-1, and TNF-α were significantly reduced in the OT group (P<0.05), whereas no significant changes in protein levels were found in the ABS-applied group. The results indicate that OT has greater potential as a therapeutic agent in experimentally induced peritoneal endometriosis, where ABS, which is a VEGF modulator, appears to act through different mechanisms to show its palliative effects on a rat model of peritoneal endometriosis.

Topics: Animals; Chemokine CCL2; Disease Models, Animal; Endometriosis; Female; Oxytocin; Plant Extracts; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

A significant decrease in the expression of spinal microRNA‑29c (miR‑29c), which is responsible for the regulation of oxytocin receptor (OXTR) expression, was observed in nerve injury pain during childbirth. The present study investigates whether spinal miR‑29c could be a potential target for the treatment of pain, via the oxytocin (OT)‑γ‑aminobutyric acid (GABA) pathway. A spared nerve injury (SNI) rat model was established to induce neuropathic pain, simulating hyperalgesia. Spinal neurons were treated with OT to mimic the hormonal changes in the central nervous system after delivery. A change in the neuronal miniature inhibitory postsynaptic currents (mIPSCs) was observed in neurons, following the silencing of miR‑29c or OT treatment with or without OXTR antagonist. The Von‑Frey apparatus was used to measure the animal behaviors. Molecular biological experiments and electrophysical recordings in vivo and in vitro were performed to reveal the potential analgesic mechanisms. miR‑29c was significantly downregulated (more than 8‑fold) in the spinal dorsal horn of delivery+SNI rats compared with the SNI rats. The silencing of miR‑29c resulted in increased pain threshold in SNI rats. Bioinformatics analysis indicated that OXTR was a potential target gene of miR‑29c. The delivery+SNI rats presented with higher levels of OT in the cerebrospinal fluid compared with SNI rats, which indicated that the OT signaling pathway may participate in pain relief response. The increased expression of OXTR and GABA in delivery+SNI rats were observed in the miR‑29c‑silenced SNI rat model, suggesting that the silencing of miR‑29c can mediate pain relief by enhancing the OT‑GABA pathway. In addition, an electrophysiology assay was performed to assess the mIPSCs in neurons. The silencing of miR‑29c in neurons increased the frequency and amplitude of mIPSCs but there was no influence on the decay time, which suggested that the spinal inhibitory neurons became more active, subsequently reducing the feeling of pain. The inhibition of OXTR reversed the enhanced inhibitory postsynaptic currents, indicating a crucial role for OXTR in the miR‑29c‑associated pain regulation. Taken together, the results of the present study suggested that spinal oxytocinergic inhibitory control plays an important role in pain relief in the neuropathic pain rat model undergoing vaginal delivery. Silencing spinal miR‑29c may be a potential target for pain relief through the OT‑GABA pathway.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Down-Regulation; Female; gamma-Aminobutyric Acid; Gene Silencing; Labor Pain; MicroRNAs; Oxytocin; Pregnancy; Primary Cell Culture; Rats; Receptors, Oxytocin; Signal Transduction; Spinal Nerves

Deficits in arginine vasopressin (AVP) and oxytocin (OT), two neuropeptides closely implicated in the modulation of social behaviours, have been reported in some early developmental disorders and autism spectrum disorders. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene are associated to Rett syndrome and other neuropsychiatric conditions. Thus, we first analysed AVP and OT expression in the brain of Mecp2-mutant mice by immunohistochemistry. Our results revealed no significant differences in these systems in young adult Mecp2-heterozygous females, as compared to WT littermates. By contrast, we found a significant reduction in the sexually dimorphic, testosterone-dependent, vasopressinergic innervation in several nuclei of the social brain network and oxytocinergic innervation in the lateral habenula of Mecp2-null males, as compared to WT littermates. Analysis of urinary production of pheromones shows that Mecp2-null males lack the testosterone-dependent pheromone darcin, strongly suggesting low levels of androgens in these males. In addition, resident-intruder tests revealed lack of aggressive behaviour in Mecp2-null males and decreased chemoinvestigation of the intruder. By contrast, Mecp2-null males exhibited enhanced social approach, as compared to WT animals, in a 3-chamber social interaction test. In summary, Mecp2-null males, which display internal testicles, display a significant reduction of some male-specific features, such as vasopressinergic innervation within the social brain network, male pheromone production and aggressive behaviour. Thus, atypical social behaviours in Mecp2-null males may be caused, at least in part, by the effect of lack of MeCP2 over sexual differentiation.

Topics: Aggression; Animals; Arginine Vasopressin; Behavior, Animal; Brain; Disease Models, Animal; Female; Intercellular Signaling Peptides and Proteins; Male; Methyl-CpG-Binding Protein 2; Mice; Mice, Knockout; Oxytocin; Pheromones; Sex Characteristics; Sex Differentiation; Social Behavior

A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases

Topics: Animals; Autistic Disorder; Cell Adhesion Molecules, Neuronal; Disease Models, Animal; Eukaryotic Initiation Factor-4E; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinases; Nerve Tissue Proteins; Neurons; Oxytocin; Phosphorylation; Protein Biosynthesis; RNA, Messenger; Signal Transduction; Social Behavior; Ventral Tegmental Area

Osteoarthritis (OA) causes chronic joint pain and significantly impacts daily activities. Hence, developing novel treatment options for OA has become an increasingly important area of research. Recently, studies have reported that exogenous, as well as endogenous, hypothalamic-neurohypophysial hormones, oxytocin (OXT) and arginine-vasopressin (AVP), significantly contribute to nociception modulation. Moreover, the parvocellular OXT neurone (parvOXT) extends its projection to the superficial spinal dorsal horn, where it controls the transmission of nociceptive signals. Meanwhile, AVP produced in the magnocellular AVP neurone (magnAVP) is released into the systemic circulation where it contributes to pain management at peripheral sites. The parvocellular AVP neurone (parvAVP), as well as corticotrophin-releasing hormone (CRH), suppresses inflammation via activation of the hypothalamic-pituitary adrenal (HPA) axis. Previously, we confirmed that the OXT/AVP system is activated in rat models of pain. However, the roles of endogenous hypothalamic-neurohypophysial hormones in OA have not yet been characterised. In the present study, we investigated whether the OXT/AVP system is activated in a knee OA rat model. Our results show that putative parvOXT is activated and the amount of OXT-monomeric red fluorescent protein 1 positive granules in the ipsilateral superficial spinal dorsal horn increases in the knee OA rat. Furthermore, both magnAVP and parvAVP are activated, concurrent with HPA axis activation, predominantly modulated by AVP, and not CRH. The OXT/AVP system in OA rats was similar to that in systemic inflammation models, including adjuvant arthritis; however, magnocellular OXT neurones (magnOXT) were not activated in OA. Hence, localised chronic pain conditions, such as knee OA, activate the OXT/AVP system without impacting magnOXT.

Topics: Animals; Arginine Vasopressin; Arthralgia; Disease Models, Animal; Hypothalamo-Hypophyseal System; Hypothalamus; Male; Neurons; Nociception; Osteoarthritis, Knee; Oxytocin; Rats; Rats, Transgenic; Rats, Wistar

The two hypothalamic neuropeptides oxytocin and melanin concentrating hormone (MCH) share several physiological actions such as the control of maternal care, sexual behavior, and emotions. In this study, we uncover the role for the oxytocin-MCH signaling pathway in mood regulation. We identify discrete effects of oxytocin-MCH signaling on depressive behavior and demonstrate that parenting and mating experiences shape these effects. We show that the selective deletion of OXT receptors from MCH neurons increases and decreases depressive behavior in sexually naïve and late postpartum female mice respectively, with no effect on sexually naïve male mice. We demonstrate that both parenting experience and mood-regulating effects of oxytocin-MCH are associated with synaptic plasticity in the reward and fear circuits revealed by the alterations of Arc expressions, which are associated with the depressive behavior. Finally, we uncover the sex-dependent effects of mating on depressive behavior; while the sexual activity reduces the basal levels of depressive behavior in male mice, it reduces in female mice evoked-depression only. We demonstrate that the oxytocin-MCH pathway mediates the effects of sexual activity on depressive behavior. Our data suggest that the oxytocin-MCH pathway can serve as a potential therapeutic target for the treatment of major depression and postpartum mood disorders.

Topics: Affect; Animals; Depression; Depression, Postpartum; Disease Models, Animal; Female; Gene Deletion; Hypothalamic Hormones; Male; Maternal Behavior; Melanins; Mice; Oxytocin; Paternal Behavior; Pituitary Hormones; Postpartum Period; Receptors, Oxytocin; Sex Characteristics; Sexual Behavior, Animal; Signal Transduction

Primary dysmenorrhea is a common occurrence in adolescent women and is a type of chronic inflammation. Dysmenorrhea is due to an increase in oxidative stress, which increases cyclooxygenase-2 (COX-2) expression, increases the concentration of prostaglandin F2α (PGF2α), and increases the calcium concentration in uterine smooth muscle, causing excessive uterine contractions and pain. The polyphenolic compound oleocanthal (OC) in extra virgin olive oil (EVOO) has been shown to have an anti-inflammatory and antioxidant effect. This study aimed to investigate the inhibitory effect of extra virgin olive oil and its active ingredient oleocanthal (OC) on prostaglandin-induced uterine hyper-contraction, its antioxidant ability, and related mechanisms. We used force-displacement transducers to calculate uterine contraction in an ex vivo study. To analyze the analgesic effect, in an in vivo study, we used an acetic acid/oxytocin-induced mice writhing model and determined uterus contraction-related signaling protein expression. The active compound OC inhibited calcium/PGF2α-induced uterine hyper-contraction. In the acetic acid and oxytocin-induced mice writhing model, the intervention of the EVOO acetonitrile layer extraction inhibited pain by inhibiting oxidative stress and the phosphorylation of the protein kinase C (PKC)/extracellular signal-regulated kinases (ERK)/ myosin light chain (MLC) signaling pathway. These findings supported the idea that EVOO and its active ingredient, OC, can effectively decrease oxidative stress and PGF2α-induced uterine hyper-contraction, representing a further treatment for dysmenorrhea.

Topics: Abdominal Pain; Aldehydes; Animals; Anti-Inflammatory Agents; Antioxidants; Calcium; Cyclooxygenase 2; Cyclopentane Monoterpenes; Dinoprost; Disease Models, Animal; Dysmenorrhea; Female; Mice; Olive Oil; Oxidative Stress; Oxytocin; Phenols; Prostaglandins; Signal Transduction; Uterine Contraction; Uterus

Oxytocin (OT) from the hypothalamus is increased in several cardiorespiratory nuclei and systemically in response to a variety of stimuli and stressors, including hypoxia. Within the nucleus tractus solitarii (nTS), the first integration site for cardiorespiratory reflexes, OT enhances synaptic transmission, action potential (AP) discharge, and cardiac baroreflex gain. The hypoxic stressor obstructive sleep apnea, and its CIH animal model, elevates blood pressure and alters heart rate variability. The nTS receives sensory input from baroafferent neurons that originate in the nodose ganglia. Nodose neurons express the OT receptor (OTR) whose activation elevates intracellular calcium. However, the influence of OT on other ion channels, especially potassium channels important for neuronal activity during CIH, is less known. This study sought to determine the mechanism (s) by which OT modulates sensory afferent-nTS mediated reflexes normally and after CIH. Nodose ganglia neurons from male Sprague-Dawley rats were examined after 10d CIH (6% O

Topics: Animals; Baroreflex; Disease Models, Animal; Electrophysiological Phenomena; Hypoxia; Male; Nodose Ganglion; Oxytocin; Patch-Clamp Techniques; Potassium Channels; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Signal Transduction; Sleep Apnea Syndromes; Visceral Afferents

The incentive sensitisation theory of addiction posits that drug-associated stimuli become imbued with incentive motivational properties, driving pathological drug seeking. However, pre-existing variability in the incentive salience to non-drug reward cues ('sign trackers' (STs); 'goal trackers' (GTs)) is also predictive of the desire for and relapse to cocaine and opioids. Here, we asked whether variation in propensity to attribute incentive salience to a food cue is predictive of reinstatement to the highly addictive psychostimulant methamphetamine (METH), and whether treatment with the promising anti-addiction therapy oxytocin differentially reduces METH behaviour between STs and GTs.. Rats were trained to associate a Pavlovian cue with delivery of a sucrose pellet over 8 days. They then received jugular vein catheters for intravenous METH self-administration, followed by behavioural extinction, and cue-induced and METH-primed reinstatement to METH-seeking behaviours. Oxytocin was administered prior to self-administration and reinstatement tests.. Despite the self-administration of similar amounts of METH, STs reinstated more to METH cues than did GTs, yet METH-priming reinstated STs and GTs similarly. Furthermore, oxytocin attenuated cue-induced reinstatement more so in STs than in GTs, and reduced METH-primed reinstatement to a greater extent in the top quartile of reinstaters, indicating that oxytocin treatment may be most effective for those at highest risk of addiction.. This pre-existing bias towards reward cues presents a possible tool to screen for METH addiction susceptibility and may be useful for understanding the neurobiology of addiction and for pharmacotherapeutic discovery.

Topics: Amphetamine-Related Disorders; Animals; Behavior, Addictive; Behavior, Animal; Central Nervous System Stimulants; Conditioning, Classical; Cues; Disease Models, Animal; Extinction, Psychological; Female; Male; Methamphetamine; Motivation; Oxytocin; Rats; Rats, Sprague-Dawley; Recurrence; Reinforcement, Psychology; Reward

Parallel processing circuits are thought to dramatically expand the network capabilities of the nervous system. Magnocellular and parvocellular oxytocin neurons have been proposed to subserve two parallel streams of social information processing, which allow a single molecule to encode a diverse array of ethologically distinct behaviors. Here we provide the first comprehensive characterization of magnocellular and parvocellular oxytocin neurons in male mice, validated across anatomical, projection target, electrophysiological, and transcriptional criteria. We next use novel multiple feature selection tools in Fmr1-KO mice to provide direct evidence that normal functioning of the parvocellular but not magnocellular oxytocin pathway is required for autism-relevant social reward behavior. Finally, we demonstrate that autism risk genes are enriched in parvocellular compared with magnocellular oxytocin neurons. Taken together, these results provide the first evidence that oxytocin-pathway-specific pathogenic mechanisms account for social impairments across a broad range of autism etiologies.

Topics: Animals; Autism Spectrum Disorder; Disease Models, Animal; Fragile X Mental Retardation Protein; Gene Knock-In Techniques; Male; Mice; Mice, Knockout; Neurons; Object Attachment; Oxytocin; Social Behavior

We evaluated the mechanisms underlying the oxytocin (OXT)-induced analgesic effect on orofacial neuropathic pain following infraorbital nerve injury (IONI). IONI was established through tight ligation of one-third of the infraorbital nerve thickness. Subsequently, the head withdrawal threshold for mechanical stimulation (MHWT) of the whisker pad skin was measured using a von Frey filament. Trigeminal ganglion (TG) neurons innervating the whisker pad skin were identified using a retrograde labeling technique. OXT receptor-immunoreactive (IR), transient receptor potential vanilloid 1 (TRPV1)-IR, and TRPV4-IR TG neurons innervating the whisker pad skin were examined on post-IONI day 5. The MHWT remarkably decreased from post-IONI day 1 onward. OXT application to the nerve-injured site attenuated the decrease in MHWT from day 5 onward. TRPV1 or TRPV4 antagonism significantly suppressed the decrement of MHWT following IONI. OXT receptors were expressed in the uninjured and Fluoro-Gold (FG)-labeled TG neurons. Furthermore, there was an increase in the number of FG-labeled TRPV1-IR and TRPV4-IR TG neurons, which was inhibited by administering OXT. This inhibition was suppressed by co-administration with an OXT receptor antagonist. These findings suggest that OXT application inhibits the increase in TRPV1-IR and TRPV4-IR TG neurons innervating the whisker pad skin, which attenuates post-IONI orofacial mechanical allodynia.

Topics: Animals; Cranial Nerve Injuries; Disease Models, Animal; Facial Neuralgia; Fluorescent Antibody Technique; Gene Expression Regulation; Neurons; Oxytocin; Pain Threshold; Rats; Receptors, Oxytocin; Transient Receptor Potential Channels; Trigeminal Ganglion

Genital endometriosis (GE) is a widespread gynecological disease which requires its further pathogenesis investigation and search for new effective treatments. The known data of oxytocin receptor presence in endometrioid heterotopy smooth muscle cells give some grounds to assume oxytocin participation in the pathogenesis of endometriosis. The present study objective was to evaluate oxytocin level in peripheral blood (PB) in patients with endometriosis associated pain syndrome and to estimate the efficacy of oxytocin receptor inhibitors (IOXTR) administration based on animal endometriosis model.. The basic group comprised 61 patients with endometriosis associated pain syndrome, while 21 patients formed the control group. VAS, MPQ, and BBS objective tests were applied for pain syndrome evaluation. Oxytocin level in PB was measured by immunoenzyme method. After confirmation of endometriosis experimental model formation in rats and further randomization, a daily IOXTR intra-abdominal injection was performed in a dose of 0.35 mg/kg/24 h in the basic group (. Oxytocin level in PB was authentically higher in patients with GE compared to the control: 51.45 (35.54-62.76) pg/mL and 27.64 (23.23-34.12) pg/mL, respectively (. The obtained results confirm the oxytocin role in the pathogenesis of endometrioid associated pain syndrome. The high efficacy of IOXTR administration based on animal model of surgically induced endometriosis allows viewing this method as a perspective therapy.

Topics: Adolescent; Adult; Animals; Case-Control Studies; Disease Models, Animal; Drug Evaluation, Preclinical; Endometriosis; Female; Humans; Middle Aged; Molecular Targeted Therapy; Oxytocin; Pelvic Pain; Peritoneal Diseases; Rats; Rats, Wistar; Receptors, Oxytocin; Syndrome; Vasotocin; Young Adult

Methamphetamine (METH) causes memory changes, but the underlying mechanisms are poorly understood. Epigenetic mechanisms, including DNA methylation, can potentially cause synaptic changes in the brain. Oxytocin (OT) plays a central role in learning and memory, but little is known of the impact of OT on METH-associated memory changes. Here, we explored the role of OT in METH-induced epigenetic alterations that underlie spatial and cognitive memory changes. METH (2.0 mg/kg, i.p.) was administered to male C57BL/6 mice once every other day for 8 days. OT (2.5 μg, i.c.v.) or aCSF was given prior to METH. Spatial and cognitive memory were assessed. In Hip and PFC, synaptic structures and proteins were examined, levels of DNA methyltransferases (DNMTs) and methyl CpG binding protein 2 (MECP2) were determined, and the DNA methylation status at the Synaptophysin (Syn) promoter was assessed. METH enhanced spatial memory, decreased synapse length, downregulated DNMT1, DNMT3A, DNMT3B, and MECP2, and induced DNA hypomethylation at the Syn promoter in Hip. In contrast, METH reduced cognitive memory, increased synapse thickness, upregulated DNMT1, DNMT3A, and MECP2, and induced DNA hypermethylation at the Syn promoter in PFC. OT pretreatment specifically ameliorated METH-induced learning and memory alterations, normalized synapse structures, and regulated DNMTs and MECP2 to reverse the DNA methylation status changes at the Syn promoter in Hip and PFC. DNA methylation is an important gene regulatory mechanism underlying METH-induced learning and memory alterations. OT can potentially be used to specifically manipulate METH-related memory changes.

Topics: Amphetamine-Related Disorders; Animals; Central Nervous System Stimulants; Disease Models, Animal; DNA Methylation; Learning; Male; Memory; Methamphetamine; Mice; Mice, Inbred C57BL; Oxytocics; Oxytocin; Promoter Regions, Genetic; Synaptophysin

Polycystic ovary syndrome (PCOS) is commonly associated with metabolic disorders, which are exacerbated by obesity. Recent studies have revealed that oxytocin contributes to metabolic, appetite, and body weight regulation. In the present study, we evaluated the effects of chronic administration of oxytocin on body weight, food intake, and fat mass in a dihydrotestosterone-induced rat model of PCOS. Body weight, body weight change, and relative cumulative food intake were significantly lower in the oxytocin-treated PCOS rats than in the vehicle-treated control PCOS rats. Similarly, visceral adipocyte size was significantly smaller in the oxytocin-treated PCOS rats than in the vehicle-treated control PCOS rats. On the other hand, the numbers of cystic follicles in the ovary did not differ between the two groups. The chronic administration of oxytocin did not affect the rats' serum aspartate aminotransferase, alanine aminotransferase, or lactate dehydrogenase levels, indicating that it does not have adverse effects on hepatic function. These findings suggest that oxytocin could be a candidate drug for preventing the onset of obesity-related metabolic disorders in PCOS patients.

Topics: Adipocytes; Alanine Transaminase; Androgens; Animals; Aspartate Aminotransferases; Body Weight; Cell Size; Dihydrotestosterone; Disease Models, Animal; Eating; Female; Intra-Abdominal Fat; L-Lactate Dehydrogenase; Ovarian Cysts; Ovary; Oxytocics; Oxytocin; Polycystic Ovary Syndrome; Rats

The nonapeptide hormone oxytocin (OT) has pivotal brain roles in social recognition and interaction and is thus a promising therapeutic drug for social deficits. Because of its peptide structure, however, OT is rapidly eliminated from the bloodstream, which decreases its potential therapeutic effects in the brain. We found that newly synthesized OT analogues in which the Pro

Topics: ADP-ribosyl Cyclase 1; Animals; Autism Spectrum Disorder; Behavior, Animal; Calcium; Disease Models, Animal; Female; HEK293 Cells; Humans; Male; Membrane Glycoproteins; Mice; Mice, Inbred ICR; Mice, Knockout; Oxytocin; Receptors, Oxytocin; Social Behavior

Promising biomarkers would be used to improve the determination of diagnosis and severity, as well as the prediction of symptomatic and functional outcomes of schizophrenia.. In this study, we used three different mouse models induced by a genetic factor (PV-Cre; ErbB4. Among the evaluated neuropeptides, increased neurotensin tends to be associated with genetic factors of schizophrenia, increased orexin A seems to be a biomarker of an interplay between genetic and social isolation, while higher plasma oxytocin might be more apt to be responsive to social isolation. The potential biomarkers are mostly independent of sex.. This research would provide novel clues to develop circulating biomarkers of plasma neuropeptides for multifactorial schizophrenia.

Topics: Animals; Biomarkers; Disease Models, Animal; Female; Male; Mice; Neuropeptides; Oxytocin; Schizophrenia; Severity of Illness Index; Social Isolation

The search for new ligands to treat neuropathic pain remains a challenge. Recently, oxytocin has emerged as an interesting molecule modulating nociception at central and peripheral levels, but no attempt has been made to evaluate the effect of recurrent oxytocin administration in neuropathic pain. Using male Wistar rats with spinal nerve ligation, we evaluated the effects of recurrent spinal (1 nmol; given by lumbar puncture) or peripheral (31 nmol; given by intraplantar injection in the ipsilateral paw to spinal nerve ligation) oxytocin administration on pain-like behavior in several nociceptive tests (tactile allodynia and thermal and mechanical hyperalgesia) on different days. Furthermore, we used an electrophysiological approach to analyze the effect of spinal 1 nmol oxytocin on the activity of spinal dorsal horn wide dynamic range cells. In neuropathic rats, spinal or peripheral oxytocin partially restored the nociceptive threshold measured with the von Frey filaments (tactile allodynia), Hargreaves (thermal hyperalgesia) and Randall-Selitto (mechanical hyperalgesia) tests for 12 days. These results agree with electrophysiological data showing that spinal oxytocin diminishes the neuronal firing of the WDR neurons evoked by peripheral stimulation. This effect was associated with a decline in the activity of primary afferent Aδ- and C-fibers. The above findings show that repeated spinal or peripheral oxytocin administration attenuates the pain-like behavior in a well-established model of neuropathic pain. This study provides a basis for addressing the therapeutic relevance of oxytocin in chronic pain conditions.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Hyperalgesia; Injections, Intramuscular; Injections, Spinal; Male; Neuralgia; Nociception; Oxytocin; Rats; Rats, Wistar

Oxytocin (OT) has been reported to have a protective effect in lipopolysaccharide-induced experimental acute lung injury (ALI). However, its role in heat stroke-related ALI has never been investigated. Herein, we aimed to explore the therapeutic effects and potential mechanism of action of OT on heat-induced ALI. Rats were treated with OT 60 min before the start of heat stress (42 °C for 80 min). Twenty minutes after the termination of heat stress, the effects of OT on lung histopathological changes, edema, acute pleurisy and the bronchoalveolar fluid levels of inflammatory cytokines and indicators of ischemia, cellular damage, and oxidative damage were assessed. We also evaluated the influence of OT pretreatment on heat-induced hypotension, hyperthermia, ALI score, and death in a rat model of heat stroke. The results showed that OT significantly reduced heat-induced lung edema, neutrophil infiltration, hemorrhage score, myeloperoxidase activity, ischemia, and the levels of inflammatory and oxidative damage markers in bronchoalveolar lavage fluid. The survival assessment confirmed the pathophysiological and biochemical results. An OT receptor antagonist (L-368,899) was administered 10 min before the OT injection to further demonstrate the role of OT in heat-induced ALI. The results showed that OT could not protect against the aforementioned heat stroke responses in rats treated with L-368,899. Interestingly, OT treatment 80 min after the start of heat shock did not affect survival. In conclusion, our data indicate that OT pretreatment can reduce the ischemic, inflammatory and oxidative responses related to heat-induced ALI in rats.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Camphanes; Cytokines; Disease Models, Animal; Fever; Heat Stroke; Heat-Shock Response; Hypotension; Lung; Male; Neutrophil Infiltration; Oxytocin; Peroxidase; Piperazines; Protective Agents; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Survival Analysis

Autism-affected individuals are characterized by lower plasma oxytocin and its ectoenzyme regulator CD38. Oxytocin, a hypothalamic hormone secreted upon the release of CD38, plays a role in social behavior and bonding. All-trans retinoic acid is a potent inducer of CD38 and can be used as a novel therapeutic strategy in autism. We investigated the role of beta-carotene in rescuing autistic-like behavior in BALB/c and BTBR mice. Beta-carotene derivatives are preferred as they are neither toxic nor teratogenic. Beta-carotene at 0.1-5.0 mg/kg was administered orally to BALB/c and BTBR newborn mice on days 1-7. They were tested at age 2-3 months for five behavioral tests for "autism"; in addition, brain CD38, oxytocin, oxytocin receptor, Brain Derived Neurotrophic Factor (BDNF) and retinoic acid receptor gene expression, serum oxytocin levels, and neurological score were evaluated. Beta-carotene administered at birth significantly increased T-maze alternations and led to longer time spent with an unfamiliar mouse in the "three-chamber test" and less time spent in the empty chamber. Furthermore, enhanced activity in the open field test; increased time spent in the reciprocal social interaction test; decreased grooming and bedding behaviors; and enhanced brain CD38, oxytocin, oxytocin receptor, BDNF, retinoic acid gene expression, and serum oxytocin levels. No changes in neurological score were observed. Beta-carotene oral supplementation to BALB/c and BTBR mice at birth significantly reduced restricted and stereotyped behaviors and interests, increased social interactions and communication, CD38, and oxytocin, probably by enhancing brain neuroplasticity without toxicity. Thus, beta-carotene administered after birth to newborns of families predisposed to "autism" has the potential to prevent/ameliorate" autistic like behavior". These results support further clinical studies.

Topics: ADP-ribosyl Cyclase 1; Animals; Animals, Newborn; Autism Spectrum Disorder; Autistic Disorder; Behavior, Animal; beta Carotene; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Female; Interpersonal Relations; Male; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Oxytocin; Receptors, Retinoic Acid; Social Behavior

Currently, there are no established pharmaceutical strategies that effectively treat social deficits in autism spectrum disorder (ASD). Oxytocin, a neurohormone that plays a role in multiple types of social behaviors, has been proposed as a possible therapeutic against social impairment and other symptoms in ASD. However, from the standpoint of pharmacotherapy, oxytocin has several liabilities as a standard clinical treatment, including rapid metabolism, low brain penetrance, and activity at the vasopressin (antidiuretic hormone) receptors. The present studies describe findings from a preclinical screening program to evaluate oxytocin receptor (OXTR) agonists and oxytocin metabolites for potential clinical use as more optimal treatments. We first investigated two synthetic oxytocin analogs, TC-OT-39 and carbetocin, using in vitro cell-based assays for pharmacological characterization and behavioral tests in the BALB/cByJ mouse model of ASD-like social deficits. Although both TC-OT-39 and carbetocin selectively activate the OXTR, neither synthetic agonist had prosocial efficacy in the BALB/cByJ model. We next evaluated two oxytocin metabolites: OT(4-9) and OT(5-9). While OT(5-9) failed to affect social deficits, the metabolite OT(4-9) led to significant social preference in the BALB/cByJ model, in a dose-dependent manner. The increased sociability was observed at both 24 h and 12 days following the end of a subchronic regimen with OT(4-9) (2.0 mg/kg). Overall, these results suggest that the prosocial effects of oxytocin could be mediated by downstream activity of oxytocin metabolites, raising the possibility of new pathways to target for drug discovery relevant to ASD.

Topics: Animals; Autism Spectrum Disorder; Compulsive Behavior; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Male; Mice, Inbred BALB C; Oxytocin; Psychotropic Drugs; Receptors, Oxytocin; Social Behavior

The neuropeptide oxytocin (OXT) plays a critical role in the regulation of social and emotional behaviors. OXT plays a role in stress response and in drug reward, but to date no studies have evaluated its implication in the long-lasting increase of the motivational effects of cocaine induced by repeated social defeat (RSD). During the social defeat procedure, 1 mg/kg of OXT was administered 30 min before each episode of RSD. Three weeks after the last defeat, the effects of cocaine on the conditioned place preference (CPP), locomotor sensitization and the self-administration (SA) paradigms were evaluated. The influence of OXT on the levels of BDNF in the prefrontal cortex (PFC), striatum and hippocampus was also measured. Our results confirm that raising the levels of OXT during social defeat stress can block the long-lasting effects of this type of stress. OXT counteracts the anxiety induced by social defeat and modifies BDNF levels in all the structures we have studied. Moreover, OXT prevents RSD-induced increases in the motivational effects of cocaine. Administration of OXT before each social defeat blocked the social defeat-induced increment in the conditioned rewarding effects of cocaine in the CPP, favored the extinction of cocaine-associated memories in both the CPP and SA, and decreased reinstatement of cocaine-seeking behavior in the SA. In conclusion, the long-lasting effects of RSD are counteracted by administering OXT prior to stress, and changes in BDNF expression may underlie these protective effects.

Topics: Animals; Anxiety; Brain-Derived Neurotrophic Factor; Cocaine; Conditioning, Classical; Conditioning, Operant; Corpus Striatum; Disease Models, Animal; Hippocampus; Male; Mice; Oxytocin; Prefrontal Cortex; Reinforcement, Psychology; Reward; Self Administration; Stress, Psychological

Guizhi Fuling capsule (GFC) was an important traditional Chinese herbal medicine used for the treatment of primary dysmenorrheal (PD). The aim of this study was to evaluate the anti-dysmenorrheal effect of GFC on dysmenorrheal rats induced by oxytocin and to investigate its mechanism of action. An integrative urinary metabolomic study based on

Topics: Animals; Biomarkers; Capsules; Chromatography, High Pressure Liquid; Disease Models, Animal; Drugs, Chinese Herbal; Dysmenorrhea; Estradiol; Female; Humans; Medicine, Chinese Traditional; Metabolome; Metabolomics; Oxytocin; Proton Magnetic Resonance Spectroscopy; Rats; Rats, Wistar; Tandem Mass Spectrometry

Prematurity and fetal growth restriction (FGR) are frequent conditions associated with adverse neurocognitive outcomes. We have previously identified early deregulation of genes controlling neuroinflammation as a putative mechanism linking FGR and abnormal trajectory of the developing brain. While the oxytocin system was also found to be impaired following adverse perinatal events, its role in the modulation of neuroinflammation in the developing brain is still unknown. We used a double-hit rat model of perinatal brain injury induced by gestational low protein diet (LPD) and potentiated by postnatal injections of subliminal doses of interleukin-1β (IL1β) and a zebrafish model of neuroinflammation. Effects of the treatment with carbetocin, a selective, long lasting, and brain diffusible oxytocin receptor agonist, have been assessed using a combination of histological, molecular, and functional tools in vivo and in vitro. In the double-hit model, white matter inflammation, deficient myelination, and behavioral deficits have been observed and the oxytocin system was impaired. Early postnatal supplementation with carbetocin alleviated microglial activation at both transcriptional and cellular levels and provided long-term neuroprotection. The central anti-inflammatory effects of carbetocin have been shown in vivo in rat pups and in a zebrafish model of early-life neuroinflammation and reproduced in vitro on stimulated sorted primary microglial cell cultures from rats subjected to LPD. Carbetocin treatment was associated with beneficial effects on myelination, long-term intrinsic brain connectivity and behavior. Targeting oxytocin signaling in the developing brain may be an effective approach to prevent neuroinflammation - induced brain damage of perinatal origin.

Topics: Animals; Animals, Genetically Modified; Animals, Newborn; Brain; Brain Injuries; Cells, Cultured; Computational Biology; Diet, Protein-Restricted; Disease Models, Animal; Female; Green Fluorescent Proteins; Interleukin-1beta; Lipopolysaccharides; Microglia; Oxytocics; Oxytocin; Peptide Fragments; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Oxytocin; RNA, Messenger; Zebrafish

Primary dysmenorrhea affects the quality of life in young women, particularly school and work performance. This study investigated the mechanisms of penehyclidine hydrochloride (PHC) efficacy on a rat model of primary dysmenorrhea. The model was induced by injecting both estradiol benzoate and oxytocin. Different doses of PHC were administrated intraperitoneally following estradiol benzoate administration. Writhing scores were assessed, and pathological changes of the uterus were observed via hematoxylin and eosin staining. Western blot and real-time PCR were used to evaluate the expression level of the M

Topics: Animals; Behavior, Animal; Calcium; Disease Models, Animal; Dysmenorrhea; Estradiol; Female; Oxytocin; Pain; Quinuclidines; Rats, Sprague-Dawley; Receptor, Muscarinic M3; Toll-Like Receptor 3; Toll-Like Receptor 4; Uterus

This study aimed to demonstrate the effects of oxytocin on penile tissues in ischemia-reperfusion injury developed after priapism.. Forty Wistar Albino strain male rats were divided into four groups. The control group (n = 10) was not intervened. In Group 2, a rat model of priapism was constructed and maintained for 1 h. In Group 3, reperfusion was ensured for 30 min following priapism. Rats in Group 4 rats were given oxytocin 30 min before the induction of reperfusion following priapism. All rats were penectomized, and adequate amounts of blood sample were drawn. Inflammation, vasocongestion, desquamation, and edema in penile tissue were scored between 0 and 3 points (0: normal, 1: mild, 2: moderate, 3: severe) to evaluate the severity of tissue damage. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the levels of malondialdehyde (MDA), and nitric oxide (NO) in blood samples were determined spectrophotometrically.. In histopathological examination, statistically significant positive changes were detected in vasocongestion, inflammation, desquamation, and edema scores in Group 4 than in Group 2 and Group 3 (p < 0.001). Biochemical test results revealed that NO levels were significantly lower in Group 4 than in Group 3 (p < 0.001). Serum GSH-Px activities in Group 4 significantly increased when compared with the other groups 2 and 3 (p = 0.002, p = 0.001, respectively). There was no statistical difference among the groups regarding SOD activities and MDA levels (p > 0.05).. Oxytocin protected against priapism-induced ischemia-reperfusion injury developed in cavernosal tissue as observed based on histopathological and biochemical evidence. Although this is an experimental study, oxytocin can be thought as an alternative drug in the treatment of priapism.

Topics: Animals; Disease Models, Animal; Glutathione Peroxidase; Male; Malondialdehyde; Nitric Oxide; Oxytocin; Penis; Priapism; Protective Factors; Rats; Rats, Wistar; Reperfusion Injury; Severity of Illness Index; Superoxide Dismutase; Time Factors

Oxytocin reduces primary sensory afferent excitability and produces analgesia in part through a peripheral mechanism, yet its actions on physiologically characterized, mechanically sensitive afferents in normal and neuropathic conditions are unknown. We recorded intracellularly from L4 dorsal root ganglion neurons characterized as low-threshold mechanoreceptors (LTMRs) or high-threshold mechanoreceptors (HTMRs) in female rats 1 week after L5 partial spinal nerve injury or sham control (n = 24 rats/group) before, during, and after ganglionic perfusion with oxytocin, 1 nM. Nerve injury desensitized and hyperpolarized LTMRs (membrane potential [Em] was -63 ± 1.8 mV in sham vs -76 ± 1.4 mV in nerve injury; P < 0.001), and sensitized HTMRs without affecting Em. In nerve-injured rats, oxytocin depolarized LTMRs towards normal (Em = -69 ± 1.9 mV) and, in 6 of 21 neurons, resulted in spontaneous action potentials. By contrast, oxytocin hyperpolarized HTMRs (Em = -68 ± 2.7 mV before vs -80 ± 3.2 mV during oxytocin exposure; P < 0.01). These effects were reversed after removal of oxytocin, and oxytocin had minimal effects in neurons from sham surgery animals. Sensory afferent neurons immunopositive for the vasopressin 1a receptor were larger (34 ± 6.3 μm, range 16-57 μm) than immunonegative neurons (26 ± 3.4 μm, range 15-43 μm; P < 0.005). These data replicate findings that neuropathic injury desensitizes LTMRs while sensitizing HTMRs and show rapid and divergent oxytocin effects on these afferent subtypes towards normal, potentially rebalancing input to the central nervous system. Vasopressin 1a receptors are present on medium to large diameter afferent neurons and could represent oxytocin's target.

Topics: Action Potentials; Afferent Pathways; Animals; Disease Models, Animal; Electric Stimulation; Female; Ganglia, Spinal; Mechanoreceptors; Nociceptors; Oxytocin; Pain Threshold; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; Sensory Receptor Cells; Touch

Women with long QT syndrome 2 (LQT2) have a particularly high postpartal risk for lethal arrhythmias. We aimed at investigating whether oxytocin and prolactin contribute to this risk by affecting repolarization.. In female transgenic LQT2 rabbits (HERG-G628S, loss of IKr), hormone effects on QT/action potential duration (APD) were assessed (0.2-200 ng/L). Hormone effects (200 ng/L) on ion currents and cellular APD were determined in transfected cells and LQT2 cardiomyocytes. Hormone effects on ion channels were assessed with qPCR and western blot. Experimental data were incorporated into in silico models to determine the pro-arrhythmic potential. Oxytocin prolonged QTc and steepened QT/RR-slope in vivo and prolonged ex vivo APD75 in LQT2 hearts. Prolactin prolonged APD75 at high concentrations. As underlying mechanisms, we identified an oxytocin- and prolactin-induced acute reduction of IKs-tail and IKs-steady (-25.5%, oxytocin; -13.3%, prolactin, P < 0.05) in CHO-cells and LQT2-cardiomyocytes. IKr currents were not altered. This oxytocin-/prolactin-induced IKs reduction caused APD90 prolongation (+11.9%/+13%, P < 0.05) in the context of reduced/absent IKr in LQT2 cardiomyocytes. Hormones had no effect on IK1 and ICa,L in cardiomyocytes. Protein and mRNA levels of CACNA1C/Cav1.2 and RyR2 were enhanced by oxytocin and prolactin. Incorporating these hormone effects into computational models resulted in reduced repolarization reserve and increased propensity to pro-arrhythmic permanent depolarization, lack of capture and early afterdepolarizations formation.. Postpartum hormones oxytocin and prolactin prolong QT/APD in LQT2 by reducing IKs and by increasing Cav1.2 and RyR2 expression/transcription, thereby contributing to the increased postpartal arrhythmic risk in LQT2.

Topics: Action Potentials; Animals; Disease Models, Animal; Female; Heart Conduction System; Long QT Syndrome; Myocytes, Cardiac; Oxytocin; Postpartum Period; Prolactin; Rabbits

Women with Marfan syndrome (MFS) are at high risk for pregnancy-associated aortic dissection. Pathogenic models that singularly invoke hemodynamic stress are difficult to reconcile with predominant postnatal occurrence of aortic tear, often occurring weeks to months after delivery. In consideration of events that peak at term, are sustained after delivery, and might synergize with previously defined signaling pathways implicated in aneurysm progression, we examined the hormone oxytocin, which initiates uterine contraction and milk letdown for the duration of lactation through phosphorylation of extracellular signal-regulated kinase (ERK). In a mouse model of MFS that shows highly penetrant postnatal aortic dissection, risk was strongly attenuated by preventing lactation or use of an oxytocin receptor antagonist. Survival correlated inversely with the extent of ERK activation in the aortic wall, and strong protection was observed upon attenuation of ERK phosphorylation using an inhibitor of ERK kinase (MEK) or the U.S. Food and Drug Administration-approved medication hydralazine, offering potential therapeutic strategies for pregnancy-associated vascular catastrophe in the setting of MFS.

Topics: Adrenergic beta-Antagonists; Animals; Aorta; Aortic Dissection; Disease Models, Animal; Female; Hydralazine; Lactation; MAP Kinase Signaling System; Marfan Syndrome; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Oxytocin; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Propranolol; Protein Kinase Inhibitors; Survival Analysis

Doxorubicin-induced (DXR) cardiomyopathy is a serious health issue in oncology patients. Effective treatment of this clinical situation still remains to be discovered. In this experimental animal study, we aimed to define therapeutic effects of liraglutide, oxytocin and granulocyte colony-stimulating factor in DXR-induced cardiomyopathy model. 40 male Sprague-Dawley rats were included to study. 32 rats were given doxorubicin (DXR) for cardiomyopathy model. DXR was administered intraperitonally (i.p.) at every other day of 2.5 mg/kg/day at six times. Eight rats were taken as normal group and no treatment was performed. 32 rats given doxorubicin were divided into 4 groups. Group 1 rats were assigned to a placebo group and was given with a 0.9% NaCl saline solution at a dose of 1 ml/kg/day i.p. (DXR + saline), Group 2 rats were given with 1.8 mg/kg/day of Liraglutide i.p. (DXR + LIR), Group 3 rats were given with 160 μg/kg/day oxytocin i.p. (DXR + OX), Group 4 rats were given with 100 μg/kg/day filgrastim i.p. (DXR + G-CSF). All medications were given for 15 days. On day 16, under anesthesia, ECG was recorded from derivation I. After that, blood samples were taken by tail vein puncture for biochemical analysis. Finally, the animals were euthanized and the heart removed and prepared for immunohistochemical examination. All three treatments were shown to ameliorate the toxic effect of doxorubicin in cardiac tissue with the best results in DXR + OX group. DXR + OX group had the most preserved tissue integrity examined by light microscopy, least immune expression level of CASPASE-3 (5.3 ± 0.9) (p < 0.001) the highest ECG QRS wave voltage amplitude (0.21 ± 0.008 mV) (p < 0.00001) least plasma MDA (115.3 ± 19.8 nm) (p < 0.001), TNF-alpha (26.6 ± 3.05 pg/ml) (p < 0.001), pentraxin-3 (2.7 ± 0.9 ng/ml) (p < 0.001), Troponin T (1.4 ± 0.08 pg/ml) (p < 0.001), pro-BNP (11.1 ± 3.6 pg/ml) (p < 0.001) levels among all three treatment groups. Consistent with previous literature, we found that OX treatment decreased oxidative, apoptotic and inflammatory activity in DXR-induced cardiomyopathy rat model as well as provided better tissue integrity and better results in clinically relevant measures of ECG assessment, plasma Troponin T and pro-BNP levels. LIR and G-CSF treatment caused similar results with less powerful effects. Our findings suggest that with the best results in OX treatment group, all three agents including LIR and G-CSF attenuates DXR-induced cardiomyopathy in

Topics: Animals; Apoptosis; C-Reactive Protein; Cardiomyopathies; Cardiotoxicity; Caspase 3; Disease Models, Animal; Doxorubicin; Granulocyte Colony-Stimulating Factor; Heart Rate; Humans; Inflammation Mediators; Lipid Peroxidation; Liraglutide; Malondialdehyde; Myocytes, Cardiac; Natriuretic Peptide, Brain; Oxidative Stress; Oxytocin; Rats, Sprague-Dawley; Serum Amyloid P-Component; Signal Transduction; Troponin T; Tumor Necrosis Factor-alpha

To investigate whether oxytocin can prevent ototoxicity related to acoustic trauma.. Twenty-eight rats were divided into four groups: noise (group 1), control (group 2), noise plus oxytocin (group 3), and oxytocin (group 4). Intratympanic oxytocin was administered on days 1, 2, 4, 6, 8 and 10 in groups 3 and 4. Groups 1 and 3 were exposed to acoustic trauma. Distortion product otoacoustic emission and auditory brainstem response testing were performed in all groups.. In group 1, auditory brainstem response thresholds increased significantly after acoustic trauma. In group 3, auditory brainstem response thresholds increased significantly on day 1 after acoustic trauma, but there were no significant differences between thresholds at baseline and on the 7th and 21st days. In group 1, significant differences were observed between distortion product otoacoustic emission signal-to-noise ratios measured before and on days 1, 7 and 21 after acoustic trauma. In group 3, no significant differences were observed between the distortion product otoacoustic emission signal-to-noise ratios measured before and on days 7 and 21 after acoustic trauma.. Oxytocin had a therapeutic effect on rats exposed to acoustic trauma in this experiment.

Topics: Animals; Biopsy, Needle; Disease Models, Animal; Evoked Potentials, Auditory, Brain Stem; Hearing Loss, Noise-Induced; Immunohistochemistry; Injections, Intralesional; Male; Otoacoustic Emissions, Spontaneous; Oxytocin; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Signal-To-Noise Ratio; Statistics, Nonparametric; Treatment Outcome; Tympanic Membrane

It is known that regular physical activity reduces anxiety. Low anxiety levels affect mood, emotions, and empathy. Oxytocin is a powerful hormone that regulates social interaction, sexual reproduction, maternal–infant bonding, milk release, empathy, and anxiety. Empathy is an important behavior in the living community; and also important for sportsmen during sportive competition and daily living life, because sportsmen are also role model of people.. To investigate the effects of voluntary physical activity on oxytocin, anxiety, and empathy levels as well as the relationship between them.. Animal experiment.. Male and female mice were made to exercise in running wheel cages for 6 weeks. Their empathy and anxiety levels were evaluated by using Helping Behavior test and elevated plus maze and open field test, respectively. And then the brain and blood oxytocin levels were measured.. Empathy-like behavior was improved in both genders of the exercise groups (door-opening time decreased in both genders of exercise groups, p for both=0.0001). As a response to exercise, both the brain and serum oxytocin levels increased in female mice (both of p=0.0001); however, in males, oxytocin levels increased in only the brain (p<0.05). Anxiety levels decreased in all the exercise groups (increased time spent in the middle area of open field test, both genders, p=0.002; increased time spent in the open arms of elevated plus maze test, females p=0.004, males p=0.0001). There was a strong negative correlation between serum oxytocin levels and door opening time of helping behavior equipment, and moderate negative correlation was found between the brain oxytocin levels and door-opening time of helping behavior equipment in females. However, there was no correlation between both the brain and serum oxytocin levels and empathy behavior in males. But there were very strong positive correlations between low anxiety indicators and both the brain and serum oxytocin levels in both the genders.. Voluntary physical activity decreases anxiety and increases empathy-like behavior in mice; which is associated with increased oxytocin levels in female mice but not in male mice. Further research is required to investigate the mechanisms of exercise effect on anxiety and empathic brain pathways in males.

Topics: Animals; Anxiety; Behavior Rating Scale; Brain; Disease Models, Animal; Empathy; Female; Male; Mice; Oxytocin; Physical Conditioning, Animal; Statistics, Nonparametric

Acute lung injury (ALI) is one of the leading causes of death in sepsis. Endothelial inflammation and dysfunction play a prominent role in development of ALI. Glycolysis is the predominant bioenergetic pathway for endothelial cells (ECs). However, the role of EC glycolysis in ALI of sepsis remains unclear. Here we show that both the expression and activity of PFKFB3, a key glycolytic activator, were markedly increased in lipopolysaccharide (LPS)-treated human pulmonary arterial ECs (HPAECs) in vitro and in lung ECs of mice challenged with LPS in vivo. PFKFB3 knockdown significantly reduced LPS-enhanced glycolysis in HPAECs. Compared with LPS-challenged wild-type mice, endothelial-specific Pfkfb3 knockout (Pfkfb3

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Endotoxemia; Glycolysis; Humans; Inflammation; Intercellular Adhesion Molecule-1; Lipopolysaccharides; Lung; Mice; Monocytes; NF-kappa B; Oxytocin; Phosphofructokinase-2; Pulmonary Edema; Sepsis; Signal Transduction; Vascular Cell Adhesion Molecule-1

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by changes in social interactions, impaired language and communication, fear responses and presence of repetitive behaviours. Although the genetic bases of ASD are well documented, the recent increase in clinical cases of idiopathic ASD indicates that several environmental risk factors could play a role in ASD aetiology. Among these, maternal exposure to psychosocial stressors during pregnancy has been hypothesized to affect the risk for ASD in offspring. Here, we tested the hypothesis that preconceptional stressful experiences might also represent crucial elements in the aetiology of ASD. We previously showed that social isolation stress during adolescence results in a marked decrease in the brain and plasma concentrations of progesterone and in the quality of maternal care that these female rats later provide to their young. Here we report that male offspring of socially isolated parents showed decreased agonistic behaviour and social transmission of flavour preference, impairment in reversal learning, increased seizure susceptibility, reduced plasma oxytocin levels, and increased plasma and brain levels of BDNF, all features resembling an ASD-like phenotype. These alterations came with no change in spatial learning, aggression, anxiety and testosterone plasma levels, and were sex-dependent. Altogether, the results suggest that preconceptional stressful experiences should be considered as crucial elements for the aetiology of ASD, and indicate that male offspring of socially isolated parents may be a useful animal model to further study the neurobiological bases of ASD, avoiding the adaptations that may occur in other genetic or pharmacologic experimental models of these disorders.

Topics: Animals; Autism Spectrum Disorder; Behavior, Animal; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Female; Hippocampus; Isoniazid; Male; Maternal Exposure; Oxytocin; Paternal Exposure; Phenotype; Prefrontal Cortex; Pregnancy; Rats; Seizures; Social Behavior; Social Isolation; Stress, Psychological; Testosterone

Topics: Animals; Autistic Disorder; Blood-Brain Barrier; Disease Models, Animal; Female; HEK293 Cells; Humans; Interpersonal Relations; Ligands; Male; Mice; Mice, Knockout; Psychotropic Drugs; Pyrazoles; Pyrrolidines; Receptors, Opioid, mu; Receptors, Oxytocin; Structure-Activity Relationship

Oxytocin (OXT) has been considered as a neuroregulator mediating social behaviors and stress-related disorders. Recent clinical studies suggest that OXT might also act as antidepressant in postpartum depression (PPD) patients, but the mechanism is still unknown. In the present study, we explored the effect of OXT in paraventricular nucleus (PVN) and possible signaling pathway involved in a PPD rat model induced by gestation restraint stress (GRS). PPD rats exhibited depressive-like behaviors with significantly longer immobility time, shorter climbing time, and lower sucrose consumption compared to the control rats. Plasma corticosterone (CORT) level was also higher in PPD rats. While PVN and supraoptic nucleus (SON) are main OXT synthesis regions in the brain, GRS-induced decrease of mRNA and peptide level of OXT was seen only in PVN. The expression of TrkB in PVN was increased in PPD rats. Local injection of OXT (20ng) into PVN reversed GRS-induced depressive-like behaviors and high plasma CORT level in PPD rats. Moreover, injection of OXT also reversed GRS-induced increase of TrkB in PVN of PPD rats. All those data suggest that OXT plays an antidepressant role by, at least in part, modulating HPA axis via TrkB in PVN of PPD rats.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Corticosterone; Depression; Depression, Postpartum; Disease Models, Animal; Female; Hypothalamo-Hypophyseal System; Injections, Intraventricular; Male; Oxytocin; Paraventricular Hypothalamic Nucleus; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; RNA, Messenger; Social Behavior; Stress, Psychological

The neuropeptide oxytocin (OT) is a key regulator of social and emotional behaviors. The effects of OT are context dependent, and it has been proposed that OT increases the salience of both positive and negative social cues. Here we tested whether the bed nucleus of the stria terminalis (BNST) mediates anxiogenic effects of OT.. First, we studied the effects of systemic administration of an OT receptor (OTR) antagonist L-368,899 on social behavior in male and female California mice exposed to social defeat. We examined the effect of L-368,899 on G protein activation and used early growth response factor 1 immunohistochemistry to identify potential sites of OTR action. Finally, we examined the effects of L-368,899 infused in the BNST on behavior.. A single dose of systemic L-368,899 increased social approach in stressed female mice and decreased social approach in male mice naïve to defeat. L-368,899 prevented OT activation of G proteins and did not activate G proteins in the absence of OT. Intranasal OT, which reduces social approach in female mice but not male mice, increased early growth response factor 1 immunoreactivity in the nucleus accumbens core and anteromedial BNST in female mice but not in male mice. Stressed female mice that received an infusion of L-368,899 into the anteromedial BNST but not the nucleus accumbens core increased social approach and decreased social vigilance responses.. Our results suggest that OTR activation in anteromedial BNST induces a vigilance response in which individuals avoid, yet attend to, unfamiliar social contexts. Our results suggest that OTR antagonists may have unappreciated therapeutic potential for stress-induced psychiatric disorders.

Topics: Animals; Behavior, Animal; Camphanes; Disease Models, Animal; Female; Male; Mice; Nucleus Accumbens; Oxytocin; Piperazines; Receptors, Oxytocin; Septal Nuclei; Sex Characteristics; Social Behavior; Stress, Psychological

Different mechanisms will be activated during ischemic stroke. Calpain proteases play a pivotal role in neuronal death after ischemia damage through apoptosis. Anti-apoptotic activities of the oxytocin (OT) in different ischemic tissues were reported in previous studies. Recently, a limited number of studies have noted the protective effects of OT in the brain. In the present study, the neuroprotective potential of OT in an animal model of transient middle cerebral artery occlusion (tMCAO) and the possible role of calpain-1 in the penumbra region were assessed.. Adult male Wistar rats underwent 1 hour of tMCAO and were treated with nasal administration of OT. After 24 hours of reperfusion, infarct size was evaluated by triphenyltetrazolium chloride. Immunohistochemical staining and Western blotting were used to examine the expression of calpain-1. Nissl staining was performed for brain tissue morphology evaluation.. OT reduced the infarct volume of the cerebral cortex and striatum compared with the ischemia control group significantly (P < .05). Calpain-1 overexpression, which was caused by ischemia, decreased after OT administration (P < .05). The number of pyknotic nuclei in neurons increased dramatically in the ischemic area and OT attenuated the apoptosis of neurons in the penumbra region (P < .01).. We provided evidence for the neuroprotective role of OT after tMCAO through calpain-1 attenuation.

Topics: Administration, Intranasal; Animals; Apoptosis; Brain; Calpain; Disease Models, Animal; Infarction, Middle Cerebral Artery; Male; Neurons; Neuroprotective Agents; Nitric Oxide; Oxytocin; Rats, Wistar; Receptors, Oxytocin; Reperfusion Injury; Signal Transduction; Time Factors

Approximately 1.7 million Americans sustain a traumatic brain injury (TBI) each year and chronic pain is a common complication.. We studied the effects of intranasally administered oxytocin as a potential treatment for chronic pain in an animal model of mild TBI.. The lateral fluid percussion model of mild TBI was chosen for this purpose and after exposure to mild TBI the rats (n = 12) developed hind paw and facial allodynia compared to sham animals (n = 6). Oxytocin or a vehicle was afterwards administered intranasally and reactive pain was assessed by hind paw and facial von Frey testing. Some animals received the oxytocin receptor antagonist, atosiban, in addition to oxytocin/vehicle treatment (n = 12). The effect of oxytocin on ongoing and spontaneous pain was examined through conditioned place preference testing. To determine whether the effects of intranasal oxytocin could be attributed to delivery via the peripheral blood stream, some TBI animals received an intravenous injection of the same oxytocin dose that was given intranasally. ELISA immunoassays were carried out (n = 6) to measure concentrations of oxytocin in the trigeminal ganglia, pons, spinal cord, and olfactory bulb after intranasal administration and evaluate the most likely route of entry.. These studies confirmed that the fluid percussion model can be used to study post-TBI facial allodynia. Oxytocin attenuated both reactive and spontaneous, ongoing non-reactive pain following mild TBI for at least 3-4 hours after intranasal administration by binding to OT or VA1-receptors most likely by a peri-trigeminal nerve mediated uptake.. Intranasal oxytocin attenuates measures of reactive and non-reactive pain in a model of mild TBI and may represent a novel treatment for chronic pain in TBI patients.

Topics: Administration, Intranasal; Administration, Intravenous; Animals; Behavior, Animal; Brain Concussion; Chronic Pain; Disease Models, Animal; Facial Pain; Hormone Antagonists; Hyperalgesia; Male; Oxytocin; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Vasotocin

Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the bloodstream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application. The aim of this study is to evaluate the disposition, nasal absorption, and therapeutic potential of OXT after nasal administration. The pharmacokinetics of OXT after intravenous bolus injection to rats followed a two-compartment model, with a rapid initial half-life of 3 min. The nasal bioavailability of OXT was approximately 2%. The brain concentration of OXT after nasal application was much higher than that after intravenous application, despite much lower concentrations in the plasma. More than 95% of OXT in the brain was directly transported from the nasal cavity. The in vivo stress-relief effect by OXT was observed only after intranasal administration. These results indicate that pharmacologically active OXT was effectively delivered to the brain after intranasal administration. In conclusion, the nasal cavity is a promising route for the efficient delivery of OXT to the brain.

Topics: Administration, Intranasal; Animals; Autism Spectrum Disorder; Behavior, Animal; Biological Availability; Brain; Disease Models, Animal; Humans; Injections, Intravenous; Male; Mice; Oxytocin; Rats; Rats, Wistar; Stress, Psychological; Treatment Outcome

The goal of this work was to investigate a new nasal carrier for enhanced drug delivery to brain, we call Phospholipid Magnesome. The system contains soft phospholipid vesicles, composed of phospholipid, water, propylene glycol, magnesium salt, and the mucoadhesive polymer, alginate. The carrier was characterized by various methods: electron microscopy, calorimetry, and dynamic light scattering. The ability of the carrier's vesicles to entrap various molecules was studied by CLSM and ultracentrifugation combined with HPLC quantification. Mucoadhesivity of the carrier was tested in vitro using porcine nasal mucosa. The delivery of rohdamine 6G, insulin, and epidermal growth factor was estimated by two methods, multiphoton microscopy and near infrared (NIR) imaging. Pharmacodynamic effects of nasal treatment with oxytocin and insulin incorporated in Phospholipid Magnesome were evaluated in animal models. Results show that the system is composed of soft multilamellar nanosized vesicles with the ability to entrap both lipophilic and hydrophilic molecules. The mucoadhesivity test results indicate a prolonged contact time of the drug with the nasal membrane as compared to control. Multiphoton microscopy and NIR imaging of brain show effective delivery of the tested molecules to brain following nasal administration in Phospholipid Magnesome relative to controls. Moreover, the results of the pharmacodynamic study measuring the antinociceptive effect of oxytocin administrated nasally to an animal model indicate the efficiency of the Phospholipid Magnesome as compared to three control systems. Further, nasal administration of insulin resulted in a strong and prolonged hypoglycemic effect for the drug incorporated in the new carrier but not for control systems. Based on the results of the histopathological test, the carrier is safe for local administration on the nasal membrane. In conclusion, the results of this study suggest that Phospholipid Magnesome nasal carrier is able to improve drug effects, probably by a combined mechanism, absorption enhancement, and prolongation of mucosal contact.

Topics: Administration, Intranasal; Alginates; Animals; Brain; Brain Chemistry; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; Female; Glucuronic Acid; Hexuronic Acids; Hyperglycemia; Insulin; Mice; Oxytocin; Pain; Particle Size; Phosphatidylcholines; Rats

Oxytocin reduces cued reinstatement of cocaine seeking in male and female rats, but the underlying neurobiology has not been uncovered. The majority of effort on this task has focused on oxytocin and dopamine interactions in the nucleus accumbens core. The nucleus accumbens core is a key neural substrate in relapse, and oxytocin administration in the nucleus accumbens core reduces reinstatement to methamphetamine cues. Further, the nucleus accumbens core has strong glutamatergic innervation from numerous regions including the prefrontal cortex. Thus, we hypothesize that oxytocin regulates presynaptic glutamate terminals in the nucleus accumbens core, thereby affecting reinstatement.. To begin to evaluate this hypothesis, we examined the effects of intra-nucleus accumbens core oxytocin on extracellular glutamate levels in this region. We next determined if direct infusion of oxytocin into the nucleus accumbens core could attenuate cued reinstatement of cocaine seeking in a manner dependent on metabotropic glutamate 2/3 receptors. Finally, we tested if site-specific application of oxytocin in the prefrontal cortex reduced cued reinstatement of cocaine seeking.. We found an increase in nucleus accumbens core extracellular glutamate for several minutes following reverse dialysis of oxytocin. In male and female rats with a history of cocaine self-administration, site-specific application of oxytocin in the nucleus accumbens core and prefrontal cortex had opposing effects, decreasing and increasing cued reinstatement, respectively. The mGlu2/3 antagonist LY-341495 reversed oxytocin's ability to attenuate cued reinstatement.. While the precise mechanism by which oxytocin increases nucleus accumbens core glutamate is yet to be determined, the present results clearly support oxytocin mediation of glutamate neurotransmission in the nucleus accumbens core that impacts cued cocaine seeking.

Topics: Animals; Behavior, Animal; Cocaine; Cocaine-Related Disorders; Cues; Disease Models, Animal; Dopamine Uptake Inhibitors; Female; Glutamic Acid; Male; Nucleus Accumbens; Oxytocin; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology

Epidemiological evidence suggests that exposure to infection during early development increases the risk for neurodevelopmental disorders associated with symptoms such as a decreased desire to engage in social interactions. In animals, disruptions in social behavior can be modelled by administering bacterial mimetics such as liposaccharide (LPS). However, when evaluating social interactions in the laboratory, attention is rarely directed on the reciprocal relationship as a whole, which is important as peers may drive social withdrawal. Previously, we have shown that male adolescent rats treated neonatally (n) with LPS receive less contact from their conspecifics in a social interaction test, and that this effect is mediated through olfactory communication. In the present study, we reconfirmed this effect using a more direct social test and evaluated the hypothesis that changes in the microbiome underlie the olfactory induced social aversion. Male and female Sprague-Dawley rats were administered nLPS (50 μg/kg, i.p) or nSaline on postnatal days (P)3 and 5. On P40, adolescent nLPS treated males received less contact in a social preference test compared to nSaline treated controls, an effect not observed in females. To confirm that nLPS led male rats to elicit a scent cue, resulting in social aversion, a subset of neurotypical conspecifics underwent an anosmia procedure that disrupted their olfactory processing via olfactory neuroepithelium degeneration. This normalized the contact that they directed towards nLPS and nSaline male rats. Although 16 s rRNA sequencing failed to detect significant differences in bacterial phyla across either sex or neonatal treatment, treating male nLPS rats with an antibiotic cocktail, which induced clear changes in microbial communities, diminished the social rejection effect. Therefore, manipulation of the microbiome appears to affect social communication where there exists an underlying deficit. Moreover, our data reaffirm that social engagement is a reciprocal process and the behavior of all individuals within a dynamic interaction should be evaluated.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Brain; Disease Models, Animal; Escherichia coli; Female; Gene Expression; Inflammation; Lipopolysaccharides; Male; Microbiota; Olfaction Disorders; Oxytocin; Rats, Sprague-Dawley; RNA, Bacterial; RNA, Ribosomal, 16S; Sex Factors; Smell; Social Behavior

Environmental conditions, such as stress and environmental enrichment (EE), influence predisposition to alcohol use/abuse; however, the underlying mechanisms remain unknown. To assess the effect of environmental conditions on the initial rewarding effects of alcohol, we examined conditioned place-preference (CPP) to alcohol following exposure to EE in mice. Since social context is a major factor contributing to initial alcohol-drinking, we also assessed the impact of EE on the levels of the "social neuropeptide" oxytocin (OT) and its receptor, OTR. Finally, we assessed the effect of pharmacological manipulations of the oxytocinergic system on EE-induced alcohol CPP. While EE increased sociability and reduced anxiety-like behaviors, it caused a ∼3.5-fold increase in alcohol reward compared to controls. EE triggered profound neuroadaptations of the oxytocinergic system; it increased hypothalamic OT levels and decreased OTR binding in the prefrontal cortex and olfactory nuclei of the brain. Repeated administration of the OT analogue carbetocin (6.4 mg/kg/day) mimicked the behavioral effects of EE on ethanol CPP and induced similar brain region-specific alterations of OTR binding as those observed following EE. Conversely, repeated administration of the OTR antagonist L,369-899 (5 mg/kg/day) during EE exposure, but not during the acquisition of alcohol CPP, reversed the pronounced EE-induced ethanol rewarding effect. These results demonstrate for the first time, a stimulatory effect of environmental enrichment exposure on alcohol reward via an oxytocinergic-dependent mechanism, which may predispose to alcohol abuse. This study offers a unique prospective on the neurobiological understanding of the initial stages of alcohol use/misuse driven by complex environmental-social interplay.

Topics: Alcohol Drinking; Alcohol-Related Disorders; Animals; Brain; Central Nervous System Depressants; Conditioning, Psychological; Disease Models, Animal; Environment; Ethanol; Housing, Animal; Mice; Oxytocin; Receptors, Oxytocin; Reward; Spatial Behavior

The neuropeptide oxytocin plays an evolutionarily conserved role in mammalian social behavior. Despite striking effects on animal social behavior after intracerebroventricular drug delivery, this delivery mode is impractical in humans. Intranasal oxytocin delivery provides a noninvasive alternative to increase central oxytocin activity, and has shown promise as a treatment for psychiatric illnesses. Intranasal oxytocin delivery is purported to increase central oxytocin concentrations via channels surrounding trigeminal and olfactory nerve fibers, which may facilitate increased activity at central oxytocin receptors. This report outlines the evidence for intranasal oxytocin delivery increasing central concentrations or activity, identifies current knowledge gaps and highlights future research opportunities. Recent efforts to enhance intranasal oxytocin delivery via improved intranasal delivery technology and dose-ranging studies are discussed.

Topics: Absorption, Physiological; Administration, Intranasal; Animals; Behavior, Animal; Brain; Disease Models, Animal; Excipients; Humans; Mental Disorders; Nasal Mucosa; Oxytocin; Social Behavior

Perinatal administration of serotonin (5HT) agonist 5-methoxytryptamine (5MT) induces developmental hyperserotonemia (DHS; elevated blood serotonin) and produces behavioral and neurochemical changes in rats relevant to Autism Spectrum Disorder (ASD), such as oxytocin dysregulation. Disruption of the oxytocin system may underlie many of the social deficits present in ASD individuals, thus we investigated the mechanism(s) underlying DHS-induced oxytocin dysregulation. The most parsimonious mechanism of 5HT action would be alteration of 5HT receptors on oxytocin cells; 5HT is known to influence cell survival as well as influence oxytocin release via 5HT

Topics: 5-Methoxytryptamine; Animals; Autism Spectrum Disorder; Autistic Disorder; Disease Models, Animal; Female; Hypothalamus; Male; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Serotonin; Sex Characteristics; Sex Factors; Sexual Behavior

Oxytocin (OT) has the suppressive effects on breast tumor formation and development. We hypothesized that OT through the NF-κB inhibition can induce the miR-195 up-regulation which it can promote the cell apoptosis and inhibit the cell proliferation. Thirty-two BALB/c female mice were equally divided into four groups to study the effects of OT and atosiban (ATO) (an oxytocin receptor antagonist) on the mammary tumor growth. The animal weight, OT plasma concentration, and the tumor weight and volume were measured. Moreover, the tumor-related signaling pathways including NF-κB, miR-195, and Cyclin D1 were evaluated by qPCR assays, and Akt and ERK proteins were assessed by western blot at the end of the study. The volume and weight of tumors were significantly decreased after OT administration. The phosphorylated Akt and ERK expressions were significantly decreased in the OT group compared to the tumor group. In contrast, the dephosphorylated Akt and ERK expressions were significantly increased in the OT group in comparison with the tumor group. The mRNA expressions of miR-195, OTR, and Bax genes were significantly increased, and the mRNA expression of ERα, PI3K, NF-κB, cyclin D1 and Bcl-2 genes were decreased in the OT group in comparison with the tumor group. Interestingly, ATO administration reversed these effects. These results can exhibit a new therapeutic potential for OT on the down-regulation of the NF-κB and up-regulation of miR-195 and consequently, decrease of the tumor volume and weight in a mouse model of breast cancer.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Proliferation; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; MicroRNAs; NF-kappa B; Oxytocin; Signal Transduction

Adolescent intermittent ethanol exposure (AIE) produces lasting, sex-specific social anxiety-like alterations in male, but not female rats. Oxytocin (OXT) and vasopressin (AVP) brain systems play opposite roles in regulating social preference/avoidance, with OXT increasing approach to, and AVP increasing avoidance of social stimuli.. To test the hypothesis that social anxiety-like alterations seen in adult males after AIE are associated with a shift in the balance between OXT and AVP toward AVP, effectiveness of pharmacological activation of the OXT system and blockade of endogenous activity at AVP receptors for reversing AIE-induced social anxiety-like alterations was assessed, along with examination of the effects of AIE on OXT, vasopressin V1a, and V1b receptor (OXT-R, V1a-R, and V1b-R) surface expression in the hypothalamus.. Sprague-Dawley male and female rats were given 4 g/kg ethanol (AIE) or water intragastrically every 48 h for a total of 11 exposures during postnatal days (P) 25-45. On P70-72, animals were given a social interaction test following administration of a selective OXT-R agonist WAY-267464, selective V1a-R antagonist SR-49059, or V1b-R antagonist SSR-149415, and hypothalamic tissue was collected.. Social anxiety-like behavior was induced by AIE in males but not females, and was selectively reversed by the selective OXT-R agonist and V1b-R antagonist, but not V1a-R antagonist. AIE was also found to decrease OXT-R, but increase V1b-R neuronal surface expression relative to water-exposed controls in the hypothalamus of males, but not females.. These findings demonstrate that AIE induces changes in OXT-R and AVP-R surface expression in the hypothalamus along with social anxiety-like alterations in male rats. These social anxiety-like alterations can be reversed either by activation of the OXT system or by suppression of the AVP system, data that support the hypothesis that social anxiety-like alterations induced by adolescent alcohol exposure in male rats are associated at least in part with an OXT/AVP imbalance.

Topics: Animals; Anxiety; Disease Models, Animal; Ethanol; Female; Hypothalamus; Male; Oxytocin; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; Sex Factors; Social Behavior; Vasopressins

Oxytocin (OT) elicits weight loss in diet-induced obese (DIO) rodents, nonhuman primates and humans by reducing food intake and increasing energy expenditure. In addition to being important in the regulation of energy balance, OT is involved in social behaviors including parent-infant bonds, friendships, and pair bonds. However, the impact of social context on susceptibility to diet-induced obesity (DIO) and feeding behavior (including food sharing) has not been investigated in a rodent model that forms strong social bonds (i.e. prairie vole). Our goals were to determine in Prairie voles (Microtus ochrogaster) whether i) social context impacts susceptibility to DIO and ii) chronic intranasal OT reverses DIO. Voles were housed in divided cages with holes in the divider and paired with a same-sex animal with either the same food [high fat diet (HFD)/HFD, [low fat diet (LFD; chow)/chow], or the opposite food (HFD/chow or chow/HFD) for 19 weeks. HFD-fed voles pair-housed with voles maintained on the HFD demonstrated increased weight relative to pair-housed voles that were both maintained on chow. The study was repeated to determine the impact of social context on DIO susceptibility and body composition when animals are maintained on purified sugar-sweetened HFD and LFD to enhance palatability. As before, we found that voles demonstrated higher weight gain on the HFD/HFD housing paradigm, in part, through increased energy intake and the weight gain was a consequence of an increase in fat mass. However, HFD-fed animals housed with LFD-fed animals (and vice versa) showed intermediate patterns of weight gain and evidence of food sharing. Of translational importance is the finding that chronic intranasal OT appeared to reduce weight gain in DIO voles through a decrease in fat mass with no reduction in lean body mass. These effects were associated with transient reductions in food intake and increased food sharing. These findings identify a role of social context in the pathogenesis of DIO and indicate that chronic intranasal OT treatment reduces weight gain and body fat mass in DIO prairie voles, in part, by reducing food intake.

Topics: Adipose Tissue; Administration, Intranasal; Animals; Anti-Obesity Agents; Arvicolinae; Diet, High-Fat; Disease Models, Animal; Disease Susceptibility; Eating; Female; Male; Obesity; Oxytocin; Sex Factors; Social Behavior; Social Environment; Weight Gain

Disturbance of neurotransmitters and neuromodulators is thought to underlie the pathophysiology of autism spectrum disorder (ASD). Studies of 15q dup mouse models of ASD with human 15q11-13 duplication have revealed that restoring serotonin (5-HT) levels can partially reverse ASD-related symptoms in adults. However, it remains unclear how serotonin contributes to the behavioral symptoms of ASD. In contrast, oxytocin (OXT) has been found to involve social and affiliative behaviors. In this study, we examined whether serotonin-OXT interaction during the early postnatal period plays a critical role in the restoration of social abnormality in 15q dup mice. OXT or the 5-HT

Topics: Animals; Animals, Newborn; Autism Spectrum Disorder; Autistic Disorder; Brain; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Oxytocin; Serotonin; Social Behavior

Deficits in empathy, the ability to share an emotion of another individual, constitute a hallmark of several psychopathological conditions, including conduct disorder. The co-occurrence of excess rates of aggression, general violation of societal norms and callous-unemotional traits confers specific risk for adult psychopathy. In the present study, we relied on a recently devised experimental model of conduct disorder in mice to test the potential efficacy of intranasal oxytocin administration. Two subgroups of BALB/cJ male mice exhibiting opposite profiles in emotional contagion (i.e. socially transmitted adoption of another's emotional states) underwent a series of tests mapping onto reactive aggression, information processing, perseverative behaviour, punishment-related emotional memory, physiological arousal and hormonal stress reactivity, with or without intranasal oxytocin administration (5.0 or 20.0 μg/kg). Collectively, our data indicate that a trait of markedly reduced emotional contagion is associated with a behavioural syndrome of sensorimotor gating deficits, impaired emotional memory, increased aggression and stereotyped behaviours, dysregulations in the circadian rhythms of activity and body temperature and dampened physiological reactivity to external stressors. Moreover, in the absence of changes in oxytocin receptor density in the neural network involved in empathy-like behaviour, we showed that oxytocin administration normalised emotional contagion, aggression and behavioural stereotypies, thereby ameliorating the phenotype of mice characterised by deficient empathy-like behaviour. Besides, oxytocin led to a lower, more prolonged neuroendocrine response of the HPA-axis to stress in all mice. Ultimately, current data support the notion that oxytocin may constitute a valid therapeutic approach in disturbances characterised by abnormal aggression and excess callousness.

Topics: Administration, Intranasal; Aggression; Animals; Brain; Conduct Disorder; Disease Models, Animal; Emotions; Empathy; Individuality; Male; Memory; Mice, Inbred BALB C; Oxytocin; Psychotropic Drugs; Punishment; Random Allocation; Receptors, Oxytocin; Social Behavior; Stress, Psychological

Recently, it has been suggested that oxytocin (OT) might play a role in the control of bone remodeling and in bone health of young and adult females. The purpose of this study was to evaluate the effect of osteogenic medium (OM) plus OT (OM + OT; 100 nmol/L) on osteoblastic differentiation of bone marrow mesenchymal stem cells (BMMSCs) from cyclic adult (12 months old) and acyclic aging (24 months old) female Wistar rats. After 14 days, OM + OT increased the oxytocin and oxytocin receptor in the BMMSCs from animals of both age groups relative to OM controls. Alkaline phosphatase activity was higher in the OM + OT than OM group in BMMSCs from 24-month-old female rats. OM + OT improved osteogenic differentiation, observed by anticipated mineralization and increased gene expression of bone morphogenetic protein 2, bone sialoprotein, osteopontin and osteocalcin in both aged relative to OM controls. These findings suggest a role for OT as an adjuvant to induce osteoblastic differentiation of BMMSCs from aged female rat.

Topics: Aging; Alkaline Phosphatase; Animals; Bone Morphogenetic Protein 2; Cell Differentiation; Cell Survival; Cells, Cultured; Disease Models, Animal; Female; Mesenchymal Stem Cells; Osteoblasts; Osteogenesis; Oxytocin; Rats; Rats, Wistar

Posttraumatic stress disorder (PTSD) is a trauma-induced mental disorder characterized by fear extinction abnormalities, which involve biological dysfunctions among fear circuit areas in the brain. Oxytocin (OXT) is a neuropeptide that regulates sexual reproduction and social interaction and has recently earned specific attention due to its role in adjusting neurobiological and behavioral correlates of PTSD; however, the mechanism by which this is achieved remains unclear. The present study aimed to examine whether the effects of OXT on traumatic stress-induced abnormalities of fear extinction (specifically induced by single prolonged stress (SPS), an animal model of PTSD) are associated with pro-inflammatory cytokines. Seven days after SPS, rats received intranasal OXT 40 min before a cue-dependent Pavlovian fear conditioning-extinction test in which rats' freezing degree was used to reflect the outcome of fear extinction. We also measured mRNA expression of

Topics: Animals; Brain; Corticosterone; Cytokines; Disease Models, Animal; Extinction, Psychological; Fear; Inflammation; Inflammation Mediators; Male; Memory; Models, Biological; Oxytocin; Rats, Sprague-Dawley; RNA, Messenger; Stress Disorders, Post-Traumatic; Stress, Psychological

Chronic stress conditions can lead to considerable and extensible changes in physiological and psychological performances, and in emergence of risk for various somatic diseases. On the other hand, the neuropeptide oxytocin is reported to increase the resistance of the organism to stress and modulate activity of autonomic nervous system. Chronic corticosterone administration is used as a rat model for a state observed in terms of chronic stress exposure, when negative feedback mechanism of hypothalamus-pituitary-adrenal axis activity is disrupted. In our study, we aimed to investigate whether chronic administration of oxytocin (10 IU/400μL/day for 14days, s.c.) influenced adrenal gland morphology and activity in adult male Wistar rats during long-term corticosterone administration via drinking water (100mg/L for 21days). We examined the influence of treatments on the levels of adrenal gland hormones, corticosterone, adrenaline and noradrenaline, as well as their response to an acute stress challenge evoked by 15-min forced swimming. In addition, the expression of two main monoamine transporters, the noradrenaline transporter (NAT) and vesicular monoamine transporter 2 (VMAT2) in adrenal medulla was measured in the rats exposed to acute stress. Our results showed that oxytocin treatment prevented corticosterone-induced decrease in body weight gain, attenuated adrenal gland atrophy by increasing glandular weight, and the area of the zona fasciculate and reticularis. Chronic corticosterone intake blunted the response of all measured hormones to acute stress, whereas concomitant oxytocin treatment reversed adrenaline and noradrenaline response to acute stress. Furthermore, in adrenal medulla, oxytocin produced significant vasodilatation and stimulated expression of both catecholamine transporters detected both on mRNA and protein level. Our data suggest that oxytocin, by reducing atrophy of adrenal gland, and by increasing catecholamine storage capacity, may be beneficial in conditions accompanied with high glucocorticoid levels, such as chronic stress exposure.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; Body Weight; Catecholamines; Chronic Disease; Corticosterone; Disease Models, Animal; Epinephrine; Hypothalamo-Hypophyseal System; Male; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Oxytocin; Pituitary-Adrenal System; Rats; Rats, Wistar; Stress, Psychological; Vesicular Monoamine Transport Proteins

Necrotizing enterocolitis (NEC), a gastrointestinal inflammatory disease of unknown etiology that may also affect the liver, causes a great deal of morbidity and mortality in premature infants. We tested the hypothesis that signaling molecules, which are endogenous to the bowel, regulate the severity of intestinal and hepatic damage in an established murine NEC model. Specifically, we postulated that mucosal serotonin (5-HT), which is proinflammatory, would exacerbate experimental NEC and that oxytocin (OT), which is present in enteric neurons and is anti-inflammatory, would oppose it. Genetic deletion of the 5-HT transporter (SERT), which increases and prolongs effects of 5-HT, was found to increase the severity of systemic manifestations, intestinal inflammation, and associated hepatotoxicity of experimental NEC. In contrast, genetic deletion of tryptophan hydroxylase 1 (TPH1), which is responsible for 5-HT biosynthesis in enterochromaffin (EC) cells of the intestinal mucosa, and TPH inhibition with LP-920540 both decrease the severity of experimental NEC in the small intestine and liver. These observations suggest that 5-HT from EC cells helps to drive the inflammatory damage to the gut and liver that occurs in the murine NEC model. Administration of OT decreased, while the OT receptor antagonist atosiban exacerbated, the intestinal inflammation of experimental NEC. Data from the current investigation are consistent with the tested hypotheses-that the enteric signaling molecules, 5-HT (positively) and OT (negatively) regulate severity of inflammation in a mouse model of NEC. Moreover, we suggest that mucosally restricted inhibition of 5-HT biosynthesis and/or administration of OT may be useful in the treatment of NEC.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Enterochromaffin Cells; Enterocolitis, Necrotizing; Enzyme Inhibitors; Inflammation; Intestinal Mucosa; Liver; Mice; Oxytocin; Phenylalanine; Pyrimidines; Serotonin; Serotonin Plasma Membrane Transport Proteins; Severity of Illness Index; Signal Transduction; Tryptophan Hydroxylase

Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2weeks improved prenatal VPA-induced social interaction deficits for at least 24h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model.

Topics: Animals; Autistic Disorder; Behavior, Animal; Disease Models, Animal; Female; Hippocampus; Interpersonal Relations; Male; Mice; Mice, Inbred ICR; Oxytocin; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins c-fos; Recognition, Psychology; Social Behavior; Social Learning; Valproic Acid

Oxytocin may be a possible treatment for multiple neuropsychiatric disorders, including cocaine addiction. Little is known about the site-specific effects of oxytocin on various drug addiction-related brain regions. Furthermore, sexually dimorphic effects of oxytocin on neural function in the addiction circuit have not been established. Here, we studied Fos expression following cocaine-cued reinstatement in both male and female rats.. Male and female rats underwent self-administration, extinction, and reinstatement tests. On test days, rats were given oxytocin or vehicle, and lever pressing was measured in response to conditioned cocaine cues. Rats were perfused and Fos staining measured in the central amygdala, medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus. Fos/oxytocin double labeling occurred in the paraventricular nucleus of the hypothalamus.. Rats reinstated to cocaine cues relative to extinction responding and oxytocin reduced cocaine seeking. Oxytocin combined with contingent cue presentations increased Fos+ oxytocin cell bodies within the paraventricular nucleus of the hypothalamus relative to vehicle. Fos expression robustly increased in the central amygdala following oxytocin administration. Oxytocin reversed cue-induced Fos expression in the medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus. Central oxytocin infusion also attenuated reinstated cocaine seeking.. Oxytocin decreased reinstated cocaine seeking, increased Fos activation in the paraventricular nucleus of the hypothalamus and central amygdala, but normalized cue-induced Fos activation in the medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus, thereby demonstrating regionally specific activation patterns. No sex differences were seen for the effects of oxytocin on cocaine seeking and Fos activation, indicating that oxytocin acts on similar central neural circuits critical to reinstated cocaine seeking in both males and females.

Topics: Animals; Brain; Central Nervous System Agents; Cocaine; Cocaine-Related Disorders; Cues; Disease Models, Animal; Dopamine Uptake Inhibitors; Drug-Seeking Behavior; Female; Male; Neurons; Oxytocin; Proto-Oncogene Proteins c-fos; Rats, Sprague-Dawley; Self Administration

Nasal pretreatment with the neuropeptide oxytocin has been reported to prevent stress-induced impairments in hippocampal synaptic plasticity and spatial memory in rats. However, no study has asked if oxytocin application following a stress experience is effective in rescuing stress-induced impairments.. Synaptic plasticity was measured in hippocampal Schaffer collateral-CA1 synapses of rats subjected to uncontrollable stress; their cognitive function was examined using an object recognition task.. Impaired induction of long-lasting, long-term potentiation by uncontrollable stress was rescued, as demonstrated both in rats and hippocampal slices. Intranasal oxytocin after experiencing uncontrollable stress blocked cognitive impairments in stressed rats and in stressed hippocampal slices treated with a perfused bath solution containing oxytocin.. These results indicated that posttreatment with oxytocin after experiencing a stressful event can keep synaptic plasticity and cognition function intact, indicating the therapeutic potential of oxytocin for stress-related disorders, including posttraumatic stress disorder.

Topics: Administration, Intranasal; Animals; Disease Models, Animal; Hippocampus; Long-Term Potentiation; Male; Memory Disorders; Nootropic Agents; Oxytocin; Rats, Sprague-Dawley; Recognition, Psychology; Stress, Psychological; Tissue Culture Techniques

Alcohol (EtOH) is one of the most widely abused recreational drugs and is arguably the most harmful. However, current treatment options for alcohol-use disorders generally have limited efficacy and poor uptake in the community. In this context, the neuropeptide oxytocin (OXT) has emerged as a promising potential treatment option for a number of substance-use disorders, including alcoholism. The utility of OXT in reducing consumption of and craving for a wide range of substances may lie in its ability to modulate drug-induced neurochemical effects within the mesolimbic dopamine pathway. However, the impact of OXT on EtOH actions in this pathway has yet to be explored. Here, we reveal that an acute intracerebroventricular (icv) infusion of OXT (1 µg/5 µl) attenuated voluntary EtOH (20 percent) self-administration after chronic intermittent access to EtOH for 59 days (28 drinking sessions) in male Wistar rats. Next, we demonstrated that an acute intraperitoneal (ip) injection of EtOH (1.5 g/kg, 15 percent w/v) increased dopamine release within the nucleus accumbens in both EtOH-naive rats and rats that had received 10 daily ip injections of EtOH. Icv OXT completely blocked the EtOH-induced dopamine release in both EtOH-naive and chronically treated rats. The attenuation of EtOH-induced dopamine release by OXT may help to explain the reduced EtOH self-administration observed following icv OXT infusion.

Topics: Alcohol Drinking; Alcoholism; Animals; Disease Models, Animal; Dopamine; Ethanol; Male; Nucleus Accumbens; Oxytocics; Oxytocin; Rats; Rats, Wistar

Few studies have addressed likely gene × gene (ie, epistatic) interactions in mediating risk for schizophrenia. Using a preclinical genetic approach, we investigated whether simultaneous disruption of the risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) would produce a disease-relevant phenotypic profile different from that observed following disruption to either gene alone. NRG1 heterozygotes exhibited hyperactivity and disruption to prepulse inhibition, both reversed by antipsychotic treatment, and accompanied by reduced striatal dopamine D2 receptor protein expression, impaired social cognition, and altered glutamatergic synaptic protein expression in selected brain areas. Single gene DISC1 mutants demonstrated a disruption in social cognition and nest-building, altered brain 5-hydroxytryptamine levels and hippocampal ErbB4 expression, and decreased cortical expression of the schizophrenia-associated microRNA miR-29b. Co-disruption of DISC1 and NRG1, indicative of epistasis, evoked an impairment in sociability and enhanced self-grooming, accompanied by changes in hypothalamic oxytocin/vasopressin gene expression. The findings indicate specific behavioral correlates and underlying cellular pathways downstream of main effects of DNA variation in the schizophrenia-associated genes NRG1 and DISC1.

Topics: Amphetamines; Animals; Behavior, Animal; Brain; Disease Models, Animal; Endophenotypes; Epistasis, Genetic; Female; Grooming; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Nesting Behavior; Neuregulin-1; Oxytocin; Prepulse Inhibition; Psychomotor Agitation; Psychotic Disorders; Schizophrenia; Social Behavior; Vasopressins

The aim of the present study is to investigate the protective effects of oxytocin (OT) on diabetic neuropathy (DNP) in rats.. Eighteen rats were used to induce diabetes using single dose streptozotocin (STZ, 60 mg/kg). Diabetic DNP was verified by electromyography (EMG) and motor function test on 21st day following STZ injection. Six rats served as naïve control group and received no drug (n = 6). Following EMG, diabetic rats were randomly divided into three groups and administered with either 1 ml/kg saline or 80 μg/kg OT or 160 μg/kg OT intraperitoneally for four weeks. Then, EMG, motor function test, biochemical analysis (plasma lipid peroxides and glutathione), histological, and immunohistochemical analysis of sciatic nerves (bax, caspase 3, caspase 9, and NGF) were performed.. Diabetic rats developed neuropathy, which was apparent from decreased compound muscle action potentials amplitudes and prolonged distal latency in saline-treated rats (p < 0.001) whereas 160 μg/kg OT significantly improved EMG findings. OT treatment significantly lessened the thickening of perineural fibrosis when compared with saline group (p < 0.001). Besides, OT significantly reduced plasma lipid peroxides (p < 0.05) and increased glutathione levels in diabetic rats (p < 0.001). The sciatic nerves of saline-treated rats showed considerable increase in bax, caspase 3 and caspase 8 expressions (p < 0.001) while OT treatment significantly suppressed these apoptosis markers. Also, OT improved NGF expression in diabetic rats compared to saline group.. Present results demonstrate that OT appears to alleviate harmful effects of hyperglycemia on peripheral neurons by suppressing inflammation, oxidative stress and apoptotic pathways.

Topics: Analysis of Variance; Animals; bcl-2-Associated X Protein; Blood Glucose; Body Weight; Caspase 3; Caspase 8; Diabetic Neuropathies; Disease Models, Animal; Electromyography; Evoked Potentials, Motor; Glutathione; Lipid Peroxides; Male; Motor Activity; Muscle, Skeletal; Nerve Growth Factor; Oxytocics; Oxytocin; Rats; Rats, Sprague-Dawley; Schwann Cells; Sciatic Nerve; Streptozocin

Recent findings concerning oxytocin indicate its anti-inflammatory, cardioprotective and parasympathetic modulating properties. In this study, we investigated the effects of systemically applied oxytocin on the cardiorespiratory activity in a rodent model of moderate endotoxemia.. Telemetrically recorded electrocardiogram (ECGs) from animals which received lipopolysaccharide (LPS); oxytocin (Ox); lipopolysaccharide+oxytocin (LPS+Ox), or vehicle (V) were analyzed using the ECG-derived respiration (EDR) technique to estimate the respiratory rate. The mean R-R interval and the spectral parameters of heart rate variability (HRV), such as the natural logarithm of the high frequency (lnHF) and low frequency (lnLF) components were also estimated up to 24h after treatment.. The endotoxemic animals (LPS) showed an elevated respiratory rate as well as a reduced mean R-R interval, lnHF and lnLF components compared to controls (V) from +5 to +12h after the treatment. The administration of oxytocin significantly attenuated the hyperventilation produced by the LPS-induced endotoxemia (LPS+Ox) and restored the values of the mean R-R interval and such spectral parameters at different time points.. Our results support the existence of a link among the respiratory, cardiovascular, and immune systems in which oxytocin seems to act as a potential cardioprotective peptide by favoring cardiac cholinergic autonomic coupling. As a result, oxytocin diminished animal's endotoxemic tachypnea and restored the cardiorespiratory interactions, which was indicated by the spectral components of HRV.

Topics: Animals; Blood Pressure; Disease Models, Animal; Electrocardiography; Endotoxemia; Heart Rate; Lipopolysaccharides; Male; Oxytocin; Rats; Respiratory Rate

Oxytocin (OXT) is a neuropeptide hormone synthesized and secreted by hypothalamic neurons and has been reported to play a significant role in pain modulation. However, the mechanisms underlying OXT's antinociceptive effect on neuropathic pain are not fully understood. In this study, we examined the peripheral effect of OXT on mechanical hypersensitivity induced by partial ligation of the infraorbital nerve (PNL) in rats. Mechanical hypersensitivity in the whisker pad skin after PNL was attenuated by the direct administration of OXT into the trigeminal ganglion (TG). The proportion of vasopressin-1A receptor (V1A-R)-immunoreactive, but not OXT-receptor-immunoreactive, neurons significantly increased among TG neurons innervating the whisker pad skin after PNL. In a patch-clamp recording from TG neurons isolated from PNL rats, the resting membrane potential of OXT-treated neurons was significantly decreased, and the current thresholds of OXT-treated neurons for spike generation (rheobases) were significantly greater than those of vehicle-treated neurons. In addition, OXT increased voltage-gated K channel currents in PNL animals. Furthermore, intra-TG administration of a selective V1A-R antagonist reversed the OXT-induced alleviation of mechanical hypersensitivity, and coapplication of the antagonist opposed OXT's effects on the resting membrane potential, rheobase, and K current. These findings suggest that OXT is effective at suppressing TG neuronal hyperexcitability after nerve injury, likely by modulation of voltage-gated K channels through V1A-R. This signaling mechanism represents a potential therapeutic target for the treatment of orofacial neuropathic pain.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Facial Pain; Hormone Antagonists; Hyperalgesia; Indoles; Male; Membrane Potentials; Neurons; Oxytocin; Pain Threshold; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Receptors, Vasopressin; Trigeminal Ganglion; Vibrissae

The lysosomal carboxypeptidase A, Cathepsin A (CathA), is a serine protease with two distinct functions. CathA protects

Topics: Animals; Behavior, Animal; Cathepsin A; Disease Models, Animal; Endothelin-1; Hippocampus; Learning; Male; Memory Consolidation; Memory Disorders; Memory, Long-Term; Mice; Mice, Inbred C57BL; Oxytocin; Spatial Memory

Mutations in the synaptic gene

Topics: Animals; Behavior, Animal; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 22; Disease Models, Animal; Hippocampus; Nerve Tissue Proteins; Oxytocin; Prefrontal Cortex; Rats; Social Behavior

Mother-infant contact has a critical role on brain development and behavior. Experiencing early-life adversities (such as maternal separation stress or MS in rodents) results in adaptations of neurotransmission systems, which may subsequently increase the risk of depression symptoms later in life. In this study, we show that Oxytocin (OT) exerted antioxidant and anti-inflammatory properties. Previous studies indicate that neuroinflammation and mitochondrial dysfunction are associated with the pathophysiology of depression. To investigate the antidepressant-like effects of OT, we applied MS paradigm (as a valid animal model of depression) to male mice at postnatal day (PND) 2 to PND 14 (3h daily, 9AM to 12AM) and investigated the depressive-like behaviors of these animals at PND 60 in different groups. Animals in this work were divided into 4 experimental groups: 1) saline-treated, 2) OT-treated, 3) atosiban (OT antagonist)-treated and, 4) OT+ atosiban-treated mice. We used forced swimming test (FST), splash test, sucrose preference test (SPT) and open field test (OFT) for behavioral assessment. Additionally, we used another set of animals to investigate the effects of MS and different treatments on mitochondrial function and the expression of the relevant genes for neuroinflammation. Our results showed that MS provoked depressive- like behaviors in the FST, SPT and splash test. In addition, our molecular findings revealed that MS is capable of inducing abnormal mitochondrial function and immune-inflammatory response in the hippocampus. Further, we observed that treating stressed animals with OT (intracerebroventricular, i.c.v. injection) attenuated the MS-induced depressive-like behaviors through improving mitochondrial function and decreasing the hippocampal expression of immune-inflammatory genes. In conclusion, we showed that MS-induced depressive-like behaviors in adult male mice are associated with abnormal mitochondrial function and immune-inflammatory responses in the hippocampus, and activation of OTergic system has protective effects against negative effects of MS on brain and behavior of animals.

Topics: Animals; Behavior, Animal; Depression; Disease Models, Animal; Hippocampus; Hormone Antagonists; Inflammation; Male; Maternal Deprivation; Mice; Mitochondrial Diseases; Oxytocin; Vasotocin

Gastric electrical stimulation (GES) has great potential for the treatment of obesity. We investigated the impact of chronic GES on the alteration of adipose tissue and the regulation of neuropeptide Y (NPY), orexin (OX), α-melanocyte-stimulating hormone (α-MSH) and oxytocin (OXT), and their receptors in several tissues.. Most of the experiments included three groups of diet-induced obesity rats: (1) sham-GES (SGES); (2) GL-6mA (GES with 6 mA, 4 ms, 40 Hz, 2 s on, 3 s off at lesser curvature); and (3) SGES-PF (SGES rats receiving pair feeding to match the consumption of GL-6mA rats). Chronic GES was applied for 2 h every day for 4 weeks. During treatment with GES, food intake and body weight were monitored weekly. The alteration of epididymal fat weight, gastric emptying, and expression of peptides and their receptors in several tissues were determined.. GL-6mA was more potent than SGES-PF in decreasing body weight gain, epididymal fat tissue weight, adipocyte size and gastric emptying. Chronic GES significantly altered NPY, OX, α-MSH and OXT and their receptors in the hypothalamus, adipose tissue and stomach.. Chronic GES effectively leads to weight loss by reducing food intake, fat tissue weight and gastric emptying. NPY, α-MSH, orexin and OXT, and their receptors in the hypothalamus, adipose tissue and stomach appear to be involved in the anti-obesity effects of chronic GES.

Topics: Adipocytes; alpha-MSH; Animals; Disease Models, Animal; Eating; Electric Stimulation Therapy; Electrodes, Implanted; Epididymis; Gastric Emptying; Gastric Mucosa; Ghrelin; Hypothalamus; Intra-Abdominal Fat; Leptin; Male; Neuropeptide Y; Obesity; Orexin Receptors; Orexins; Oxytocin; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 3; Receptors, G-Protein-Coupled; Receptors, Melanocortin; Receptors, Neuropeptide; Receptors, Neuropeptide Y; Receptors, Oxytocin; RNA, Messenger; Weight Loss

Previous studies suggest that oxytocin (OT) negatively modulates adipogenesis while promoting osteogenesis in vitro. Because of its effects on marrow stromal cells, OT might have potential utility in therapy for glucocorticoid-induced osteoporosis (GIO).. To explore the effects of OT on marrow adipogenesis in a rabbit model of GIO.. Thirty-six-month-old female New Zealand rabbits were randomly assigned to the control, GIO, and GIO + OT groups. Magnetic resonance (MR) spectroscopy and multi-detector computed tomography (MDCT) were performed to detect marrow fat content (MFC) and bone mineral density (BMD) at baseline, and 1, 2, and 3 months. After 3 months of treatment, marrow adipocytes were quantitatively evaluated by histopathology.. In the GIO group, MFC substantially increased from 34.1% to 43.2% at month 1, and it was maintained until month 3 (by 59.2%, all P <0.01). MFC values in the GIO group were significantly different from the control and OT-treated groups over time. Early OT treatment reversed marrow adiposity to levels of the controls. BMD values were significantly lower in the GIO group at months 2 and 3 compared to the controls; however, partial recovery of vertebral BMD (87.1% of baseline) and femoral BMD (89.3% of baseline) in the OT-treated group were observed. The mean diameter and density of adipocyte and percentage of adipocyte area increased by 30.0%, 70.1%, and 88.9%, respectively (all P <0.05) in the GIO group, but remained unchanged in the OT-treated group.. Early OT treatment was sufficient to eliminate glucocorticoid-induced marrow adiposity.

Topics: Adipocytes; Adipogenesis; Animals; Bone and Bones; Bone Density; Bone Marrow; Disease Models, Animal; Female; Glucocorticoids; Magnetic Resonance Spectroscopy; Methylprednisolone; Multidetector Computed Tomography; Oxytocin; Rabbits

Maternal obesity is associated with prolonged and dysfunctional labour and emergency caesarean section, but the mechanisms are unknown. The present study investigated the effects of an adiposity-inducing high-fat, high-cholesterol (HFHC) diet on uterine contractile-associated protein (CAP) expression and ex vivo uterine contractility in term non-labouring (TNL) and term labouring (TL) rats. Female rats were fed either control chow (CON n=20) or HFHC (n=20) diet 6 weeks before conception and during pregnancy. On gestational day 21 (TNL) or day 22 (TL) CON and HFHC (n=10) rats were killed to determine plasma cholesterol, triacylglycerol and progesterone concentrations and collection of myometrium for contractility studies and expression of CAPs caveolin-1 (Cav-1), connexin-43 (CX-43) and it's phosphorylated form (pCX-43), oxytocin receptor (OXTR) and cyclooxygenase-2 (COX-2). HFHC feeding increased visceral fat (P≤0.001), plasma cholesterol (P≤0.001) and triacylglycerol (P=0.039) concentrations. Stage of labour effected uterine expression of CAV-1 (P<0.02), pCX43 and COX-2 (both P<0.03). CAV-1 and pCX43 decreased but COX-2 increased with parturition. Significant diet- and labour-stage interactions were evident for CX-43 and pCX43 (P<0.03 and P<0.004 respectively). CX-43 decreased with TL in HFHC animals but was unaltered in CON. pCX-43 fell with labour in CON but remained high in HFHC. OXTR expression was significantly higher in HFHC compared with CON animals (P<0.03). Progesterone was higher in HFHC rats at term (P<0.014) but fell significantly with labour to similar concentrations as CON. Contractility studies identified synchronous contractions of stable amplitude in lean animals, but unstable asynchronous contractions with obesity. Uterine dose response to oxytocin was blunted during labour in HFHC rats with a log EC50 of -8.84 compared with -10.25 M in CON for integral activity (P<0.05). In conclusion, our adiposity model exhibits adverse effects on contractile activity during labour that can be investigated further to unravel the mechanisms causing uterine dystocia in obese women.

Topics: Animals; Caveolin 1; Cholesterol, Dietary; Connexin 43; Contractile Proteins; Cyclooxygenase 2; Diet, High-Fat; Dinoprost; Disease Models, Animal; Female; Lipids; Litter Size; Male; Obesity; Oxytocin; Pregnancy; Pregnancy Complications; Progesterone; Rats, Wistar; Uterine Contraction; Uterus; Weight Gain

Oxytocin (OT) is considered to be a stress-buffering hormone, dampening the physiologic effects of stress. However, OT can also be anxiogenic. We examined acute and long-lasting effects of social defeat on OT neurons in male and female California mice.. We used immunohistochemistry for OT and c-fos cells to examine OT neuron activity immediately after defeat (n = 6-9) and 2 weeks (n = 6-9) and 10 weeks (n = 4-5) later. We quantified Oxt messenger RNA with quantitative polymerase chain reaction (n = 5-9). Intranasal OT was administered to naïve and stressed mice tested in social interaction and resident-intruder tests (n = 8-14).. Acute exposure to a third episode of defeat increased OT/c-fos colocalizations in the paraventricular nucleus of both sexes. In the medioventral bed nucleus of the stria terminalis, defeat increased Oxt messenger RNA, total OT neurons, and OT/c-fos colocalizations in female mice but not male mice. Intranasal OT failed to reverse stress-induced social withdrawal in female mice and reduced social interaction behavior in female mice naïve to defeat. In contrast, intranasal OT increased social interaction in stressed male mice and reduced freezing in the resident-intruder test.. Social defeat induces long-lasting increases in OT production and OT/c-fos cells in the medioventral bed nucleus of the stria terminalis of female mice but not male mice. Intranasal OT largely reversed the effects of stress on behavior in male mice, but effects were mixed in female mice. These results suggest that changes in OT-sensitive networks contribute to sex differences in behavioral responses to stress.

Topics: Administration, Intranasal; Animals; Disease Models, Animal; Female; Male; Mice; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Proto-Oncogene Proteins c-fos; RNA, Messenger; Sex Characteristics; Social Behavior; Stress, Psychological; Time Factors

Social deficits are a hallmark feature of autism spectrum disorder (ASD) and related developmental syndromes. Although there is no standard treatment for social dysfunction, clinical studies have identified oxytocin as a potential therapeutic with prosocial efficacy. We have previously reported that peripheral oxytocin treatment can increase sociability and ameliorate repetitive stereotypy in adolescent mice from the C58/J model of ASD-like behavior. In the present study, we determined that prosocial oxytocin effects were not limited to the adolescent period, since C58/J mice, tested in adulthood, demonstrated significant social preference up to 2 weeks following subchronic oxytocin treatment. Oxytocin was also evaluated in adult mice with underexpression of the N-methyl-d-aspartate receptor NR1 subunit (encoded by Grin1), a genetic model of autism- and schizophrenia-like behavior. Subchronic oxytocin had striking prosocial efficacy in male Grin1 knockdown mice; in contrast, chronic regimens with clozapine (66 mg/kg/day) or risperidone (2 mg/kg/day) failed to reverse deficits in sociability. Neither the subchronic oxytocin regimen, nor chronic treatment with clozapine or risperidone, reversed impaired prepulse inhibition in the Grin1 knockdown mice. Overall, these studies demonstrate oxytocin can enhance sociability in mouse models with divergent genotypes and behavioral profiles, adding to the evidence that this neurohormone could have therapeutic prosocial efficacy across a spectrum of developmental disorders.

Topics: Animals; Autism Spectrum Disorder; Behavior, Animal; Choice Behavior; Disease Models, Animal; Female; Gene Knockdown Techniques; Hyperkinesis; Male; Mice; Nerve Tissue Proteins; Oxytocin; Prepulse Inhibition; Receptors, N-Methyl-D-Aspartate; Social Behavior

Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia. The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families, and there was dramatic phenotypic overlap among affected individuals who were independently ascertained without bias from clinical features. Analysis of the deletions revealed a ∼350 kb critical region on chromosome 6q16.1 that encompasses a gene for proneuronal transcription factor POU3F2, which is important for hypothalamic development and function. Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area. We show that this finding is consistent with the expression patterns of POU3F2 and related genes in the human brain. Our work helps to further delineate the neuro-endocrine control of energy balance/body mass and demonstrates that this molecular pathway is conserved across multiple species.

Topics: Adolescent; Adult; Animals; Basic Helix-Loop-Helix Transcription Factors; Body Mass Index; Cell Line; Child; Child, Preschool; Chromosomes, Human, Pair 6; Disease Models, Animal; Energy Metabolism; Female; Homeodomain Proteins; Humans; Hypothalamus; Intellectual Disability; Male; Middle Aged; Obesity; Oxytocin; Pedigree; Phenotype; POU Domain Factors; Repressor Proteins; Sequence Deletion; Young Adult; Zebrafish

Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.

Topics: Action Potentials; Animals; Cholecystokinin; Disease Models, Animal; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Inflammation; Neural Pathways; Neuralgia; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Quinoxalines; Rats; Rats, Wistar; Receptors, Oxytocin; Spinal Cord; Supraoptic Nucleus; Transduction, Genetic; Vasopressins; Vesicular Glutamate Transport Protein 2

Hypertension is a common outcome associated with obstructive sleep apnea (OSA), a prevalent yet poorly treated cardiovascular disease. Recent studies showed oxytocin (OXT), released from hypothalamic paraventricular nucleus (PVN) neurons, activates cardiac vagal neurons in the dorsal motor nucleus of the vagus (DMNX) and may blunt cardiovascular responses to stress. This study tests whether the release of OXT from PVN fibers in the DMNX is diminished with chronic intermittent hypoxia-hypercapnia (CIH/H) exposure, an animal model of OSA, and whether activation of PVN OXT neurons restores OXT release in the DMNX and prevents the hypertension resulting from CIH/H. To assess OXT release from PVN fibers, Chinese hamster ovarian (CHO) cells were engineered to be highly sensitive to OXT by stable expression of the human recombinant OXT receptor and the calcium indicator R-GECO1. PVN fibers in the DMNX were selectively photoactivated in vitro by expression of channelrhodopsin. The release of OXT onto CHO cells in the DMNX was blunted in rats exposed to 21 days of CIH/H. Chronic activation of PVN OXT neurons in vivo, using designer receptors exclusively activated by designer drugs, restored the release of OXT onto CHO cells in the DMNX. Chronic PVN OXT neuron activation in vivo also prevented the hypertension that occurred in conscious unrestrained telemetry-equipped sham rats exposed to 3 wk of CIH/H. These results demonstrate that chronic activation of OXT neurons restores the release of OXT from PVN fibers in the DMNX and prevents the hypertension that occurs with 3 wk of CIH/H exposure.

Topics: Animals; Biosensing Techniques; Blood Pressure; Channelrhodopsins; CHO Cells; Chronic Disease; Cricetulus; Disease Models, Animal; Hypercapnia; Hypertension; Hypoxia; Male; Neurons; Optogenetics; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats, Sprague-Dawley; Receptors, Oxytocin; Signal Transduction; Telemetry; Time Factors; Transfection

HPC-1/syntaxin1A (STX1A), a neuronal soluble N-ethylmaleimide-sensitive fusion attachment protein receptor, contributes to neural function in the CNS by regulating transmitter release. Recent studies reported that STX1A is associated with human neuropsychological disorders, such as autism spectrum disorder and attention deficit hyperactivity disorder. Previously, we showed that STX1A null mutant mice (STX1A KO) exhibit neuropsychological abnormalities, such as fear memory deficits, attenuation of latent inhibition, and unusual social behavior. These observations suggested that STX1A may be involved in the neuropsychological basis of these abnormalities. Here, to study the neural basis of social behavior, we analyzed the profile of unusual social behavior in STX1A KO with a social novelty preference test, which is a useful method for quantification of social behavior. Interestingly, the unusual social behavior in STX1A KO was partially rescued by intracerebroventricular administration of oxytocin (OXT). In vivo microdialysis studies revealed that the extracellular OXT concentration in the CNS of STX1A KO was significantly lower compared with wild-type mice. Furthermore, dopamine-induced OXT release was reduced in STX1A KO. These results suggested that STX1A plays an important role in social behavior through regulation of the OXTergic neural system. Dopamine (DA) release is reduced in CNS of syntaxin1A null mutant mice (STX1A KO). Unusual social behavior was observed in STX1A KO. We found that oxytocin (OXT) release, which was stimulated by DA, was reduced and was rescued the unusual social behavior in STX1A KO was rescued by OXT. These results indicated that STX1A plays an important role in promoting social behavior through regulation of DA-induced OXT release in amygdala.

Topics: Amygdala; Analysis of Variance; Animals; Benzoxazines; Disease Models, Animal; Dopamine; Dopamine Uptake Inhibitors; Exploratory Behavior; Female; Gene Expression Regulation; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microdialysis; Ovariectomy; Oxytocin; Piperazines; Piperidines; Receptors, Oxytocin; Social Behavior Disorders; Syntaxin 1

Sildenafil is a phosphodiesterase type 5 inhibitor mainly used for male erectile dysfunction. One of rare yet serious adverse effects of Sildenafil is its potential to decrease seizure threshold. Ample evidence suggests that Sildenafil exerts central effects through induction of Oxytocin (OT) secretion and CREB phosphorylation. The aim of the present study is to evaluate potential roles of OT and CREB in the proconvulsant effects of Sildenafil. The Pentylenetetrazole-induced seizure was used as a standard convulsion model in this study. OT release and pCREB expression were evaluated in the hippocampus of mice using ELISA and western blot assays, respectively. Our results showed that Sildenafil at the dose of 10mgkg(-1) or higher, significantly decreased seizure threshold. Pretreatment with a non-effective dose of OT, potentiated while OT receptor antagonist, Atosiban, reversed fully the proconvulsant effects of Sildenafil (5mgkg(-1)). At biochemical inspection, Sildenafil markedly increased CREB which was attenuated by coadministration of Atosiban. The present study shows for the first time that OT release and the subsequent CREB phosphorylation are involved in the proconvulsant effects of acute Sildenafil treatment in an experimental model of seizure.

Topics: Animals; CREB-Binding Protein; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Hormone Antagonists; Male; Mice; Oxytocin; Pentylenetetrazole; Phosphodiesterase 5 Inhibitors; Phosphorylation; Receptors, Oxytocin; Seizures; Signal Transduction; Sildenafil Citrate; Time Factors; Vasotocin

Research on social instability has focused on its detrimental consequences, but most people are resilient and respond by invoking various coping strategies. To investigate cellular processes underlying such strategies, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Social disruption produced a preference for familiar over novel conspecifics, a change that did not involve global memory impairments or increased anxiety. Using the neuropeptide oxytocin as a tool to increase neurogenesis in the hippocampus of disrupted rats restored preference for novel conspecifics to predisruption levels. Conversely, reducing the number of new neurons by limited inhibition of adult neurogenesis in naive transgenic GFAP-thymidine kinase rats resulted in social behavior similar to disrupted rats. Together, these results provide novel mechanistic evidence that social disruption shapes behavior in a potentially adaptive way, possibly by reducing adult neurogenesis in the hippocampus.. To investigate cellular processes underlying adaptation to social instability, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Unexpectedly, these changes were accompanied by changes in social strategies without evidence of impairments in cognition or anxiety regulation. Restoring adult neurogenesis in disrupted rats using oxytocin and conditionally suppressing the production of new neurons in socially naive GFAP-thymidine kinase rats showed that loss of 6-week-old neurons may be responsible for adaptive changes in social behavior.

Topics: Adaptation, Psychological; Animals; Anxiety; Disease Models, Animal; Glial Fibrillary Acidic Protein; Hippocampus; Hydrocortisone; Idoxuridine; Male; Neurogenesis; Nucleic Acid Synthesis Inhibitors; Oxytocin; Phosphopyruvate Hydratase; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Rats, Transgenic; Social Behavior; Testosterone; Vocalization, Animal

Rewarding social behaviors including positive social interactions and sexual behaviors are shown to regulate adult neurogenesis, but the underlying biological mechanisms remain elusive. Oxytocin, a neurohypophysial hormone secreted after exposure to social interaction or sexual behaviors, has a profound role in the formation of social bonding and regulation of emotional distress. While the acute effect of oxytocin was usually studied, relatively scarce evidence showed the behavioral consequence of repeated oxytocin treatment. The purpose of the current study was to investigate the effect of repeated oxytocin treatment on hippocampal cell proliferation, dendritic maturation of new born neurons and social/emotional behaviors. Adult male Sprague-Dawley rats received treatment with either vehicle or oxytocin (1mg/kg) daily for two weeks. Behavioral tests revealed that oxytocin increased social behaviors and reduced the anxiety- and depression-like behaviors. Cell proliferation, differentiation and the dendritic complexity of new born neurons in the hippocampus were promoted by oxytocin treatment. Depression- and anxiety-like behaviors were induced by repeated treatment of corticosterone (40mg/kg) for two weeks while oxytocin treatment reversed the behavioral disturbances. Suppression of cell proliferation caused by corticosterone was reverted by oxytocin treatment in which cell proliferation, cell differentiation, and dendritic complexity increased. The present findings reveal that oxytocin not only enhances cell proliferation, but also promotes the development of the new neurons which is associated with the induction of positive emotional and social behaviors. The results also suggest that oxytocin may be a potential therapeutic agent for treatment of emotional and social dysfunction.

Topics: Animals; Anxiety; Cell Proliferation; Corticosterone; Dendrites; Dentate Gyrus; Depression; Disease Models, Animal; Male; Motor Activity; Neurogenesis; Oxytocin; Psychotropic Drugs; Rats, Sprague-Dawley; Social Behavior

Social impairments in autism remain poorly understood and without approved pharmacotherapies. Novel animals models are needed to elucidate mechanisms and evaluate novel treatments for the social deficits in autism. Recently, serotonin 1B receptor (5-HT1B) agonist challenge in mice was shown to induce autism-like behaviors including perseveration, reduced prepulse inhibition, and delayed alternation deficits. However, the effects of 5-HT1B agonists on autism-related social behaviors in mice remain unknown. Here, we examine the effects of 5-HT1B agonist challenge on sociability and preference for social novelty in mice. We also examine the effects of 5-HT1B agonist treatment on average rearing duration, a putative rodent measure of non-selective attention. Non-selective attention is an associated feature of autism that is also not well understood. We show that 5-HT1B receptor activation reduces sociability, preference for social novelty, and rearing in mice. In addition, we examine the ability of oxytocin, an off-label treatment for the social impairments in autism, to reverse 5-HT1B agonist-induced social and attention deficits in mice. We show that oxytocin restores social novelty preference in mice treated with a 5-HT1B agonist. We also show that oxytocin attenuates 5-HT1B agonist-induced sociability and rearing deficits in mice. Our results suggest that 5-HT1B agonist challenge provides a useful pharmacological mouse model for aspects of autism, and implicate 5-HT1B in autism social and attention deficits. Moreover, our findings suggest that oxytocin may treat the social deficits in autism through a mechanism involving 5-HT1B.

Topics: Animals; Autistic Disorder; Behavior, Animal; Disease Models, Animal; Exploratory Behavior; Male; Mice, Inbred C57BL; Oxytocin; Receptor, Serotonin, 5-HT1B; Serotonin; Serotonin 5-HT1 Receptor Agonists; Social Behavior

Besides the well-known roles of oxytocin on birth, maternal bonding, and lactation, recent evidence shows that this hypothalamic hormone possesses cardioprotective, anti-inflammatory and parasympathetic neuromodulation properties. In this study, we explore the heart rate fluctuations (HRF) in an endotoxemic rodent model that was accompanied by the administration of exogenous oxytocin. The assessment of HRF has been widely used as an indirect measure of the cardiac autonomic function. In this context, adult male Dark Agouti rats were equipped with a telemetric transmitter to continuously and remotely measure the electrocardiogram, temperature, and locomotion. In a between-subjects experimental design, rats received the following peripheral treatment: saline solution as a vehicle (V); lipopolysaccharide (LPS); oxytocin (Ox); lipopolysaccharide + oxytocin (LPS+Ox). Linear and non-linear parameters of HRF were estimated starting 3h before to 24h after treatments. Our results showed that exogenous oxytocin does not modify by itself the HRF of oxytocin-treated rats in comparison to vehicle-treated rats. However, in animals undergoing endotoxemia it: a) provokes a less anticorrelated pattern in HRF, b) decreased mean heart rate, c) moderated the magnitude and duration of the LPS-induced hyperthermia, and d) increased locomotion, up to 6h after the LPS injection. The less anticorrelated pattern in the HRF and decreased mean heart rate may reflect a cardiac pacemaker coupling with cholinergic influences mediated by oxytocin during LPS-induced endotoxemia. Finally, the anti-lethargic and long-term temperature moderating effects of the administration of oxytocin during endotoxemia could be a consequence of the systemic anti-inflammatory properties of oxytocin.

Topics: Animals; Area Under Curve; Body Temperature; Disease Models, Animal; Electrocardiography; Endotoxemia; Endotoxins; Heart Rate; Illness Behavior; Lipopolysaccharides; Male; Oxytocin; Rats; Statistics, Nonparametric; Time Factors

Traumatic events such as natural disasters, violent crimes, tragic accidents, and war, can have devastating impacts on social relationships, including marital partnerships. We developed a single prolonged stress (SPS) paradigm, which consisted of restraint, forced swimming, and ether anesthesia, to establish an animal model relevant to post-traumatic stress disorder. We applied a SPS paradigm to a monogamous rodent, the prairie vole (Microtus ochrogaster) in order to determine whether a traumatic event affects the establishment of pair bonds. We did not detect effects of the SPS treatment on anhedonic or anxiety-like behavior. Sham-treated male voles huddled with their partner females, following a 6day cohabitation, for a longer duration than with a novel female, indicative of a pair bond. In contrast, SPS-treated voles indiscriminately huddled with the novel and partner females. Interestingly, the impairment of pair bonding was rescued by oral administration of paroxetine, a selective serotonin reuptake inhibitor (SSRI), after the SPS treatment. Immunohistochemical analyses revealed that oxytocin immunoreactivity (IR) was significantly decreased in the supraoptic nucleus (SON), but not in the paraventricular nucleus (PVN), 7days after SPS treatment, and recovered 14days after SPS treatment. After the presentation of a partner female, oxytocin neurons labeled with Fos IR was significantly increased in SPS-treated voles compared with sham-treated voles regardless of paroxetine administration. Our results suggest that traumatic events disturb the formation of pair bond possibly through an interaction with the serotonergic system, and that SSRIs are candidates for the treatment of social problems caused by traumatic events. Further, a vole SPS model may be useful for understanding mechanisms underlying the impairment of social bonding by traumatic events.

Topics: Animals; Arvicolinae; Brain; Disease Models, Animal; Exploratory Behavior; Female; Male; Neurons; Oxytocin; Pair Bond; Paroxetine; Receptors, Glucocorticoid; Receptors, Vasopressin; Selective Serotonin Reuptake Inhibitors; Stress Disorders, Post-Traumatic; Supraoptic Nucleus; Time Factors; Tyrosine 3-Monooxygenase

Wnt1-Cre- and Wnt1-GAL4 double transgenic (dTg) mice are used to study neural crest cell lineages by utilizing either the Cre/loxP or the GAL4/UAS system. We have previously shown that these mice exhibit behavioral abnormalities that resemble certain behaviors of psychiatric disorders and histologic alterations in the cholinergic and glutamatergic systems in the brain. The objective of the current study was to extend the behavioral analyses in these mice and to determine whether there were any sex-specific differences in the prevalence or severity of these behaviors. In the present study, we demonstrate additional behavioral abnormalities in dTg mice, such as increased locomotor activity, decreased social behavior, and an increased frequency in vertical jumping. Of these, the proclivity for vertical jumping was observed only in male dTg mice. In contrast, MK-801 administration induced increased locomotion in only female dTg mice. Furthermore, the concentrations of prolactin in the sera and oxytocin in the hypothalamus were both reduced only in female dTg mice, compared to controls. These sex-dependent behavioral and hormonal abnormalities in the dTG mice suggest that the phenotype of certain psychiatric disorders may be influenced by both genetic and sex-specific factors.

Topics: Animal Communication; Animals; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Hypothalamus; Male; Maternal Behavior; Mental Disorders; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Oxytocin; Phenotype; Prolactin; Sex Characteristics; Social Behavior; Stereotyped Behavior

Post-traumatic stress disorder (PTSD) is in part due to a deficit in memory consolidation and extinction. Oxytocin (OXT) has anxiolytic effects and promotes prosocial behaviors in both rodents and humans, and evidence suggests that it plays a role in memory consolidation. We studied the effects of administered OXT and social co-housing in a rodent model of PTSD. Acute OXT yielded a short-term increase in the recall of the traumatic memory if administered immediately after trauma. Low doses of OXT delivered chronically had a cumulating anxiolytic effect that became apparent after 4 days and persisted. Repeated injections of OXT after short re-exposures to the trauma apparatus yielded a long-term reduction in anxiety. Co-housing with naive nonshocked animals decreased the memory of the traumatic context compared with single-housed animals. In the long term, these animals showed less thigmotaxis and increased interest in novel objects, and a low OXT plasma level. Co-housed PTSD animals showed an increase in risk-taking behavior. These results suggest beneficial effects of OXT if administered chronically through increases in memory consolidation after re-exposure to a safe trauma context. We also show differences between the benefits of social co-housing with naive rats and co-housing with other shocked animals on trauma-induced long-term anxiety.

Topics: Animals; Anxiety; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Housing, Animal; Male; Memory; Memory Consolidation; Mental Recall; Oxytocin; Rats; Rats, Sprague-Dawley; Risk-Taking; Social Behavior; Stress Disorders, Post-Traumatic; Time Factors

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent impairment in social communication and social interaction. Recent studies revealed that environmental factors, especially the intrauterine developmental environment, played important roles in the development of ASD. It is hypothesized that maternal hyperandrogenism during pregnancy may increase the susceptibility of the fetus to ASD. In the present study, pregnant rats were treated with a low dose of letrozole (1μg/kg/day) in an attempt to produce a hyperandrogenic intrauterine environment for the developing fetus. Results showed that rat pups prenatally exposed to hyperandrogenic intrauterine environment emitted less number of ultrasonic vocalizations when isolated from their dams and littermates. Additionally, the female rats in the treatment group spent less time in social interaction in adolescence and exhibited impaired heterosexual interaction in adult. Moreover, the duration of social interaction and heterosexual interaction of the female offspring were negatively correlated with maternal serum testosterone levels during pregnancy. These results suggest that prenatal exposure to hyperandrogenic intrauterine environment could induce autistic-like behavior in female rats and maternal hyperandrogenism during pregnancy should be considered as a potential risk factor for the etiology of ASD.

Topics: Androgens; Animals; Arginine Vasopressin; Child Development Disorders, Pervasive; Disease Models, Animal; Estrous Cycle; Female; Letrozole; Male; Nitriles; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Sprague-Dawley; Receptors, Vasopressin; RNA, Messenger; Sex Characteristics; Social Behavior; Sound; Testosterone; Triazoles; Vocalization, Animal

Oxytocin (Oxt), a neuropeptide produced in the hypothalamus, is implicated in regulation of feeding. Recent studies have shown that peripheral administration of Oxt suppresses feeding and, when infused subchronically, ameliorates hyperphagic obesity. However, the route through which peripheral Oxt informs the brain is obscure. This study aimed to explore whether vagal afferents mediate the sensing and anorexigenic effect of peripherally injected Oxt in mice. Intraperitoneal Oxt injection suppressed food intake and increased c-Fos expression in nucleus tractus solitarius to which vagal afferents project. The Oxt-induced feeding suppression and c-Fos expression in nucleus tractus solitarius were blunted in mice whose vagal afferent nerves were blocked by subdiaphragmatic vagotomy or capsaicin treatment. Oxt induced membrane depolarization and increases in cytosolic Ca(2+) concentration ([Ca(2+)]i) in single vagal afferent neurons. The Oxt-induced [Ca(2+)]i increases were markedly suppressed by Oxt receptor antagonist. These Oxt-responsive neurons also responded to cholecystokinin-8 and contained cocaine- and amphetamine-regulated transcript. In obese diabetic db/db mice, leptin failed to increase, but Oxt increased [Ca(2+)]i in vagal afferent neurons, and single or subchronic infusion of Oxt decreased food intake and body weight gain. These results demonstrate that peripheral Oxt injection suppresses food intake by activating vagal afferent neurons and thereby ameliorates obesity in leptin-resistant db/db mice. The peripheral Oxt-regulated vagal afferent neuron provides a novel target for treating hyperphagia and obesity.

Topics: Action Potentials; Animals; Anti-Obesity Agents; Appetite Depressants; Calcium; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Eating; Feeding Behavior; Hyperphagia; Injections, Intraperitoneal; Male; Mice, Inbred C57BL; Mice, Inbred ICR; Neurons, Afferent; Obesity; Oxytocin; Proto-Oncogene Proteins c-fos; Sensory System Agents; Solitary Nucleus; Time Factors; Vagotomy; Vagus Nerve; Weight Gain

Despite compelling evidence that oxytocin (OT) is effective in reducing body weight (BW) in diet-induced obese (DIO) rodents, studies of the effects of OT in humans and rhesus monkeys have primarily focused on noningestive behaviors. The goal of this study was to translate findings in DIO rodents to a preclinical translational model of DIO. We tested the hypothesis that increased OT signaling would reduce BW in DIO rhesus monkeys by inhibiting food intake and increasing energy expenditure (EE). Male DIO rhesus monkeys from the California National Primate Research Center were adapted to a 12-h fast and maintained on chow and a daily 15% fructose-sweetened beverage. Monkeys received 2× daily subcutaneous vehicle injections over 1 wk. We subsequently identified doses of OT (0.2 and 0.4 mg/kg) that reduced food intake and BW in the absence of nausea or diarrhea. Chronic administration of OT for 4 wk (0.2 mg/kg for 2 wk; 0.4 mg/kg for 2 wk) reduced BW relative to vehicle by 3.3 ± 0.4% (≈0.6 kg; P < 0.05). Moreover, the low dose of OT suppressed 12-h chow intake by 26 ± 7% (P < 0.05). The higher dose of OT reduced 12-h chow intake by 27 ± 5% (P < 0.05) and 8-h fructose-sweetened beverage intake by 18 ± 8% (P < 0.05). OT increased EE during the dark cycle by 14 ± 3% (P < 0.05) and was associated with elevations of free fatty acids and glycerol and reductions in triglycerides suggesting increased lipolysis. Together, these data suggest that OT reduces BW in DIO rhesus monkeys through decreased food intake as well as increased EE and lipolysis.

Topics: Animals; Anti-Obesity Agents; Appetite Depressants; Biomarkers; Dietary Carbohydrates; Disease Models, Animal; Drug Administration Schedule; Eating; Energy Metabolism; Feeding Behavior; Fructose; Injections, Subcutaneous; Lipids; Lipolysis; Macaca mulatta; Male; Obesity; Oxytocin; Time Factors; Weight Loss

Mutations of MAGEL2 have been reported in patients presenting with autism, and loss of MAGEL2 is also associated with Prader-Willi syndrome, a neurodevelopmental genetic disorder. This study aimed to determine the behavioral phenotype of Magel2-deficient adult mice, to characterize the central oxytocin (OT) system of these mutant mice, and to test the curative effect of a peripheral OT treatment just after birth.. We assessed the social and cognitive behavior of Magel2-deficient mice, analyzed the OT system of mutant mice treated or not by a postnatal administration of OT, and determined the effect of this treatment on the brain.. Magel2 inactivation induces a deficit in social recognition and social interaction and a reduced learning ability in adult male mice. In these mice, we reveal anatomical and functional modifications of the OT system and show that these defects change from birth to adulthood. Daily administration of OT in the first postnatal week was sufficient to prevent deficits in social behavior and learning abilities in adult mutant male mice. We show that this OT treatment partly restores a normal OT system. Thus, we report that an alteration of the OT system around birth has long-term consequences on behavior and on cognition. Importantly, an acute OT treatment of Magel2-deficient pups has a curative effect.. Our study reveals that OT plays a crucial role in setting social behaviors during a period just after birth. An early OT treatment in this critical period could be a novel therapeutic approach for the treatment of neurodevelopmental disorders such as Prader-Willi syndrome and autism.

Topics: Animals; Antigens, Neoplasm; Autistic Disorder; Brain; Cognition; Disease Models, Animal; Female; Male; Mice; Mice, Inbred C57BL; Oxytocin; Prader-Willi Syndrome; Proteins; Recognition, Psychology; Social Behavior; Spatial Learning

Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homolog of CNTNAP2 (contactin-associated protein-like 2), in which mutations cause cortical dysplasia and focal epilepsy (CDFE) syndrome, displays many features that parallel those of the human disorder. Because CDFE has high penetrance for autism spectrum disorder (ASD), we performed an in vivo screen for drugs that ameliorate abnormal social behavior in Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in Cntnap2 knockout mice and suggest that there may be critical developmental windows for optimal treatment to rectify this deficit.

Topics: Animals; Animals, Newborn; Autistic Disorder; Behavior, Animal; Disease Models, Animal; Humans; Membrane Proteins; Mice, Knockout; Mice, Mutant Strains; Nerve Tissue Proteins; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Social Behavior

Oxytocin (OXT) is a well-known neurohypophysial hormone that is synthesised in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus. The projection of magnocellular neurosecretory cells, which synthesise OXT and arginine vasopressin in the PVN and SON, to the posterior pituitary plays an essential role in mammalian labour and lactation through its peripheral action. However, previous studies have shown that parvocellular OXTergic cells in the PVN, which project to the medulla and spinal cord, are involved in various physiological functions (e.g. sensory modulation and autonomic). In the present study, we examined OXT expression in the PVN, SON and spinal cord after chronic inflammation from adjuvant arthritis (AA). We used transgenic rats that express OXT and the monomeric red fluorescent protein 1 (mRFP1) fusion gene to visualise both the magnocellular and parvocellular OXTergic pathways. OXT-mRFP1 fluorescence intensity was significantly increased in the PVN, SON, dorsal horn of the spinal cord and posterior pituitary in AA rats. The levels of OXT-mRFP1 mRNA were significantly increased in the PVN and SON of AA rats. These results suggested that OXT was up-regulated in both hypothalamic magnocellular neurosecretory cells and parvocellular cells by chronic inflammation, and also that OXT in the PVN-spinal pathway may be involved in sensory modulation. OXT-mRFP1 transgenic rats are a very useful model for visualising the OXTergic pathways from vesicles in a single cell to terminals in in vitro preparations.

Topics: Animals; Arthritis; Chronic Disease; Disease Models, Animal; Inflammation; Luminescent Agents; Luminescent Proteins; Male; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats; Rats, Transgenic; Rats, Wistar; Red Fluorescent Protein; Signal Transduction; Spinal Cord; Supraoptic Nucleus

Depression and anxiety can be severely detrimental to the health of both the affected woman and her offspring. In a rodent model of postpartum depression and anxiety, chronic social stress exposure during lactation induces deficits in maternal care and increases anxiety. Here, we extend previous findings by expanding the behavioral analyses, assessing lactation, and examining several neural systems within amygdalar and hypothalamic regions involved in the control of the stress response and expression of maternal care that may be mediating the behavioral changes in stressed dams. Compared with control dams, those exposed to chronic social stress beginning on day 2 of lactation show impaired maternal care and lactation and increased maternal anxiety on day 9 of lactation. Saccharin-based anhedonia and maternal aggression were increased and lactation was also impaired on day 16 of lactation. These behavioral changes were correlated with a decrease in oxytocin mRNA expression in the medial amygdala, and increases in the expressions of corticotrophin-releasing hormone mRNA in the central nucleus of the amygdala, glucocorticoid receptor mRNA in the paraventricular nucleus, and orexin 2 receptor mRNA in the supraoptic nucleus of stressed compared with control dams. The increase in glucocorticoid receptor mRNA in the paraventricular nucleus was negatively correlated with methylation of a CpG site in the promoter region. In conclusion, the data support the hypothesis that social stress during lactation can have profound effects on maternal care, lactation, and anxiety, and that these behavioral effects are mediated by central changes in stress and maternally relevant neuropeptide systems.

Topics: Aggression; Anhedonia; Animals; Anxiety Disorders; Brain; Chronic Disease; Depression, Postpartum; Disease Models, Animal; Female; Gene Expression; Lactation; Maternal Behavior; Orexin Receptors; Oxytocin; Rats, Sprague-Dawley; Receptors, Glucocorticoid; RNA, Messenger; Saccharin; Social Behavior; Stress, Psychological; Taste Perception

We measured the short-circuit current (Isc) in rat ileum mucosa to identify the effect of oxytocin (OT) on mucosal secretion in small intestine. We identified a COX-2-derived pulsatile PGE2 release triggered by OT in rat ileum mucosa. OT receptors (OTR) are expressed in intestine crypt epithelial cells. Notably, OT evoked a dynamic change of [Ca(2+)]i in ileum crypts, which was responsible for this pulsatile release of PGE2. OT ameliorated 5-FU-, radiation- or DSS- induced injury in vivo, including the improvement of weight loss, reduced villus height and impaired survival of crypt transit-amplifying cells as well as crypt. Moreover, these protective effects of OT against intestinal injury were eliminated by coadministration of a selective inhibitor of PGE2, AH6809. Our findings strongly suggest that OT, a novel and important regulator of intestine mucosa barrier, is required for repair of intestinal epithelium after injury. Considering that OT is an FDA-approved drug, this work reveals a potential novel and safe way to combat or prevent chemo-radiotherapy induced intestine injury or to treat IBD.

Topics: Animals; Antineoplastic Agents; Calcium; Cyclooxygenase 2; Dextran Sulfate; Dinoprostone; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Evoked Potentials; Fluorouracil; Ileum; Immunohistochemistry; Indomethacin; Intestinal Diseases; Intestinal Mucosa; Ions; Male; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Neoplasms; Oxytocin; Rats; Rats, Wistar; Receptors, Oxytocin; Wound Healing; Xanthones

Previous studies from our laboratory have shown that methysergide, a serotonergic antagonist, injected into the lateral parabrachial nucleus (LPBN) combined with a pre-load of 2 M NaCl, given by gavage, induces 0.3 M NaCl intake. The mechanisms involved in this paradoxical behavior are still unknown. In the present work, we investigated the effect of serotonergic blockade into the LPBN on hindbrain and hypothalamic activity, gastric emptying and arterial blood pressure in cell-dehydrated rats. Methysergide plus 2 M NaCl infused intragastrically or intravenously promoted 0.3 M NaCl intake in two-bottle tests. In cell-dehydrated rats with no access to fluids, methysergide compared to vehicle increased Fos immunoreactivity in the medial nucleus of the solitary tract, area postrema and non-oxytocinergic cells of the ventral portion of the hypothalamic paraventricular nucleus (PVN). There was no alteration in the number of neurons double-labeled for Fos-ir and oxytocin in the PVN and supraoptic nuclei. There was also no alteration in plasma oxytocin and vasopressin, or arterial pressure. In rats cell-dehydrated by i.v. 2 M NaCl, methysergide also did not change the amount of an intragastric load of 0.3 M NaCl retained in the stomach or intestine. The results suggest that methysergide injected into the LPBN of cell-dehydrated rat does not alter primary inhibitory signals that control sodium intake. The inhibitory signals blocked by methysergide in the LPBN possibly originated from activation of brain osmoreceptors, second order visceral/hormonal signals or a combination of both.

Topics: Animals; Area Postrema; Arterial Pressure; Dehydration; Disease Models, Animal; Gastric Emptying; Male; Methysergide; Neurons; Oxytocin; Parabrachial Nucleus; Proto-Oncogene Proteins c-fos; Rats, Sprague-Dawley; Saline Solution, Hypertonic; Serotonin Antagonists; Sodium Chloride, Dietary; Solitary Nucleus; Supraoptic Nucleus; Vasopressins

Standard dopamine therapies for schizophrenia are not efficacious for negative symptoms of the disease, including asociality. This reduced social behavior may be due to glutamatergic dysfunction within the amygdala, leading to increased fear and social anxiety. Several studies have demonstrated the prosocial effects of oxytocin in schizophrenia patients. Therefore, this study evaluates the effect of subchronic oxytocin on EEG activity in amygdala of mice during performance of the three-chamber social choice and open field tests following acute ketamine as a model of glutamatergic dysfunction. Oxytocin did not restore social deficits introduced by ketamine but did significantly increase sociality in comparison to the control group. Ketamine had no effect on time spent in the center during the open field trials, whereas oxytocin increased overall center time across all groups, suggesting a reduction in anxiety. Amygdala activity was consistent across all drug groups during social and nonsocial behavioral trials. However, oxytocin reduced overall amygdala EEG power during the two behavioral tasks. Alternatively, ketamine did not significantly affect EEG power throughout the tasks. Decreased EEG power in the amygdala, as caused by oxytocin, may be related to both reduced anxiety and increased social behaviors. Data suggest that separate prosocial and social anxiety pathways may mediate social preference.

Topics: Amygdala; Animals; Anxiety; Brain Waves; Disease Models, Animal; Electroencephalography; Excitatory Amino Acid Antagonists; Ketamine; Male; Mice; Mice, Inbred C57BL; Motor Activity; Oxytocin; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Social Behavior

The major regulator of the neuroendocrine stress response in the brain is corticotropin releasing factor (CRF), whose transcription is controlled by CREB and its cofactors CRTC2/3 (TORC2/3). Phosphorylated CRTCs are sequestered in the cytoplasm, but rapidly dephosphorylated and translocated into the nucleus following a stressful stimulus. As the stress response is attenuated by oxytocin (OT), we tested whether OT interferes with CRTC translocation and, thereby, Crf expression. OT (1 nmol, i.c.v.) delayed the stress-induced increase of nuclear CRTC3 and Crf hnRNA levels in the paraventricular nucleus of male rats and mice, but did not affect either parameter in the absence of the stressor. The increase in Crf hnRNA levels at later time points was parallel to elevated nuclear CRTC2/3 levels. A direct effect of Thr(4) Gly(7)-OT (TGOT) on CRTC3 translocation and Crf expression was found in rat primary hypothalamic neurons, amygdaloid (Ar-5), hypothalamic (H32), and human neuroblastoma (Be(2)M17) cell lines. CRTC3, but not CRCT2, knockdown using siRNA in Be(2)M17 cells prevented the effect of TGOT on Crf hnRNA levels. Chromatin-immunoprecipitation demonstrated that TGOT reduced CRTC3, but not CRTC2, binding to the Crf promoter after 10 min of forskolin stimulation. Together, the results indicate that OT modulates CRTC3 translocation, the binding of CRTC3 to the Crf promoter and, ultimately, transcription of the Crf gene.. The neuropeptide oxytocin has been proposed to reduce hypothalamic-pituitary-adrenal (HPA) axis activation during stress. The underlying mechanisms are, however, elusive. In this study we show that activation of the oxytocin receptor in the paraventricular nucleus delays transcription of the gene encoding corticotropin releasing factor (Crf), the main regulator of the stress response. It does so by sequestering the coactivator of the transcription factor CREB, CRTC3, in the cytosol, resulting in reduced binding of CRTC3 to the Crf gene promoter and subsequent Crf gene expression. This novel oxytocin receptor-mediated intracellular mechanism might provide a basis for the treatment of exaggerated stress responses in the future.

Topics: Animals; Cells, Cultured; Colforsin; Corticotropin-Releasing Hormone; CREB-Binding Protein; Disease Models, Animal; Female; Gene Expression Regulation; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Neurons; Oxytocics; Oxytocin; Protein Transport; Rats; Rats, Wistar; Receptors, Oxytocin; Signal Transduction; Stress, Psychological; Thromboplastin

Growth factors such as nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) have been shown to play a role in the healing process of nerve injury. Recent researches have also shown that oxytocin administration activates these growth factors of importance for the healing of nerve tissue. The objective of the present study was to evaluate the effects of oxytocin on peripheral nerve regeneration in rats.. Twenty-four male Sprague-Dawley rats were underwent transection damage model on the right sciatic nerve and defective damage model on the left sciatic nerve. The animals were assigned to one of two groups: control group or treatment group (received 80 mg/kg oxytocin intraperitoneally for 12 weeks). The sciatic nerve was examined, both functionally (on the basis of climbing platform test) and histologically (on the basis of axon count), 3, 6, 9, and 12 weeks after the injury. Also, stereomicroscopic and electrophysiological evaluations were carried out.. Significantly greater improvements in electrophysiological recordings and improved functional outcome measures were presented in the treatment group at 12-week follow-up. Stereomicroscopic examinations disclosed prominent increases in vascularization on proximal cut edges in the oxytocin group in comparison with the control group. Higher axon counts were also found in this group.. Intraperitoneal oxytocin administration resulted in accelerated functional, histological, and electrophysiological recovery after different sciatic injury models in rats.

Topics: Animals; Axons; Disease Models, Animal; Drug Evaluation, Preclinical; Electromyography; Male; Nerve Regeneration; Oxytocin; Peripheral Nerve Injuries; Rats, Sprague-Dawley; Recovery of Function; Sciatic Nerve

This study investigated the efficacy of the hypothalamic nonapeptide oxytocin (OT) by direct delivery to local defects using a microporous β-tricalcium phosphate (TCP) as the carrier for the future applications as a method to achieve predictable bone regeneration of large osseous defects requiring sinus bone graft and guided bone regeneration procedures for implant placement.. Both the ectopic and new bone formation induced by the OT-loaded microporous β-TCP powder was histomorphometrically compared with unloaded β-TCP in a subcutaneous ectopic bone formation model and calvarial critical-sized defects (CSDs) in 45 rats.. The OT-loaded β-TCP clearly enhanced ectopic bone formation compared with the unloaded control group. A High initial OT dose (250 μg) significantly increased ectopic bone formation at an early healing time-point compared with a lower OT dose (50 μg). The OT-loaded samples displayed greater new bone formation in the rat calvarial CSDs. Extensive new bone formation was achieved in the calvarial CSDs with the higher OT dose.. These results suggest that local OT delivery to bone substitute promotes new bone formation via an osteoinductive mode of action.

Topics: Animals; Biocompatible Materials; Bone Diseases; Bone Regeneration; Calcium Phosphates; Diffusion; Disease Models, Animal; Drug Carriers; Guided Tissue Regeneration; Male; Ossification, Heterotopic; Osteogenesis; Oxytocin; Particle Size; Rats; Rats, Sprague-Dawley; Skull; Subcutaneous Tissue; Time Factors; Wound Healing

Primary dysmenorrhea (PDM), a common, clinically heterogeneous endocrine disorder affecting young women, is associated with endocrinopathy and metabolic abnormalities. The Xiang-Fu-Si-Wu Decoction (XFSWD) is a traditional Chinese medicine preparation used to treat PDM.. In the current study, a plasma metabonomics method based on the ultra-high-performance liquid chromatography-quantitative time-of-flight-mass spectrometry (UHPLC-Q-TOF-MS) system was employed to examine the mechanism of XFSWD action in PDM.. Estradiol benzoate (0.01 g/kg/d) and oxytocin (5 mL/kg) were used to create the dysmenorrhea rat model. Based on the chromatographic data of plasma samples at different time-points following oral administration of XFSWD mixed in water (37.8 g crude herbs/kg) on day 7, partial least square (PLS) and discriminate analysis (DA) were applied to visualize group differentiation and marker selection.. Systemic changes occurring in PDM reflect alterations in not only uterus function but also whole-body metabolism. The XFSWD was effective as a therapeutic agent for PDM by reflect metabolic pathway. Prostaglandins and lysophospholipids were identified as two marker types for oxytocin-induced dysmenorrhea syndrome, including LysoPC(18:4), LysoPE(22:2/0:0), LysoPC(17:0), PGJ₂, 11-deoxy-11-methylene-PGD₂, 15-deoxy-δ-12,14-PGJ₂, LysoPC(20:3), etc. Specifically, the concentrations of prostaglandins compounds (PGJ₂, 11-deoxy-11-methylene-PGD₂, 15-deoxy-δ-12,14-PGJ₂) were increased while those of lysophospholipid compounds [lysoPC(18:4), LysoPE(22:2/0:0), LysoPC(17:0)] were decreased to a significant extent (p < 0.05) in dysmenorrheal rats. Upon treatment with the XFSWD at 12 h, the concentrations of lysophospholipids showed no significant differences (P > 0.05) between the model and normal groups. The lysophospholipid levels were restored. Lysophospholipids were the key factors in phospholipid metabolism. Thus, disruption of phospholipids metabolism appears critical for the development of dysmenorrhea. The XFSWD exerted its effects by interfering with the sphingolipid metabolic pathway.. The metabonomics method presents a promising tool to treat PDM in animal models, and may be applicable for clinical treatment of the human disease in the future.

Topics: Animals; Biomarkers; Discriminant Analysis; Disease Models, Animal; Drugs, Chinese Herbal; Dysmenorrhea; Estradiol; Female; Least-Squares Analysis; Lysophospholipids; Metabolic Networks and Pathways; Metabolome; Oxytocin; Prostaglandins; Syndrome

Oxytocin (OXT), a nonapeptide posterior hormone of the pituitary, is mainly synthesized and secreted in the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). The present study was to investigate in which level, brain or periphery, OXT effecting on the behavioral activity in the behavioral despair depression rat model. The results showed that (1) either the forced swimming or the tail suspension significantly increased OXT concentration in the brain (PVN, SON, frontal cortex, hippocampus, amygdala, lumbar spinal cord) and in the periphery (posterior pituitary and serum); (2) intraventricular injection (icv) of OXT decreased the animal immobility time, whereas OXT receptor antagonist-desGly-NH2, d(CH2)5[D-Tyr2, Thr-sup-4]OV (icv) increased the animal immobility time in a dose-dependent manner in forced swimming test (FST) and in tail suspension test (TST); (3) neither OXT nor OXT receptor antagonist (intravenous injection) influenced the animal immobility time in FST and in TST. OXT levels were increased in several areas of the brain and in the periphery following the behavioral despair, one stressor, yet pre-treatment with OXT appeared to be beneficial in term of reducing immobility time. The data suggested that behavioral despair could enhance OXT synthesis and secretion not only in the brain but also in the periphery, and OXT in the brain rather than the periphery played a role in the behavioral despair depression.

Topics: Animals; Behavior, Animal; Central Nervous System; Depression; Disease Models, Animal; Hindlimb Suspension; Injections, Intravenous; Injections, Intraventricular; Male; Oxytocin; Rats, Sprague-Dawley; Swimming

To determine the effects of oxytocin (OT) on surgically induced endometriosis in a rat model.. Twelve female Sprague-Dawley rats were included. After the implantation and establishment of autologous endometrium onto the abdominal wall peritoneum, the rats were randomly divided into two groups, treated with intramuscular oxytocin (OT group, 160μgkg/day, n=6) or isotonic NaCl solution (control group, 1mLkg/day, n=6) for 28 days. To evaluate the therapeutic effects of OT, the explant volumes were calculated and the levels of vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1, and TNF-α were measured in plasma and peritoneal fluid. Endometriotic explants were examined histologically by semiquantitative analysis.. After treatment, the mean endometriotic explant volume was decreased in the OT group (p=0.016). The histopathological score and VEGF immunoexpression of endometriotic explants were significantly lower in the OT group (p=0.007) than in controls (p=0.000). Inflammatory cytokine levels in plasma and peritoneal fluid were considerably decreased in the OT group. Moreover, TUNEL immunohistochemistry clearly demonstrated more apoptotic changes in the mononuclear cells of the OT group compared with controls.. We suggest that oxytocin might be considered as a potential candidate therapeutic agent for endometriosis.

Topics: Animals; Ascitic Fluid; Chemokine CCL2; Disease Models, Animal; Drug Evaluation, Preclinical; Endometriosis; Female; Oxytocin; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

We report that the oxytocin-mediated neuroprotective γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.

Topics: Animals; Autistic Disorder; Behavior, Animal; Bumetanide; Chlorides; Cytoprotection; Disease Models, Animal; Female; Fragile X Mental Retardation Protein; gamma-Aminobutyric Acid; Maternal-Fetal Exchange; Mice; Oxytocin; Parturition; Pregnancy; Rats; Valproic Acid

Osteoporosis and overweight/obesity constitute major worldwide public health burdens that are associated with aging. A high proportion of women develop osteoporosis and increased intraabdominal adiposity after menopause. which leads to bone fractures and metabolic disorders. There is no efficient treatment without major side effects for these 2 diseases. We previously showed that the administration of oxytocin (OT) normalizes ovariectomy-induced osteopenia and bone marrow adiposity in mice. Ovariectomized mice, used as an animal model mimicking menopause, were treated with OT or vehicle. Trabecular bone parameters and fat mass were analyzed using micro-computed tomography. Herein, we show that this effect on trabecular bone parameters was mediated through the restoration of osteoblast/osteoclast cross talk via the receptor activator of nuclear factor-κB ligand /osteoprotegerin axis. Moreover, the daily administration of OT normalized body weight and intraabdominal fat depots in ovariectomized mice. Intraabdominal fat mass is more sensitive to OT that sc fat depots, and this inhibitory effect is mediated through inhibition of adipocyte precursor's differentiation with a tendency to lower adipocyte size. OT treatment did not affect food intake, locomotors activity, or energy expenditure, but it did promote a shift in fuel utilization favoring lipid oxidation. In addition, the decrease in fat mass resulted from the inhibition of the adipose precursor's differentiation. Thus, OT constitutes an effective strategy for targeting osteopenia, overweight, and fat mass redistribution without any detrimental effects in a mouse model mimicking the menopause.

Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Bone Diseases, Metabolic; Cell Culture Techniques; Coculture Techniques; Disease Models, Animal; Female; Leptin; Lipids; Menopause; Mice; Mice, Inbred C57BL; Osteoblasts; Osteoclasts; Osteoporosis; Ovariectomy; Oxygen; Oxytocin; Weight Gain; X-Ray Microtomography

Nesfatin-1 is produced in the periphery and in the brain where it has been demonstrated to regulate appetite, stress hormone secretion, and cardiovascular function. The anorexigenic action of central nesfatin-1 requires recruitment of neurons producing the melanocortins and centrally projecting oxytocin (OT) and corticotropin-releasing hormone (CRH) neurons. We previously have shown that two components of this pathway, the central melanocortin and oxytocin systems, contribute to the hypertensive action of nesfatin-1 as well. We hypothesized that the cardiovascular effect of nesfatin-1 also was dependent on activation of neurons expressing CRH receptors, and that the order of activation of the melanocortin-CRH-oxytocin circuit was preserved for both the anorexigenic and hypertensive actions of the peptide. Pretreatment of male rats with the CRH-2 receptor antagonist astressin2B abrogated nesfatin-1-induced increases in mean arterial pressure (MAP). Furthermore, the hypertensive action of CRH was blocked by pretreatment with an oxytocin receptor antagonist ornithine vasotocin (OVT), indicating that the hypertensive effect of nesfatin-1 may require activation of oxytocinergic (OTergic) neurons in addition to recruitment of CRH neurons. Interestingly, we found that the hypertensive effect of α-melanocyte stimulating hormone (α-MSH) itself was not blocked by either astressin2B or OVT. These data suggest that while α-MSH-producing neurons are part of a core melanocortin-CRH-oxytocin circuit regulating food intake, and a subpopulation of melanocortin neurons activated by nesfatin-1 do mediate the hypertensive action of the peptide, α-MSH can signal independently from this circuit to increase MAP.

Topics: alpha-MSH; Animals; Blood Pressure; Calcium-Binding Proteins; Corticotropin-Releasing Hormone; Disease Models, Animal; DNA-Binding Proteins; Hormones; Hypertension; Male; Melanocortins; Melanocyte-Stimulating Hormones; Nerve Net; Nerve Tissue Proteins; Nucleobindins; Oxytocin; Peptide Fragments; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Receptors, Oxytocin; Vasotocin

A growing number of studies have demonstrated that oxytocin (OT) plays an analgesic role in modulation of nociception and pain. Most work to date has focused on the central mechanisms of OT analgesia, but little is known about whether peripheral mechanisms are also involved. Acid-sensing ion channels (ASICs) are distributed in peripheral sensory neurons and participate in nociception. Here, we investigated the effects of OT on the activity of ASICs in dorsal root ganglion (DRG) neurons.. Electrophysiological experiments were performed on neurons from rat DRG. Nociceptive behaviour was induced by acetic acid in rats and mice lacking vasopressin, V1A receptors.. OT inhibited the functional activity of native ASICs. Firstly, OT dose-dependently decreased the amplitude of ASIC currents in DRG neurons. Secondly, OT inhibition of ASIC currents was mimicked by arginine vasopressin (AVP) and completely blocked by the V1A receptor antagonist SR49059, but not by the OT receptor antagonist L-368899. Thirdly, OT altered acidosis-evoked membrane excitability of DRG neurons and significantly decreased the amplitude of the depolarization and number of action potentials induced by acid stimuli. Finally, peripherally administered OT or AVP inhibited nociceptive responses to intraplantar injection of acetic acid in rats. Both OT and AVP also induced an analgesic effect on acidosis-evoked pain in wild-type mice, but not in V1A receptor knockout mice.. These results reveal a novel peripheral mechanism for the analgesic effect of OT involving the modulation of native ASICs in primary sensory neurons mediated by V1A receptors.

Topics: Acetic Acid; Acid Sensing Ion Channel Blockers; Acid Sensing Ion Channels; Action Potentials; Analgesics; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Ganglia, Spinal; Mice, Inbred C57BL; Mice, Knockout; Nociception; Nociceptive Pain; Oxytocin; Rats, Sprague-Dawley; Receptors, Vasopressin; Sensory Receptor Cells

Research concerning non-reproductive sociability in rodents is mainly restricted to assessing the effects of oxytocin (OXT) and arginine-vasopressin (AVP) in male rats and mice. Comparable studies on natural social preference and social avoidance in females are substantially lacking.. Here, we adapted a behavioral paradigm for monitoring social preference of female rats consisting of two consecutive exposures to either non-social or social stimuli. Further, to induce stimulus-specific social avoidance, female rats were exposed to a single 10-min maternal defeat by a lactating dam.. Social preference towards same-sex conspecifics in female rats was shown to be independent of the estrous cycle and even more pronounced than in male rats. Intracerebroventricular (icv) application of OXT, AVP, or their selective receptor antagonists or agonists, did not alter naturally-occurring social preference in female rats. Stimulus-specific social avoidance could be induced by prior exposure to a lactating rat: an effect that could not be reversed/overcome by icv OXT.. The female social preference paradigm for rats established in this study detected subtle sex differences in social preference behavior of rats. Further, stimulus-specific social deficits could be induced in female rats using an acute exposure to social defeat - as previously observed in male rodents.. Female rats show strong social preference behavior, which can be prevented by social defeat, but does not seem to be regulated by the OXT or AVP systems. Accordingly, icv application of synthetic OXT does not reverse maternal defeat-induced social avoidance in female rats.

Topics: Analysis of Variance; Animals; Arginine Vasopressin; Brain; Disease Models, Animal; Escape Reaction; Estrous Cycle; Female; Gene Expression Regulation; Male; Ornipressin; Oxytocin; Rats; Rats, Wistar; Sex Characteristics; Social Behavior; Stress, Psychological; Vasopressins

This study was undertaken to evaluate the effects of magnesium sulfate (MgSO4) on the contractile activity of the uterus in a pregnant rat model of preeclampsia induced by N-nitro-arginine methyl ester (L-NAME).. Twenty-eight, 160-220 gram, three to four month old female Sprague-Dawley rats were used in this study. After conception was confirmed by vaginal smears on the first day of pregnancy, the animals were allocated into four groups according to the chemicals fed in their drinking water as control (nothing administered), L-NAME (50 mg/kg L-NAME), MgSO4 (600 mg/kg MgSO4), and MgSO4 + L-NAME group (600 mg/kg MgSO4 + 50 mg/kg L-NAME). The pregnant uterus strips were isolated on the 19th day and the contractile activity of uterus was examined by applying 0, 0.1, 0.2, 0.4, 0.8, and 2.5 mIU/ml oxytocin to each group and responses are recorded accordingly.. There were no statistically significant differences regarding fetal parameters and peak amplitudes of the oxytocin stimulated pregnant rat myometrial strips among groups. In L-NAME group at 0 and 0.1 mIU/ml oxytocin, the contraction frequency in a ten-min period was statistically lower than the control group (Z = -2.850, p = 0.004; Z = -2.902, p = 0.004, respectively). In MgSO4 group only at 0 mIU/ml oxytocin, the frequencies of the contractions in ten-min period were statistically lower than the control group (Z = -2.973,p = 0.003). In L-NAME + MgSO4 group at 0, 0.1 and 0.2 mIU/ml oxytocin concentrations the frequencies of the contractions in ten-min period were statistically lower than the control group (Z = - 4.018, p = 0.000; Z = -3.237, p = 0.001; Z = -2.902, p = 0.004, respectively). In L-NAME + MgSO4 given group at each oxytocin concentrations, the frequencies of the contractions in ten-min period were lower but not statistically different than the L-NAME group.. MgSO4 has no significant effect on the amplitude of spontaneous or oxytocin induced myometrial contractions, but decreased the frequency of spontaneous contractions. At each doses of oxytocin, MgSO4 has no significant effect on the frequency of contraction in a pregnant rat model of preeclampsia induced by L-NAME.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Female; Magnesium Sulfate; NG-Nitroarginine Methyl Ester; Oxytocics; Oxytocin; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Uterine Contraction

Individuals in many species increase their proximity to others in threatening situations (defensive aggregation), increasing their chance of survival and reducing the adverse psychological impact of stressors. However, the basic neurobiology of defensive aggregation is not well understood. Here we examined the role of the social neuropeptides oxytocin (OT) and vasopressin (AVP) in this response. Groups of rats were exposed to a ball of cat fur (an innate threat stimulus) in a large arena, causing prolonged periods of tight social grouping (huddling). The modulatory effects of OT and AVP on huddling were examined both alone and in conjunction with relevant antagonists. To determine specificity of treatment effects to social grouping, the effects of the same treatments were also assessed in individual rats exposed to cat fur and given the opportunity to hide. OT (0.5 mg/kg, i.p.) and AVP (0.01 mg/kg, i.p.) increased huddling in rats socially exposed to cat fur, whereas the selective V1A AVP receptor antagonist SR49059 (3 mg/kg, i.p.) decreased huddling. The effects of OT were prevented by pre-treatment with SR49059 (3 mg/kg), while those of AVP were prevented by the V1B receptor antagonist SSR149415 (30 mg/kg, i.p.). OT had no effect on huddling when groups of four rats were tested with no cat fur present whereas AVP increased huddling under these conditions. Neither OT, nor SR49059, affected hiding in individual rats exposed to cat fur. However, AVP increased hiding, an effect prevented by SSR149415 (30 mg/kg, i.p.). These results suggest that OT acts on V1A receptors to promote a social response to threat without altering the more general defensive response. Conversely, AVP appears to increase generalised anxiety via V1B receptors, which subsequently results in huddling. A hitherto unrecognised function of oxytocin is therefore to promote social affiliation during threatening situations.

Topics: Aggression; Analysis of Variance; Animals; Cats; Disease Models, Animal; Drug Interactions; Hormone Antagonists; Indoles; Male; Odorants; Oxytocin; Pyrrolidines; Rats; Rats, Wistar; Stress, Psychological; Vasopressins

Xiang-Fu-Si-Wu Decoction (XFSWD) has been widely used to treat primary dysmenorrhea in clinical practice for hundreds of years and shown great efficacy. One fraction of XFSWD, which was an elution product by macroporous adsorption resin from aqueous extract solution with 60% ethanol (XFSWE), showed great analgesic effect. The present study was conducted to investigate the possible pharmacokinetic and tissue distribution profiles of four major bioactive constituents (berberine, protopine, tetrahydrocoptisine and tetrahydropalmatine) after oral administration of XFSWE in dysmenorrheal symptom rats, and to compare the difference between normal and dysmenorrheal symptom rats.. Estradiol benzoate and oxytocin were used to produce dysmenorrheal symptom rat model. The experimental period was seven days. At the final day of experimental period, both normal and dysmenorrheal symptom rats were orally administrated with XFSWE, and then the blood and tissues samples were collected at different time points. Berberine, protopine, tetrahydrocoptisine and tetrahydropalmatine in blood and tissue samples were determined by LC-MS/MS. Pharmacokinetic parameters were calculated from the plasma concentration-time data using non-compartmental methods. The differences of pharmacokinetic parameters among groups were tested by one-way analysis of variance (ANOVA).. There were statistically significant differences (P<0.05) in Cmax, Tmax, AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞) and CL/F between normal and dysmenorrheal symptom rats that orally administered with same dosage of XFSWE. In tissue distribution study, the results showed that the overall trend was C(Spleen)>C(Liver)>C(Kidney)>C(Uterus)>C(Heart)>C(Lung)>C(Ovary)>C(Brain)>C(Thymus), C(M-60 min)>C(M-120 min)>C(M-30 min)>C(C-60 min)>C(C-120 min)>C(C-30 min). The contents of protopine in liver, spleen and uterus were more than that in other tissues of dysmenorrheal symptom rats. Compared to normal rats, partial contents of the compounds in dysmenorrheal symptom rats׳ tissues at different time points had significant difference (P<0.05).. This study was the first report about pharmacokinetic and tissue distribution investigation in dysmenorrheal symptom animals. The results indicated that berberine, protopine, tetrahydrocoptisine and tetrahydropalmatine have higher uptake and slower elimination in the rats with dysmenorrheal syndrome, which suggests that the rate and extent of drug metabolism were altered in dysmenorrheal syndrome rats. And the results also demonstrated that berberine, protopine and tetrahydropalmatine in normal and dysmenorrheal symptom rats had obvious differences in some organs and time points, suggesting that the blood flow and perfusion rate of the organ were altered in dysmenorrheal symptom animals.

Topics: Administration, Oral; Animals; Disease Models, Animal; Drugs, Chinese Herbal; Dysmenorrhea; Estradiol; Female; Oxytocin; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Tissue Distribution

Development of new treatments for drug addiction will depend on high-throughput screening in animal models. However, an addiction biomarker fit for rapid testing, and useful in both humans and animals, is not currently available. Economic models are promising candidates. They offer a structured quantitative approach to modeling behavior that is mathematically identical across species, and accruing evidence indicates economic-based descriptors of human behavior may be particularly useful biomarkers of addiction severity. However, economic demand has not yet been established as a biomarker of addiction-like behavior in animals, an essential final step in linking animal and human studies of addiction through economic models. We recently developed a mathematical approach for rapidly modeling economic demand in rats trained to self-administer cocaine. We show here that economic demand, as both a spontaneous trait and induced state, predicts addiction-like behavior, including relapse propensity, drug seeking in abstinence, and compulsive (punished) drug taking. These findings confirm economic demand as a biomarker of addiction-like behavior in rats. They also support the view that excessive motivation plays an important role in addiction while extending the idea that drug dependence represents a shift from initially recreational to compulsive drug use. Finally, we found that economic demand for cocaine predicted the efficacy of a promising pharmacotherapy (oxytocin) in attenuating cocaine-seeking behaviors across individuals, demonstrating that economic measures may be used to rapidly identify the clinical utility of prospective addiction treatments.

Topics: Animals; Behavior, Animal; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Drug-Seeking Behavior; Humans; Male; Models, Economic; Motivation; Oxytocin; Rats; Rats, Sprague-Dawley; Self Administration

Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8  IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse's chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT.

Topics: Administration, Intranasal; Animals; Autistic Disorder; Behavior, Animal; Disease Models, Animal; Female; Interpersonal Relations; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Oxytocin; Sex Factors; Social Behavior

This study analyzed the effects of systemic oxytocin (OT) administration and 48-h food deprivation on the polydipsia, hyperphagia, and polyuria produced by electrolytic lesions of the mediobasal hypothalamus (MBH). In a first experiment, food deprivation transiently decreased the polydipsic response, whereas food deprivation plus OT administration reduced the water intake and urine excretion of polydipsic animals but not their subsequent food intake. These results were replicated in a second experiment (20 days), which also showed that OT potentiates sodium excretion, reducing the estimated plasma sodium levels in food-deprived MBH-lesioned animals. Administration of OT on day 21 to food-deprived (from day 20 to 22) animals (second period of the experiment 2) blocked the differences in water intake and urine excretion volumes between MBH and control animals on days 21 and 22. Subsequently, this 48-h food deprivation induced an additional and lasting (days 23-40) reduction in the intake of water and food of MBH animals. According to these findings, OT administration and/or food deprivation may potentially exert enduring reducing effects on the polydipsia, polyuria, and hyperphagia of MBH syndrome.

Topics: Animals; Disease Models, Animal; Food Deprivation; Hyperphagia; Hypothalamus; Male; Oxytocin; Polydipsia; Polyuria; Rats; Rats, Wistar; Syndrome

Clinical evidence suggests that oxytocin treatment improves social deficits and repetitive behavior in autism spectrum disorders (ASDs). However, the neuropeptide has a short plasma half-life and poor ability to penetrate the blood-brain barrier. In order to facilitate the development of more bioavailable oxytocinergic compounds as therapeutics to treat core ASD symptoms, small animal models must be validated for preclinical screens. This study examined the preclinical utility of two inbred mouse strains, BALB/cByJ and C58/J, that exhibit phenotypes relevant to core ASD symptoms. Mice from both strains were intraperitoneally administered oxytocin, using either acute or sub-chronic regimens. Acute oxytocin did not increase sociability in BALB/cByJ; however, sub-chronic oxytocin had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 h following the final oxytocin dose in BALB/cByJ, while prosocial effects of oxytocin emerged 1-2 weeks post-treatment in C58/J. Furthermore, acute oxytocin decreased motor stereotypy in C58/J and did not induce hypoactivity or anxiolytic-like effects in an open field test. This study demonstrates that oxytocin administration can attenuate social deficits and repetitive behavior in mouse models of ASD, dependent on dose regimen and genotype. These findings provide validation of the BALB/cByJ and C58/J models as useful platforms for screening novel drugs for intervention in ASDs and for elucidating the mechanisms contributing to the prosocial effects of oxytocin.

Topics: Analysis of Variance; Animals; Child Development Disorders, Pervasive; Choice Behavior; Cohort Studies; Disease Models, Animal; Exploratory Behavior; Female; Impulsive Behavior; Male; Mice; Mice, Inbred BALB C; Oxytocin; Sex Factors; Social Behavior; Social Behavior Disorders; Species Specificity; Stereotyped Behavior; Time Factors

Oxytocin (OT) and arginine vasopressin (AVP) are 2 neuropeptides that display well-known effects on the reproductive system. Although still controversial, oxytocin and vasopressin were demonstrated to exert potent effects on the nociceptive system when administered directly in various central nervous structures. On the other hand, little is known about their peripheral (hormonal) actions on nociception and pain responses. The aim of the present work was to characterize the effects of physiological blood concentrations of OT and AVP on spinal nociception and on pain responses. To do so, growing doses of OT or AVP were administered intravenously and the nociceptive processing by spinal cord neurons was analyzed in anesthetized male rats in vivo. We observed that the action potentials mediated by C-type nociceptive fibers was strongly reduced (antinociception) after intravenous injections of low doses of OT (<5 μg) or AVP (<500 pg), whereas an increase (pronociception) was observed at higher doses. Interestingly, antinociceptive and pronociceptive effects were fully abolished in the presence of the OT receptor antagonist and the AVP receptor antagonist type 1A (V1A), respectively. We confirmed this result with a behavioral model of forced swim stress-induced analgesia associated with plasmatic release of OT (and not vasopressin). Stress-induced analgesia was transiently lost after i.v. administration of OTR antagonist. Together, the present work provides straightforward evidence that blood levels of OT and AVP modulate nociception, windup plasticity and pain responses. The final target structures explaining these effects remains to be identified but are likely to be C-type nociceptors.

Topics: Action Potentials; Analgesics; Animals; Arginine Vasopressin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Hyperalgesia; Male; Nerve Fibers, Unmyelinated; Neurons; Oxytocin; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; Spinal Cord; Swimming

Increased oscillatory activity has been demonstrated in the basal ganglia of Parkinson's disease (PD) patients. The aim of the present study was to evaluate the effects of oxytocin on local field potentials (LFPs) in a rotenone-induced rat model of PD. Adult male Sprague-Dawley rats were unilaterally injected with rotenone (3 µg/µl in DMSO) into the left substantia nigra pars compacta whereas vehicle group was received only DMSO. PD developed rats were then administered either oxytocin (160 µg/kg/day, i.p.) or saline for three weeks. Following treatment period, LFPs were recorded from the left striatum of freely moving rats and neuronal cell loss was evaluated by Nissl staining. We found significant increase in all frequency bands except delta in saline group when compared with vehicle (p < 0.0005), while treatment of oxytocin prevented these alterations in EEG recordings. Besides, histopathological evaluation of the striatal sections revealed a significant cell loss (p < 0.005), whereas administration of rats with oxytocin significantly lessened the neuronal death. These findings suggest that injury of dopaminergic neurons triggers exaggerated neuronal oscillations in the striatum and oxytocin may have some inhibitory effects on neuronal activity in PD.

Topics: Animals; Apomorphine; Behavior, Animal; Disease Models, Animal; Electroencephalography; Electrophysiological Phenomena; Male; Neostriatum; Neurons; Oxytocin; Parkinson Disease; Rats; Rats, Sprague-Dawley; Rotation

Alzheimer's disease affects more than 35 million people worldwide but there is no known cure. Age is the strongest risk factor for Alzheimer's disease but it is not clear how age-related changes impact the disease. Here, we used a mouse model of Alzheimer's disease to identify age-specific changes that occur prior to and at the onset of traditional Alzheimer-related phenotypes including amyloid plaque formation. To identify these early events we used transcriptional profiling of mouse brains combined with computational approaches including singular value decomposition and hierarchical clustering.. Our study identifies three key events in early stages of Alzheimer's disease. First, the most important drivers of Alzheimer's disease onset in these mice are age-specific changes. These include perturbations of the ribosome and oxidative phosphorylation pathways. Second, the earliest detectable disease-specific changes occur to genes commonly associated with the hypothalamic-adrenal-pituitary (HPA) axis. These include the down-regulation of genes relating to metabolism, depression and appetite. Finally, insulin signaling, in particular the down-regulation of the insulin receptor substrate 4 (Irs4) gene, may be an important event in the transition from age-related changes to Alzheimer's disease specific-changes.. A combination of transcriptional profiling combined with computational analyses has uncovered novel features relevant to Alzheimer's disease in a widely used mouse model and offers avenues for further exploration into early stages of AD.

Topics: Alzheimer Disease; Animals; Cerebral Cortex; Cluster Analysis; Disease Models, Animal; Female; Humans; Hypothalamo-Hypophyseal System; Insulin; Insulin Receptor Substrate Proteins; Mice; Mice, Inbred C57BL; Oxytocin; Phenotype; Pituitary-Adrenal System; Signal Transduction; Transcription, Genetic; Transcriptome

We showed previously that sino-aortic denervation prevented training-induced plasticity in pre-autonomic oxytocinergic neurons and blocked the beneficial effects of training. In this study, we investigate the combined effect of training and removal of specific chemoreceptor afferents on both cardiovascular parameters and oxytocin (OT) gene and protein expression within the hypothalamic paraventricular nucleus (PVN). Wistar rats and spontaneously hypertensive rats (SHRs) underwent carotid body denervation or sham surgery and were trained or kept sedentary for 3 months. After haemodynamic measurements at rest, rats were anaesthetized for brain perfusion. Fresh (perfused with PBS) and fixed brains (perfused with 4% paraformaldehyde) were processed for PVN OT mRNA (real-time PCR) and OT immunoreactivity within PVN subnuclei. In sham-operated rats, training improved treadmill performance and reduced resting heart rate (Wistar, -8%; SHRs, -10%), with a reduction in blood pressure only in SHRs (-8%). Training was accompanied by increased PVN OT mRNA expression (twofold increase in sham-operated SHRs) and peptide density in the posterior, ventromedial and dorsal cap PVN subnuclei (on average 70% increase in both strains), with significant correlations between OT content and training-induced resting bradycardia in sham-operated groups. Carotid body denervation did not interfere with the performance gain, abolished chemoreflex activation (without changing baroreflex control) and blocked training-induced cardiovascular adaptations and training-induced changes in PVN OT content in both strains. After carotid body denervation, there was no correlation between OT mRNA or OT immunoractivity and resting heart rate. The chronic absence of chemoreceptor inputs uncovers an unknown role of chemoreceptor signalling in driving the plasticity/activity of PVN oxytocinergic pre-autonomic neurons, thus mediating training-induced cardiovascular adaptive responses.

Topics: Adaptation, Physiological; Animals; Autonomic Denervation; Baroreflex; Blood Pressure; Carotid Body; Disease Models, Animal; Gene Expression Regulation; Heart Rate; Hypertension; Immunohistochemistry; Male; Neuronal Plasticity; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Physical Exertion; Rats; Rats, Inbred SHR; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sedentary Behavior; Signal Transduction; Time Factors

Septic shock is a serious condition with a consequent drop in blood pressure and inadequate tissue perfusion. Small-volume resuscitation with hypertonic saline (HS) has been proposed to restore physiological haemodynamics during haemorrhagic and endotoxic shock. In the present study, we sought to determine the effects produced by an HS infusion in rats subjected to caecal ligation and perforation (CLP). Male Wistar rats were randomly grouped and submitted to either CLP or sham surgery. Either HS (7.5% NaCl, 4 ml kg(-1) i.v.) or isotonic saline (IS; 0.9% NaCl, 4 ml kg(-1) i.v.) was administered 6 h after CLP. Recordings of mean arterial pressure and heart rate were made during this protocol. Moreover, measurements of electrolyte, vasopressin and oxytocin secretion were analysed after either the HS or the IS treatment. Six hours after CLP, we observed a characteristic decrease in mean arterial pressure that occurs after CLP. The HS infusion in these rats produced a transient elevation of the plasma sodium concentration and osmolality and increased plasma vasopressin and oxytocin levels. Moreover, the HS infusion could restore the mean arterial pressure after CLP, which was completely blunted by the previous injection of the vasopressin but not the oxytocin antagonist. The present study demonstrated that rats subjected to CLP and an infusion of hypertonic saline respond with secretion of neurohypophyseal hormones and a transient increase in blood pressure mediated by the V(1) receptor.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arterial Pressure; Disease Models, Animal; Fluid Therapy; Heart Rate; Homeostasis; Hormone Antagonists; Infusions, Intravenous; Male; Osmolar Concentration; Oxytocin; Pituitary Gland, Posterior; Rats; Rats, Wistar; Receptors, Oxytocin; Receptors, Vasopressin; Saline Solution, Hypertonic; Shock, Septic; Sodium; Time Factors; Vasopressins; Water-Electrolyte Balance

Oxytocin (OT) is a neurohypophyseal peptide traditionally associated with female reproductive functioning, and more recently with prosocial behavior. OT and its receptor are also expressed in the heart and vascular tissue and play a role in cardiovascular homeostasis. In vitro, it has been demonstrated that OT decreases NADPH-dependent superoxide production and pro-inflammatory cytokine release from vascular endothelial cells and macrophages, suggesting that OT may attenuate pathophysiological processes involved with atherosclerotic lesion formation. The present study sought to determine the effect of chronic exogenous OT administration on inflammation and atherosclerosis in an animal model of dyslipidemia and atherosclerosis, the Watanabe Heritable Hyperlipidemic (WHHL) rabbit. Twenty-two, 3-month-old WHHLs were surgically implanted with osmotic mini-pumps containing OT (n=11) or vehicle (n=11), and then were individually housed for the entire study. Blood and 24-h urine samples were taken at baseline and after 8 (midpoint) and 16 (endpoint) weeks of treatment. At endpoint, the aortas and visceral fat samples were dissected and stored for analyses. There were no group differences in body weight, serum lipids, plasma/urinary measures of oxidative stress, plasma cortisol or urinary catecholamines over the 16-week treatment. OT-treated animals exhibited significantly lower plasma C-reactive protein levels at midpoint and endpoint and developed significantly less atherosclerosis in the thoracic aorta relative to vehicle control animals at endpoint (p<0.05). Cytokine gene expression from visceral adipose tissue samples suggested that there was a decrease in adipose tissue inflammation in the OT-treated group compared to the vehicle control group, however these differences were not statistically significant. These results suggest that chronic peripheral OT administration can inhibit inflammation and atherosclerotic lesion development.

Topics: Adipose Tissue; Animals; Atherosclerosis; Biomarkers; Blood Glucose; Disease Models, Animal; Inflammation; Infusion Pumps; Insulin; Lipids; Male; Oxytocin; Rabbits; Stress, Physiological; Validation Studies as Topic

Genetically modified mice mimicking ODDD (oculodentodigital dysplasia), a disease characterized by reduced Cx43 (connexin 43)-mediated gap junctional intercellular communication, represent an in vivo model to assess the role of Cx43 in mammary gland development and function. We previously reported that severely compromised Cx43 function delayed mammary gland development and impaired milk ejection in mice that harboured a G60S Cx43 mutant, yet there are no reports of lactation defects in ODDD patients. To address this further, we obtained a second mouse model of ODDD expressing an I130T Cx43 mutant to assess whether a mutant with partial gap junction channel activity would be sufficient to retain mammary gland development and function. The results of the present study show that virgin Cx43I130T/+ mice exhibited a temporary delay in ductal elongation at 4 weeks. In addition, Cx43I130T/+ mice develop smaller mammary glands at parturition due to reduced cell proliferation despite similar overall gland architecture. Distinct from Cx43G60S/+ mice, Cx43I130T/+ mice adequately produce and deliver milk to pups, suggesting that milk ejection is unaffected. Thus the present study suggests that a loss-of-function mutant of Cx43 with partial gap junction channel coupling conductance results in a less severe mammary gland phenotype, which may partially explain the lack of reported lactation defects associated with ODDD patients.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Connexin 43; Craniofacial Abnormalities; Disease Models, Animal; Epithelial Cells; Eye Abnormalities; Female; Foot Deformities, Congenital; Gap Junctions; Green Fluorescent Proteins; Humans; Lactation; Male; Mammary Glands, Animal; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Oxytocin; Point Mutation; Pregnancy; Severity of Illness Index; Syndactyly; Tooth Abnormalities

Chronic stress is known to enhance the susceptibility for addiction disorders including alcoholism. While these findings have been recapitulated in animal models, the majority of these studies have utilized non-social rather than social stress paradigms; the latter of which are believed to be more relevant to the human situation. Therefore, the major aim of this study was to investigate, if 14 days of chronic subordinate colony housing (CSC), a pre-clinically validated psychosocial stress paradigm relevant for human psychiatric and somatic disorders, enhances ethanol (EtOH) consumption in male mice. To assess this, we employed the well-established two-bottle free-choice paradigm where mice were given access to water and 2, 4, 6 and 8% EtOH solutions (with the concentrations increasing each fourth day) following termination of the stress procedure. After 14 days of CSC, stressed mice consumed significantly more EtOH at all concentrations tested and displayed increased EtOH preference at concentrations of 6 and 8%. This effect was not due to an altered taste preference in CSC mice as assessed by saccharine- and quinine-preference tests, but was accompanied by increased anxiety-related behavior. Systemic administration of baclofen (2.5 mg/kg) or oxytocin (OXT; 10 mg/kg) reduced the EtOH intake in single housed control (baclofen, OXT) and CSC (baclofen) mice, whereas intracerebroventricular OXT (0.5 μg/2 μl) was ineffective in both groups. Taken together, these results suggest that (i) chronic psychosocial stress enhances EtOH consumption, and (ii) baclofen and OXT differentially affect EtOH intake in mice.

Topics: Adolescent; Alcohol Drinking; Alcoholism; Analysis of Variance; Animals; Baclofen; Disease Models, Animal; Drinking Behavior; Ethanol; Food Preferences; GABA-B Receptor Agonists; Housing, Animal; Humans; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Mice, Inbred C57BL; Oxytocin; Self Administration; Stress, Psychological

Relaxin-3 is a neuropeptide that is abundantly expressed by discrete brainstem neuron populations that broadly innervate forebrain areas rich in the relaxin-3 G-protein-coupled-receptor, RXFP3. Acute and subchronic central administration of synthetic relaxin-3 or an RXFP3-selective agonist peptide, R3/I5, increase feeding and body weight in rats. Intrahypothalamic injection of relaxin-3 also increases feeding. In this study, we developed a recombinant adeno-associated virus 1/2 (rAAV1/2) vector that drives expression and constitutive secretion of bioactive R3/I5 and assessed the effect of intrahypothalamic injections on daily food intake and body weight gain in adult male rats over 8 weeks. In vitro testing revealed that the vector rAAV1/2-fibronectin (FIB)-R3/I5 directs the constitutive secretion of bioactive R3/I5 peptide. Bilateral injection of rAAV1/2-FIB-R3/I5 vector into the paraventricular nucleus produced an increase in daily food intake and body weight gain (P<0.01, ~23%, respectively), relative to control treatment. In a separate cohort of rats, quantitative polymerase chain reaction analysis of hypothalamic mRNA revealed strong expression of R3/I5 transgene at 3 months post-rAAV1/2-FIB-R3/I5 infusion. Levels of mRNA transcripts for the relaxin-3 receptor RXFP3, the hypothalamic 'feeding' peptides neuropeptide Y, AgRP and POMC, and the reproductive hormone, GnRH, were all similar to control, whereas vasopressin and oxytocin (OT) mRNA levels were reduced by ~25% (P=0.051) and ~50% (P<0.005), respectively, in rAAV1/2-FIB-R3/I5-treated rats (at 12 weeks, n=9/8 rats per group). These data demonstrate for the first time that R3/I5 is effective in modulating feeding in the rat by chronic hypothalamic RXFP3 activation and suggest a potential underlying mechanism involving altered OT signalling. Importantly, there was no desensitization of the feeding response over the treatment period and no apparent deleterious health effects, indicating that targeting the relaxin-3-RXFP3 system may be an effective long-term therapy for eating disorders.

Topics: Animals; Body Weight; Dependovirus; Disease Models, Animal; Eating; Feeding and Eating Disorders; Feeding Behavior; Fibronectins; HEK293 Cells; Humans; Hypothalamus; Male; Nerve Tissue Proteins; Oxytocin; Peptides; Rats; Receptors, G-Protein-Coupled; Receptors, Peptide; Relaxin

There is growing evidence that stress contributes to cardiovascular disease and triggers the release of oxytocin. Moreover previous studies confirmed oxytocin mimics the protection associated with ischemic preconditioning. The present study was aimed to assess the possible cardioprotective effects of the centrally released oxytocin in response to stress and intracerebroventricular (i.c.v.) administration of exogenous oxytocin in ischemic-reperfused isolated rat heart.. Rats were divided in two main groups and all of them were subjected to i.c.v. infusion of vehicle or drugs: unstressed rats [control: vehicle, oxytocin (OT; 100 ng/5 μl), atosiban (ATO; 4.3 μg/5 μl) as oxytocin antagonist, ATO+OT] and stressed rats [St: stress, OT+St, ATO+St]. After anesthesia, hearts were isolated and subjected to 30 min regional ischemia and 60 min reperfusion (IR). Acute stress protocol included swimming for 10 min before anesthesia. Myocardial function, infarct size, coronary flow, ventricular arrhythmia, and biochemical parameters such as creatine kinase and lactate dehydrogenase were measured. Ischemia-induced ventricular arrhythmias were counted during the occlusion period.. The plasma levels of oxytocin and corticosterone were significantly elevated by stress. Unexpectedly hearts of stressed rats showed a marked depression of IR injury compared to control group. I.c.v. infusion of oxytocin mimicked the cardioprotective effects of stress, yet did not elevate plasma oxytocin level. The protective effects of both stress and i.c.v. oxytocin were blocked by i.c.v. oxytocin antagonist.. These findings suggest that i.c.v. infusion of exogenous oxytocin and centrally released endogenous oxytocin in response to stress could play a role in induction of a preconditioning effect in ischemic-reperfused rat heart via brain receptors.

Topics: Animals; Brain; Cardiotonic Agents; Disease Models, Animal; In Vitro Techniques; Injections, Intraventricular; Ischemic Preconditioning, Myocardial; Male; Myocardial Reperfusion Injury; Oxytocin; Rats; Rats, Wistar; Receptors, Oxytocin; Stress, Physiological; Stress, Psychological

Oxytocin is a neuromodulator with antidepressant-like effects. In vitro, oxytocin is rapidly cleaved by insulin-regulated aminopeptidase (IRAP). Oxytocin metabolites are known to exert strong central activities that are different from the effects of the parent molecule. Our goal is to investigate in vivo whether IRAP deletion modifies the antidepressant-like effects of oxytocin. Male and female C57Bl/6 mice, IRAP wild-type (IRAP(+/+)) and knock-out (IRAP(-/-)) mice were injected subcutaneously with saline, oxytocin or oxytocin combined with angiotensin IV. One hour after injection, immobility was timed during a 5 min forced swim that was preceded by an open field to study locomotor behaviour. Oxytocin induced antidepressant-like effects in male (0.25 mg/kg oxytocin) and female (0.15 mg/kg oxytocin) C57Bl/6 mice subjected to the forced swim test. Oxytocin did not influence locomotor behaviour in mice, as shown with the open field. These findings were reproduced in transgenic male (aged 3-6 months) and female (aged 12-18 months) IRAP(+/+) mice. However, the major findings of our study were that the antidepressant-like effect was reversed in angiotensin IV treated IRAP(+/+) mice and was completely absent in age- and gender-matched IRAP(-/-) mice. The lack of an antidepressant-like effect of oxytocin in young male and middle-aged female IRAP(-/-) mice attributes an important role to IRAP in mediating this effect.

Topics: Age Factors; Aminopeptidases; Angiotensin II; Animals; Antidepressive Agents; Cell Membrane; Cerebral Cortex; Cystinyl Aminopeptidase; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Female; Imipramine; Immobility Response, Tonic; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Oxytocin

We aimed to reveal the anti-convulsant effects of oxytocin (OT) in pentylenetetrazol (PTZ)-induced seizures in rats. Thirty rats were randomly divided into 5 equal groups. Using stereotaxy, we implanted electroencephologram (EEG) electrodes in the left nucleus of the posterior thalamus. After 2 days, the first and second groups were used as the control and PTZ (35 mg/kg) groups, respectively. We administered 40, 80 and 160 nmol/kg OT+35 mg/kg PTZ to the rats, constituting the third, fourth, and fifth groups, respectively, for 5 days. At the end of 5 days, we recorded EEGs via bipolar EEG electrodes. After 12h, all groups except the first received 70 mg/kg PTZ and we determined the dose-response ratio. Racine's Convulsion Scale was used to evaluate seizures. The spike-wave complex percentage in the EEG was determined as 0% for the first group, 38.6%±7.2 for the second group, 36.4%±5.6 for the third group, 4.3%±1.8 for the fifth group and 4.1%±1.1 for the fifth group. The fourth and fifth groups had significantly decreased spike-wave complex percentages compared to the second group (p<0.0001). OT may prevent PTZ-induced epilepsy on an EEG. OT may also be considered for use in the treatment of epilepsy in the future.

Topics: Animals; Disease Models, Animal; Electrodes, Implanted; Electroencephalography; Epilepsy; Male; Oxytocin; Pentylenetetrazole; Rats; Seizures

Physical injury, including surgery, can result in chronic pain; yet chronic pain following childbirth, including cesarean delivery in women, is rare. The mechanisms involved in this protection by pregnancy or delivery have not been explored.. We examined the effect of pregnancy and delivery on hypersensitivity to mechanical stimuli of the rat hindpaw induced by peripheral nerve injury (spinal nerve ligation) and after intrathecal oxytocin, atosiban, and naloxone. Additionally, oxytocin concentration in lumbar spinal cerebrospinal fluid was determined.. Spinal nerve ligation performed at mid-pregnancy resulted in similar hypersensitivity to nonpregnant controls, but hypersensitivity partially resolved beginning after delivery. Removal of pups after delivery prevented this partial resolution. Cerebrospinal fluid concentrations of oxytocin were greater in normal postpartum rats prior to weaning. To examine the effect of injury at the time of delivery rather than during pregnancy, spinal nerve ligation was performed within 24 h of delivery. This resulted in acute hypersensitivity that partially resolved over the next 2-3 weeks. Weaning of pups resulted only in a temporary return of hypersensitivity. Intrathecal oxytocin effectively reversed the hypersensitivity following separation of the pups. Postpartum resolution of hypersensitivity was transiently abolished by intrathecal injection of the oxytocin receptor antagonist, atosiban.. These results suggest that the postpartum period rather than pregnancy protects against chronic hypersensitivity from peripheral nerve injury and that this protection may reflect sustained oxytocin signaling in the central nervous system during this period.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Female; Hormone Antagonists; Hypersensitivity; Injections, Spinal; Naloxone; Narcotic Antagonists; Oxytocics; Oxytocin; Peripheral Nerve Injuries; Physical Stimulation; Postpartum Period; Rats; Rats, Sprague-Dawley; Spinal Nerves; Vasotocin; Weaning

Chronic restraint stress can induce depressive and anxiety-like behavior and neurophysiological disturbances. The social living shows the health-promoting and stress-protective effects on both human and animal. However, whether group housing exerts effects on development of depression and anxiety induced by chronic restraint treatments and its detailed neuroendocrine mechanism remain unclear. Following repeated restraint, the anxiety and depression-like behaviors of single and group housing mice were examined using the elevated plus-maze, open field test and forced swimming test. The levels of central oxytocin (OT) expression in the paraventricular nucleus (PVN), glucocorticoid receptors (GR) in the hippocampus and serum OT and corticosterone (CORT) were also measured using immunohistochemistry and ELISA methods. Our results show that chronic restraint significantly decreased time in open arm of elevated plus maze and increased immobility time in forced swimming test in single-housed mice. However, chronic restraint exerted no effects on these aspects in group-housed mice. Accompanying the changes of behaviors, chronic restraint up-regulated levels of serum CORT and reduced the hippocampus GR in single-housed animals, but did not change these measures in group-housed mice. Furthermore, repeated restraint had no effect on OT levels in these two housing conditions although group-housing significantly increased the PVN OT levels. Taken together, these results provide substantial evidence that group housing can reduce levels of anxiety and depression induced by chronic restraint stress in mice. The elevation of central GR and OT, and decrease of circulating CORT may possibly be involved in these buffering effects.

Topics: Analysis of Variance; Animals; Corticosterone; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation; Hippocampus; Male; Maze Learning; Mice; Mice, Inbred BALB C; Mood Disorders; Oxytocin; Paraventricular Hypothalamic Nucleus; Receptors, Glucocorticoid; Restraint, Physical; Social Isolation; Swimming

Pineal and melatonin interactions with the hypothalamo-neurohypophysial system are well documented. In addition, vasopressin and oxytocin secretion are known to be part of the neuroendocrine response to chronic heart failure evoked by myocardial infarction. The present study was undertaken to evaluate the possible regulatory role of melatonin in the vasopressin and oxytocin release in rats with myocardial infarction.. The vasopressin and oxytocin content of the hypothalamus and neurohypophysis, as well as their plasma levels, were radioimmunoassayed in sham-operated or pinealectomized rats with left coronary artery ligation (CAL)-evoked myocardial infarction as well as under melatonin treatment.. Infarcted rats demonstrated increased vasopressin and oxytocin plasma levels, but melatonin restricted the release of both neurohormones in these rats. Experimental myocardial infarction in pinealectomized rats caused a distinct inhibition of vasopressin release but intensified oxytocin secretion. In pinealectomized rats substituted with melatonin, pineal indole amine was seen to inhibit oxytocin release and stimulate vasopressin secretion.. (i) CAL-induced myocardial infarction is the reason for increased hypothalamo-neurohypophysial system activity in rats; melatonin plays the role of inhibitory neuromodulator of vasopressin and oxytocin release in this state. (ii) Myocardial infarction evoked in pinealectomized rats is characterized by the inversion of the neurohumoral response pattern in respect of inhibited vasopressin release. (iii) Melatonin stimulates vasopressin (but decreases oxytocin) release in pinealectomized rats with myocardial infarction.

Topics: Animals; Arginine Vasopressin; Disease Models, Animal; Feedback, Physiological; Hypothalamo-Hypophyseal System; Male; Melatonin; Myocardial Infarction; Oxytocin; Pineal Gland; Radioimmunoassay; Rats; Rats, Wistar

Oxytocin (OT) levels in plasma increase during sexual response and are significantly lower in patients with depression. A drug for the treatment of sexual dysfunction, sildenafil, enhances the electrically evoked release of OT from the posterior pituitary. In this study, we showed that sildenafil had an antidepressant-like effect through activation of an OT signaling pathway. Application of sildenafil reduced depression-related behavior in male mice. The antidepressant-like effect was blocked by an OT receptor (OTR) antagonist and was absent in OTR knockout (KO) mice. Sildenafil increased the phosphorylation of cAMP response element-binding protein (CREB) in the hippocampus. The OTR antagonist inhibited sildenafil-induced CREB phosphorylation and sildenafil had no effect on CREB phosphorylation in OTR KO mice. These results suggest sildenafil to have an antidepressant-like effect through the activation of OT signaling and to be a promising drug for the treatment of depression.

Topics: Aniline Compounds; Animals; Antidepressive Agents; Benzamides; Cyclic AMP Response Element-Binding Protein; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Exploratory Behavior; Female; Gene Expression Regulation; Immobility Response, Tonic; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxytocin; Phosphorylation; Piperazines; Purines; Receptors, Oxytocin; Sex Factors; Sexual Behavior, Animal; Sildenafil Citrate; Sulfones; Swimming

The Chinese herbs of myrrh and frankincense are often combined for treating some inflammatory pain diseases with synergistic therapeutic effects. In this study, we investigated the effects of individual herbal extracts and combined extract on anti-inflammatory and analgesic activities in vivo and analyzed the potential bioactive components from the combination extract by ultra-performance liquid chromatography coupled with mass spectrum (UPLC-MS/MS).. The anti-inflammatory activities were investigated by utilizing the paw edema mice induced by formalin and carrageenan. In addition, we determined the levels of PGE(2) and nitrite in the edema paw. The analgesic activity was examined against oxytocin-induced dysmenorrhea in mice. The effects of the administration of dolantin or indomethacin were also studied for references. The components in combination extract (CWE) were analyzed by UPLC-MS/MS.. The results showed that myrrh water extract (MWE) and the combined extract (CWE) at the 3.9 g/kg, and 5.2 g/kg showed inhibition of formalin-induced paw edema with inhibition rate of 30.44%, and 23.50%, respectively. The PGE(2) production was inhibited significantly by all samples (P<0.01 or P<0.05). CWE showed stronger suppression on carrageenan-induced mice paw edema at 2 and 3h after administration of drugs. The inhibitory effect of CWE on nitrite production was between that of MWE and water extract of frankincense (FWE) at 5.2 g/kg. The dysmenorrhea mice test showed MWE could remarkably reduce the writhing times (P<0.05) and prolong the latency period, while FWE showed no obvious effects on the writhing times. CWE significantly reduced the writhing times and prolong the latency period (P<0.01).. These results demonstrated MWE, FWE, and CWE exhibited significant anti-inflammatory and analgesic activities. The findings suggest that CWE may be therapeutically more useful for mitigating inflammatory pain than individual herbal extract. In addition, 12 potential active compounds were identified from CWE. These data may support the fact the traditional application of this combined extract in treating various diseases associated with inflammatory pain.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Boswellia; Carrageenan; Chromatography, Liquid; Commiphora; Dinoprostone; Disease Models, Animal; Drug Combinations; Dysmenorrhea; Edema; Female; Formaldehyde; Indomethacin; Meperidine; Mice; Mice, Inbred ICR; Molecular Structure; Motor Activity; Nitrites; Oxytocin; Pain Measurement; Pain Threshold; Plant Extracts; Plants, Medicinal; Reaction Time; Tandem Mass Spectrometry; Time Factors

The possible involvement of oxytocin (OT) in the generation of seizures has not received a lot of attention in the past, although generalized epileptic convulsions were observed in humans following intravenous OT infusion. We here aimed to investigate the effect of exogenous OT administration on seizure susceptibility in C57Bl/6 mice subjected to the pentylenetetrazol (PTZ) model. In addition, we studied via which receptor possible effects on seizure thresholds could be mediated since OT binds to both the OT receptor (OTR) and the vasopressin 1a receptor (V1aR). We showed that C57Bl/6 mice treated with 0.5 mg/kg OT had decreased PTZ thresholds for ear twitch, myoclonic twitch, tail twitch, forelimb clonus and falling. This pronconvulsive effect was reversed by the OTR antagonist L-368.899, however, it was not mimicked by the OTR agonist carbetocin (CBT). Nevertheless, CBT had antidepressant-like effects in the forced swim test that could be reversed by L-368.899. These experiments shed some doubt on the involvement of OTR in the observed effect of OT on seizure thresholds. Therefore, we investigated the role of the V1aR as a possible mediator of the proconvulsive effects of OT. We found that the proconvulsive effects of both arginine vasopressin and OT were reversed by the V1aR antagonist SR49059. In summary, OT has proconvulsive effects in our mouse model of generalized seizures that could not be mimicked by CBT. Our results suggest that the binding of OT to V1aRs is the most plausible explanation for the proconvulsive effects of OT.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Mice; Mice, Inbred C57BL; Oxytocin; Pentylenetetrazole; Receptors, Vasopressin; Seizures

Disorders of colonic motility may contribute to symptoms in patients with irritable bowel syndrome (IBS), and stress is widely believed to play a major role in developing IBS. Stress increases corticotropin releasing factor (CRF) of the hypothalamus, resulting in acceleration of colonic transit in rodents. In contrast, hypothalamic oxytocin (OXT) has an anti-stress effect via inhibiting CRF expression and hypothalamic-pituitary-adrenal axis activity. Although transcutaneous electrical nerve stimulation (TENS) and acupuncture have been shown to have anti-stress effects, the mechanism of the beneficial effects remains unknown.. We tested the hypothesis that TENS upregulates hypothalamic OXT expression resulting in reduced CRF expression and restoration of colonic dysmotility in response to chronic stress.. Male SD rats received different types of stressors for seven consecutive days (chronic heterotypic stress). TENS was applied to the bilateral hind limbs every other day before stress loading. Another group of rats did not receive TENS treatment.. TENS significantly attenuated accelerated colonic transit induced by chronic heterotypic stress, which was antagonized by a central injection of an OXT antagonist. Immunohistochemical study showed that TENS increased OXT expression and decreased CRF expression at the paraventricular nucleus (PVN) following chronic heterotypic stress.. It is suggested that TENS upregulates hypothalamic OXT expression which acts as an anti-stressor agent and mediates restored colonic dysmotility following chronic stress. TENS may be useful to treat gastrointestinal symptoms associated with stress.

Topics: Animals; Chronic Disease; Colon; Corticotropin-Releasing Hormone; Disease Models, Animal; Feedback, Physiological; Gastrointestinal Motility; Hypothalamo-Hypophyseal System; Irritable Bowel Syndrome; Male; Oxytocin; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Stress, Psychological; Transcutaneous Electric Nerve Stimulation; Treatment Outcome

The cycle of chronic cocaine (CC) use and withdrawal results in increased anxiety, depression and disrupted stress-responsiveness. Oxytocin and corticosterone (CORT) interact to mediate hormonal stress responses and can be altered by cocaine use. These neuroendocrine signals play important regulatory roles in a variety of social behaviours, specifically during the postpartum period, and are sensitive to disruption by CC exposure in both clinical settings and preclinical models. To determine whether CC exposure during pregnancy affected behavioural and hormonal stress response in the early postpartum period in a rodent model, Sprague-Dawley rats were administered cocaine daily (30 mg/kg) throughout gestation (days 1-20). Open field test (OFT) and forced swim test (FST) behaviours were measured on postpartum day 5. Plasma CORT concentrations were measured before and after testing throughout the test day, whereas plasma and brain oxytocin concentrations were measured post-testing only. The results obtained indicated increased CORT response after the OFT in CC-treated dams (P ≤ 0.05). CC-treated dams also exhibited altered FST behaviour (P ≤ 0.05), suggesting abnormal stress responsiveness. Peripheral, but not central, oxytocin levels were increased by cocaine treatment (P ≤ 0.05). Peripheral oxytocin and CORT increased after the FST, regardless of treatment condition (P ≤ 0.05). Changes in stress-responsiveness, both behaviourally and hormonally, may underlie some deficits in maternal behaviour; thus, a clearer understanding of the effect of CC on the stress response system may potentially lead to treatment interventions that could be relevant to clinical populations. Additionally, these results indicate that CC treatment can have long-lasting effects on peripheral oxytocin regulation in rats, similar to changes observed in persistent social behaviour and stress-response deficits in clinical populations.

Topics: Animals; Body Weight; Brain; Cocaine; Corticosterone; Disease Models, Animal; Female; Immobility Response, Tonic; Male; Motor Activity; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Stress, Psychological

Methamphetamine is a highly addictive stimulant drug whose illicit use and resultant addiction has become an alarming global phenomenon. The mesolimbic dopaminergic pathway has been shown to be fundamental to the establishment of addictive behaviour. This pathway, as part of the reward system of the brain, has also been shown to be important in classical conditioning, which is a learnt response. Within the modulation of learning and memory, the neurohypophyseal hormones vasopressin and oxytocin have been reported to play a vital role, with vasopressin exerting a long- term facilitatory effect and oxytocin exerting an inhibitory effect. Therefore we adopted a conditioned place preference model to investigate whether vasopressin V1b receptor antagonist SSR 149415 or oxytocin treatment would cause a decrease in the seeking behaviour in a reinstatement paradigm. Behavioural findings indicated that methamphetamine induced a change in the place preference in the majority of our animals. This change in place preference was not seen when vasopressin was administered during the extinction phase. On the other hand the methamphetamine-induced change in place preference was enhanced during the reinstatement phase in the animals that were treated with oxytocin. Striatal dopamine levels were determined, as methamphetamine is known to increase dopamine transmission in this area. Significant changes in dopamine levels were observed in some of our animals. Rats that received both methamphetamine and oxytocin had significantly higher striatal dopamine than those that received oxytocin alone. Western blot analysis for hippocampal cyclic AMP response element binding protein (CREB) was also conducted as a possible indicator of glutamatergic NMDA receptor activity, a pathway that is important for learning and memory. The Western blot analysis showed no changes in hippocampal pCREB expression. Overall our data led us to conclude that methamphetamine treatment can change place preference behaviour in rats and that this change may be partially restored by vasopressin antagonism, but exaggerated by oxytocin.

Topics: Amphetamine-Related Disorders; Animals; Central Nervous System Stimulants; Disease Models, Animal; Male; Methamphetamine; Oxytocin; Rats; Rats, Sprague-Dawley; Vasopressins

Bile duct ligation (BDL), a model of hepatic cirrhosis, is associated with dilutional hyponatremia and inappropriate vasopressin release. ΔFosB staining was significantly increased in vasopressin and oxytocin magnocellular neurosecretory cells in the supraoptic nucleus (SON) of BDL rats. We tested the role of SON ΔFosB in fluid retention following BDL by injecting the SON (n = 10) with 400 nl of an adeno-associated virus (AAV) vector expressing ΔJunD (a dominant negative construct for ΔFosB) plus green fluorescent protein (GFP) (AAV-GFP-ΔJunD). Controls were either noninjected or injected with an AAV vector expressing only GFP. Three weeks after BDL or sham ligation surgery, rats were individually housed in metabolism cages for 1 wk. Average daily water intake was significantly elevated in all BDL rats compared with sham ligated controls. Average daily urine output was significantly greater in AAV-GFP-ΔJunD-treated BDL rats compared with all other groups. Daily average urine sodium concentration was significantly lower in AAV-GFP-ΔJunD-treated BDL rats than the other groups, although average daily sodium excretion was not different among the groups. SON expression of ΔJunD produced a diuresis in BDL rats that may be related to decreased circulating levels of vasopressin or oxytocin. These findings support the view that ΔFosB expression in SON magnocellular secretory cells contribute to dilutional hyponatremia in BDL rats.

Topics: Animals; Cholestasis; Disease Models, Animal; Green Fluorescent Proteins; Hyponatremia; Ligation; Liver Cirrhosis; Male; Oxytocin; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Supraoptic Nucleus; Vasopressins; Water-Electrolyte Balance

Because of the difficulties in developing suitable animal models, the pathogenesis of stress-induced functional gastrointestinal disorders is not well known. Here we applied the communication box technique to induce psychological stress in rats and then examined their gastrointestinal motility. We measured upper and lower gastrointestinal motility induced by acute and chronic psychological stress and examined the mRNA expression of various neuropeptides in the hypothalamus. Chronic psychological stress disrupted the fasted motility in the antrum and accelerated motility in the proximal colon. mRNA expression of AVP, oxytocin, and urocortin 3 was increased by chronic psychological stress. Intracerebroventricular (ICV) injection of urocortin 3 disrupted the fasted motility in the antrum, while ICV injection of Ucn3 antiserum prevented alteration in antral motility induced by chronic psychological stress. ICV injection of AVP accelerated colonic motility, while ICV injection of SSR 149415, a selective AVP V1b receptor antagonist, prevented alteration in proximal colonic motility induced by chronic psychological stress. Oxytocin and its receptor antagonist L 371257 had no effect on colonic motility in either the normal or chronic psychological stress model. These results suggest that chronic psychological stress induced by the communication box technique might disrupt fasted motility in the antrum via urocortin 3 pathways and accelerates proximal colonic motility via the AVP V1b receptor in the brain.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Colon; Corticotropin-Releasing Hormone; Disease Models, Animal; Duodenum; Fasting; Gastrointestinal Diseases; Gastrointestinal Motility; Hormone Antagonists; Hypothalamus; Immune Sera; Indoles; Injections, Intraventricular; Male; Manometry; Oxytocin; Pressure; Pyloric Antrum; Pyrrolidines; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Vasopressin; RNA, Messenger; Stress, Psychological; Time Factors; Up-Regulation; Urocortins

Xiang-fu-si-wu decoction has been widely used to treat blood stasis syndromes in gynecology diseases, such as primary dysmenorrhea in clinical practice for hundreds of years and show great efficacy. The efficient components and mechanism of action on uterus contraction were seldom reported.. The present study was conducted to evaluate the inhibitory effects of active fractions and its main bioactive components of xiang-fu-si-wu decoction on uterine contraction.. Model of non-pregnant mice uterine contraction induced by oxytocin was used to evaluate activity. Levels of Ca(2+) and nitric oxide (NO) in primary dysmenorrheal model mice uterus were also been detected. Components in active fraction were identified and quantified by HPLC-DAD.. It was found the active fraction of xiang-fu-si-wu decoction may become potential Ca(2+) channel blocking agents. Alkaloids like berberine were main active components in bioactive fraction of xiang-fu-si-wu decoction for dysmenorrhea on uterus contraction.

Topics: Alkaloids; Animals; China; Disease Models, Animal; Drugs, Chinese Herbal; Dysmenorrhea; Ethnopharmacology; Female; Humans; In Vitro Techniques; Medicine, Chinese Traditional; Mice; Mice, Inbred ICR; Oxytocin; Phytotherapy; Plants, Medicinal; Uterine Contraction

Oxytocin (OT) has been suggested as a treatment to improve social behavior in autistic patients. Accordingly, the OT (Oxt(-/-)) and the OT receptor null mice (Oxtr(-/-)) display autistic-like deficits in social behavior, increased aggression, and reduced ultrasonic vocalization.. Oxtr(-/-) mice were characterized for general health, sociability, social novelty, cognitive flexibility, aggression, and seizure susceptibility. Because vasopressin (AVP) and OT cooperate in controlling social behavior, learning, and aggression, they were tested for possible rescue of the impaired behaviors. Primary hyppocampal cultures from Oxtr(+/+) and Oxtr(-/-) mouse embryos were established to investigate the balance between gamma-aminobutyric acid (GABA) and glutamate synapses and the expression levels of OT and AVP (V1a) receptors were determined by autoradiography.. Oxtr(-/-) mice display two additional, highly relevant, phenotypic characteristics: 1) a resistance to change in a learned pattern of behavior, comparable to restricted interests and repetitive behavior in autism, and 2) an increased susceptibility to seizures, a frequent and clinically relevant symptom of autism. We also show that intracerebral administration of both OT and AVP lowers aggression and fully reverts social and learning defects by acting on V1a receptors and that seizure susceptibility is antagonized by peripherally administered OT. Finally, we detect a decreased ratio of GABA-ergic versus total presynapses in hippocampal neurons of Oxtr(-/-) mice.. Autistic-like symptoms are rescued on administration of AVP and OT to young Oxtr(-/-) adult animals. The Oxtr(-/-) mouse is thus instrumental to investigate the neurochemical and synaptic abnormalities underlying autistic-like disturbances and to test new strategies of pharmacologic intervention.

Topics: Aggression; Analysis of Variance; Animals; Arginine Vasopressin; Autistic Disorder; Autoradiography; Cells, Cultured; Cognition; Disease Models, Animal; Hippocampus; Immunohistochemistry; Male; Mice; Mice, Knockout; Neurons; Oxytocin; Receptors, Oxytocin; Seizures; Social Behavior

Many chemicals utilized by humans are present as environmental pollutants and may influence homeostasis from neurological, immunological, endocrinological and/or behavioral aspects. Such agents, acting alone or in ambient mixtures, may be biologically active even at extremely low doses, and it may be postulated that stable, bioaccumulative, reactive endocrine disruptors may affect central and/or peripheral secretion of arginine-vasopressin (AVP) and oxytocin (OXT) and thereby related physiological and behavioral functions, potentially leading to disorders in exposed subjects. The primary aim of this study was to demonstrate effects of chronic exposure to a low dose of an orally administered chlorobenzene mixture on anxiety-related and aggressive behavior mediated largely by AVP and OXT. Chlorobenzenes were applied to model ambient mixtures of endocrine disruptors. Adult, male Wistar rats were exposed daily to 0.1 μg/kg of 1,2,4-trichlorobenzene and hexachlorobenzene via a stomach tube for 30, 60 or 90 days, after which anxiety-related and aggressive behavioral elements were examined in open-field, elevated plus maze and resident-intruder tests. The plasma levels of AVP, OXT and adrenocorticotrophic hormone at the endpoints were measured by radioimmunoassay or immunochemiluminescence assay. The levels of basal and serotonin- or norepinephrine-stimulated AVP and OXT secretion in pituicyte cultures prepared from the posterior lobe of the pituitaries were also measured. The hormone levels proved to be increased to extents depending on the duration of exposure to the chlorobenzenes. Several anxiety-related and aggressive behavioral elements were also enhanced following chlorobenzene exposure, while certain explorative and locomotive elements of the animals were decreased. As both physiological and behavioral elements were modulated by chronic, subtoxic doses of chlorobenzenes, it is concluded that doses of such environmental pollutants low enough to fall outside the range of legal regulation may pose potential risks of anxiogenic and/or aggressive consequences in exposed subjects, including humans.

Topics: Adrenocorticotropic Hormone; Aggression; Animals; Anxiety; Arginine Vasopressin; Cells, Cultured; Chlorobenzenes; Disease Models, Animal; Drug Administration Schedule; Environmental Pollutants; Hexachlorobenzene; Male; Maze Learning; Motor Activity; Norepinephrine; Oxytocin; Pituitary Gland, Posterior; Rats; Rats, Wistar; Serotonin

Life stress frequently occurs within the context of homeostatic challenge, requiring integration of physiological and psychological need into appropriate hormonal, cardiovascular, and behavioral responses. To test neural mechanisms underlying stress integration within the context of homeostatic adversity, we evaluated the impact of a pronounced physiological (hypernatremia) challenge on hypothalamic-pituitary-adrenal (HPA), cardiovascular, and behavioral responses to an acute psychogenic stress. Relative to normonatremic controls, rats rendered mildly hypernatremic had decreased HPA activation in response to physical restraint, a commonly used rodent model of psychogenic stress. In addition, acute hypernatremia attenuated the cardiovascular response to restraint and promoted faster recovery to prestress levels. Subsequent to restraint, hypernatremic rats had significantly more c-Fos expression in oxytocin- and vasopressin-containing neurons within the supraoptic and paraventricular nuclei of the hypothalamus. Hypernatremia also completely eliminated the increased plasma renin activity that accompanied restraint in controls, but greatly elevated circulating levels of oxytocin. The endocrine and cardiovascular profile of hypernatremic rats was predictive of decreased anxiety-like behavior in the social interaction test. Collectively, the results indicate that acute hypernatremia is a potent inhibitor of the HPA, cardiovascular, and behavioral limbs of the stress response. The implications are that the compensatory responses that promote renal-sodium excretion when faced with hypernatremia also act on the nervous system to decrease reactivity to psychogenic stressors and facilitate social behavior, which may suppress the anxiety associated with approaching a communal water source and support the social interactions that may be encountered when engaging in drinking behavior.

Topics: Adrenocorticotropic Hormone; Analysis of Variance; Animals; Behavior, Animal; Blood Pressure; Corticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Rate; Hypodermoclysis; Male; Osmosis; Oxytocin; Paraventricular Hypothalamic Nucleus; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Social Behavior; Sodium Chloride; Stress, Psychological; Supraoptic Nucleus; Time Factors; Vasoactive Intestinal Peptide

We showed previously that oxytocinergic (OTergic) projections from the hypothalamic paraventricular nucleus (PVN) to the dorsal brain stem mediate training-induced heart rate (HR) adjustments and that beneficial effects of training are blocked by sinoaortic denervation (SAD; Exp Physiol 94: 630-640; 1103-1113, 2009). We sought now to determine the combined effect of training and SAD on PVN OTergic neurons in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Rats underwent SAD or sham surgery and were trained (55% of maximal capacity) or kept sedentary for 3 mo. After hemodynamic measurements were taken at rest, rats were deeply anesthetized. Fresh brains were frozen and sliced to isolate the PVN; samples were processed for OT expression (real-time PCR) and fixed brains were processed for OT immunofluorescence. In sham rats, training improved treadmill performance and increased the gain of baroreflex control of HR. Training reduced resting HR (-8%) in both groups, with a fall in blood pressure (-10%) only in SHR rats. These changes were accompanied by marked increases in PVN OT mRNA expression (3.9- and 2.2-fold in WKY and SHR rats, respectively) and peptide density in PVN OTergic neurons (2.6-fold in both groups), with significant correlations between OT content and training-induced resting bradycardia. SAD abolished PVN OT mRNA expression and markedly reduced PVN OT density in WKY and SHR. Training had no effect on HR, PVN OT mRNA, or OT content following SAD. The chronic absence of inputs from baroreceptors and chemoreceptors uncovers the pivotal role of afferent signaling in driving both the plasticity and activity of PVN OTergic neurons, as well as the beneficial effects of training on cardiovascular control.

Topics: Animals; Autonomic Pathways; Blood Pressure; Denervation; Disease Models, Animal; Heart Rate; Hypertension; Male; Models, Animal; Neuronal Plasticity; Neurons, Afferent; Oxytocin; Paraventricular Hypothalamic Nucleus; Physical Conditioning, Animal; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Sinoatrial Node; Supraoptic Nucleus

A major problem in understanding mechanisms of pathogenesis in autism spectrum disorder (ASD) is deciphering how risk factors act via the brain to influence the behavioral symptoms of this disorder. We may start to bridge this gap in our understanding by systematically examining the structure and function of cell types that make up circuits underlying behavioral endophenotypes in animal models for ASD. A confluence of advances in basic behavioral neurobiology, in ASD mechanisms and animal models, and in genetic tools for imaging and manipulating brain circuits will make this possible. Through a process of elimination of candidates and comparison across models, we may hope to understand how ASD risk factors influence the development and function of neural circuitry at the level of genetically defined cell types. As an example of how this candidate circuit approach may be applied to investigating ASD, here I focus on social behavior as an endophenotype, and I discuss recent findings regarding the development and function of the oxytocin system, which is implicated in both normal social behavior and ASD pathogenesis. I stress the importance of a collaborative, multidisciplinary approach to probing candidate cell types and circuits across mouse models of ASD.

Topics: Animals; Autistic Disorder; Brain; Child; Disease Models, Animal; Endophenotypes; Humans; Mice; Oxytocin; Social Behavior

Central oxytocin (OXT) has been shown to promote numerous social behaviours, to attenuate hormonal stress responsiveness of the HPA axis and to decrease anxiety. Wistar rats selectively bred for high (HAB) and low (LAB) anxiety-related behaviour, respectively, have been shown to represent a suitable animal model to study the underlying aetiology of psychopathologies like anxiety- and depression-related disorders. The goal of the present studies was to assess the effects of central OXT on anxiety- and depression-related behaviour in male and female HAB and LAB rats. Acute icv OXT (1 microg) or OXT receptor antagonist (OXT-A; 0.75 microg) administration did not affect anxiety-related behaviour in male or female HAB and LAB rats as assessed in the light-dark box. In contrast, chronic icv OXT infusion (10 ng/h; 6 d) attenuated the high level of anxiety-related behaviour in female, but not male, HAB rats, whereas chronic OXT-A infusion (7.5 ng/h; 6 d) increased anxiety-related behaviour in female, but not male, LAB rats. Neither acute nor chronic manipulation of the OXT system altered depression-related behaviour as assessed by the forced swim test. Combined, these results suggest that pharmacological manipulation of the brain OXT system is effective to attenuate extremes in trait anxiety in an animal model of psychopathological anxiety. Moreover, the data indicate that differences in the activity of the brain OXT systems between HAB and LAB rats may, at least partially, contribute to the opposing anxiety but not depression-related behaviour.

Topics: Analysis of Variance; Animals; Anti-Arrhythmia Agents; Anxiety; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Delivery Systems; Female; Injections, Intraventricular; Male; Maze Learning; Oxytocin; Rats; Rats, Wistar; Sex Factors; Swimming

The effects of oxytocin (OT) on cardiovascular endpoints were assessed in a myocardial infarct (MI) model. OT (10 ng.kg(-1).hour(-1)) or saline infusion was initiated at reperfusion (D0) or 8 days (D8) after MI. Our hypothesis was that OT administration to individuals with a low pretreatment OT levels (PTOT) may be beneficial, whereas individuals with an elevated PTOT would be prone to adverse effects. Starting OT on D0 reduced left ventricular fraction shortening evaluated 8 days post MI and had no effect on infarct size. OT initiated on D8 in animals with high PTOT decreased ejection fraction (EF) and increased left ventricular end-systolic diameter at 28 days post MI but had no significant effects on EF and left ventricular end-systolic diameter in low PTOT animals. OT infusion reduced OT receptor protein expression in high PTOT animals but not in low PTOT animals. Among placebo-treated individuals, low PTOT presented a trend toward reduced EF and larger infarct size compared with high PTOT. MI areas of fibrosis presented lower Annexin V expression compared with MI with cardiomyocyte predominance. Pretreatment endogenous OT levels and timing of OT administration post MI seem to impact outcome in this porcine model, and further investigations are warranted to define potential role of OT in cardiac regenerative therapy.

Topics: Animals; Annexin A5; Disease Models, Animal; Drug Administration Schedule; Fibrosis; Male; Myocardial Infarction; Myocytes, Cardiac; Oxytocics; Oxytocin; Swine; Time Factors

An imbalance of excitatory and inhibitory functions has been shown to contribute to numerous pathological disorders. Accumulating evidence supports the idea that a change in hypothalamic gamma-aminobutyric acid (GABA)-ergic inhibitory and glutamatergic excitatory synaptic functions contributes to exacerbated neurohumoral drive in prevalent cardiovascular disorders, including hypertension. However, the precise underlying mechanisms and neuronal substrates are still not fully elucidated. In the present study, we combined quantitative immunohistochemistry with neuronal tract tracing to determine whether plastic remodeling of afferent GABAergic and glutamatergic inputs into identified RVLM-projecting neurons of the hypothalamic paraventricular nucleus (PVN-RVLM) contributes to an imbalanced excitatory/inhibitory function in renovascular hypertensive rats (RVH). Our results indicate that both GABAergic and glutamatergic innervation densities increased in oxytocin-positive, PVN-RVLM (OT-PVN-RVLM) neurons in RVH rats. Despite this concomitant increase, time-dependent and compartment-specific differences in the reorganization of these inputs resulted in an altered balance of excitatory/inhibitory inputs in somatic and dendritic compartments. A net predominance of excitatory over inhibitory inputs was found in OT-PVN-RVLM proximal dendrites. Our results indicate that, along with previously described changes in neurotransmitter release probability and postsynaptic receptor function, remodeling of GABAergic and glutamatergic afferent inputs contributes as an underlying mechanism to the altered excitatory/inhibitory balance in the PVN of hypertensive rats.

Topics: Animals; Biomarkers; Cardiovascular System; Dendrites; Disease Models, Animal; Excitatory Postsynaptic Potentials; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Glutamic Acid; Hypertension, Renovascular; Immunohistochemistry; Inhibitory Postsynaptic Potentials; Kidney; Male; Medulla Oblongata; Neural Pathways; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats; Rats, Wistar; Reticular Formation; Synaptic Transmission; Vesicular Glutamate Transport Protein 2

Stressful social experiences during early-life can increase the risk of developing neuropsychiatric disorders associated with anxiety, mood, and personality. Early neglect also alters peripheral arginine vasopression (AVP) and oxytocin (OXT). We hypothesized that a lack of social stimuli should adversely affect developmental AVP and OXT systems. To test this idea, we examined changes of central AVP- and OXT-immunoreactive (ir) cell number as well as its related behaviors in socially isolated rats. Animals were weaned at 23 days of age, divided into group- or isolation-reared conditions, and maintained for at least 2 weeks. At 38-48 days of age, animals were sacrificed for immunohistochemistry, or used for two behavioral tests: elevated plus-maze test and social recognition test. The results from immunohistochemistry showed that isolation-reared males have decreased AVP-ir cells in the paraventricular nucleus hypothalamus (PVH), medial parvicellular part, ventral zone, and that isolation-reared females have decreased OXT-ir cells in the PVH, medial parvicellular part, dorsal zone, when compared with group-reared counterparts. The results from behavioral assessment showed that isolation-reared animals have difficulty with social recognition, and that isolation-reared males, but not females, have anxiogenic profile. The present study demonstrates that post-weaning social isolation results in decrease of male AVP-ir cells and female OXT-ir cells in the PVH parvocellular divisions, and supports the idea that juvenile social environment may play a critical role in neuronal and behavioral development.

Topics: Animals; Anxiety Disorders; Arginine Vasopressin; Behavior, Animal; Cell Count; Disease Models, Animal; Female; Immunohistochemistry; Male; Maze Learning; Mood Disorders; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats; Rats, Long-Evans; Social Behavior; Social Isolation

To determine the effect of exogenous oxytocin (OT) administration on inflammation and atherosclerosis in socially isolated apoE(-/-) mice. Hyperlipidemic animals housed in isolated or stressful social environments display more extensive atherosclerosis than those in an affiliative social environment. The neurohypophyseal peptide OT may be involved in both affiliative social behavior and cardiovascular homeostasis, suggesting a role in mediating the benefits of positive social interactions on atherosclerosis.. A total of 43, 12-week-old, apoE(-/-) mice were surgically implanted with osmotic minipumps containing OT (n = 23) or vehicle (n = 20). Blood samples were taken at baseline and after 6 weeks and 12 weeks of treatment. After 12 weeks of treatment, animals were killed, and samples of adipose tissue were dissected from a subset of OT-treated (n = 12) and vehicle-treated (n = 12) animals and incubated in culture media for 6 hours. Media samples were analyzed for interleukin (IL)-6 concentration corrected by sample dry weight. Aortas were dissected, formalin-fixed, and stained with oil-red O for en face quantification of lesion area. t tests were used to compare group means on measures of percent lesion area and IL-6 concentrations.. There were no group differences in plasma lipids. Adipose tissue samples taken from OT-treated animals secreted significantly less IL-6 over 6 hours (p < .01). OT-treated animals displayed significantly less atherosclerosis in the thoracic aorta (p < .05).. These results indicate that peripheral OT administration can inhibit atherosclerotic lesion development and adipose tissue inflammation, suggesting a potential role for this neuropeptide in mediating the benefits of stable group housing on atherosclerosis.

Topics: Adipose Tissue; Animals; Aorta, Thoracic; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Inflammation; Interleukin-6; Male; Mice; Oxytocin; Receptors, Oxytocin; Social Isolation; Sympathetic Nervous System

To examine the salubrious role of social interaction in modulating the development of allodynia (increased sensitivity to typically innocuous physical stimuli) and depressive-like behavior post peripheral nerve injury in mice. The determination of potential mechanisms that mediate social influences on the behavioral and physiological response to peripheral nerve injury.. Mice were pair housed or socially isolated for 2 weeks before spared nerve injury (SNI). Animals were cannulated; socially isolated animals were centrally treated with oxytocin; and socially paired animals were centrally treated with an oxytocin receptor antagonist. Animals were subsequently monitored for the development of mechanical allodynia and depressive-like behavior, and tissue was collected for analysis of the central levels of the cytokine interleukin 1 beta (IL-1beta).. Depressive-like behavior was assessed via the Porsolt forced swim test, developed only among socially isolated mice with nerve injury. Socially isolated mice with nerve injury also were the only experimental group to exhibit increased frontal cortex IL-1beta gene expression on day 7 post injury. Moreover, central treatment of socially isolated mice with oxytocin, a neuropeptide associated with social bonding, attenuated the effects of SNI on depressive-like behavior and reduced frontal cortex IL-1beta protein levels in socially isolated animals. Conversely, pair-housed animals treated with a selective oxytocin receptor antagonist developed depressive-like behavior equivalent to that of socially isolated animals and displayed increased IL-1beta protein levels within the frontal cortex.. These data suggest that social interaction significantly alters the affective and neuroinflammatory responses to SNI through a mechanism that could involve oxytocin.

Topics: Animals; Behavior, Animal; Depressive Disorder; Disease Models, Animal; Female; Gene Expression; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Oxytocin; Pain Threshold; Peripheral Nerve Injuries; Physical Exertion; Prefrontal Cortex; Receptors, Oxytocin; Social Behavior; Social Environment; Social Isolation; Swimming

A significant association between plasma oxytocin (OT) levels and depression has been demonstrated. A recent study found that sexual activity and mating with a female induced the release of OT in the central nervous system of male rats. Here we examined the effect of mating behavior on depression-related behavior in wild-type (WT) and OT receptor-deficient (OTR KO) male mice. The WT males showed a reduction in depression-related behavior after mating behavior, but the OTR KO mice did not. Application of an OTR antagonist inhibited mating behavior-induced antidepressant effect in WT males. OT may mediate the antidepressant effects of mating behavior.

Topics: Animals; Depression; Disease Models, Animal; Female; Freezing Reaction, Cataleptic; Hormone Antagonists; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxytocin; Receptors, Oxytocin; Sexual Behavior, Animal; Swimming; Vasotocin

Oxytocin reportedly decreases anxious feelings in humans and may therefore have therapeutic value for anxiety disorders, such as post-traumatic stress disorder (PTSD). As PTSD patients have exaggerated startle responses, a fear-potentiated startle paradigm in rats may have face validity as an animal model to examine the efficacy of oxytocin in treating these symptoms. Oxytocin (0, 0.01, 0.1, or 1.0 μg, subcutaneously) was given either 30 min before fear conditioning, immediately after fear conditioning, or 30 min before fear-potentiated startle testing to assess its effects on acquisition, consolidation, and expression of conditioned fear, respectively. Startle both in the presence and absence of the fear-conditioned light was significantly diminished by oxytocin when administered at acquisition, consolidation, or expression. There was no specific effect of oxytocin on light fear-potentiated startle. In an additional experiment, oxytocin had no effects on acoustic startle without previous fear conditioning. Further, in a context-conditioned test, previous light-shock fear conditioning did not increase acoustic startle during testing when the fear-conditioned light was not presented. The data suggest that oxytocin did not diminish cue-specific conditioned nor contextually conditioned fear, but reduced background anxiety. This suggests that oxytocin has unique effects of decreasing background anxiety without affecting learning and memory of a specific traumatic event. Oxytocin may have antianxiety properties that are particularly germane to the hyper-vigilance and exaggerated startle typically seen in PTSD patients.

Topics: Acoustic Stimulation; Animals; Anxiety; Conditioning, Classical; Cues; Disease Models, Animal; Dose-Response Relationship, Drug; Fear; Male; Oxytocin; Photic Stimulation; Rats; Rats, Sprague-Dawley; Reflex, Startle

Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. BTBR T+tf/J (BTBR) is an inbred mouse strain that displays robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including low social interactions, reduced vocalizations in social settings, and high levels of repetitive self-grooming. Autism-relevant phenotypes in BTBR offer translational tools to discover neurochemical mechanisms underlying unusual mouse behaviors relevant to symptoms of autism. Because repetitive self-grooming in mice may be a displacement behavior elevated by stressors, we investigated neuroendocrine markers of stress and behavioral reactivity to stressors in BTBR mice, as compared to C57BL/6J (B6), a standard inbred strain with high sociability. Radioimmunoassays replicated previous findings that circulating corticosterone is higher in BTBR than in B6. Higher basal glucocorticoid receptor mRNA and higher oxytocin peptide levels were detected in the brains of BTBR as compared to B6. No significant differences were detected in corticotrophin releasing factor (CRF) peptide or CRF mRNA. In response to behavioral stressors, BTBR and B6 were generally similar on behavioral tasks including stress-induced hyperthermia, elevated plus-maze, light ↔ dark exploration, tail flick, acoustic startle and prepulse inhibition. BTBR displayed less reactivity than B6 to a noxious thermal stimulus in the hot plate, and less immobility than B6 in both the forced swim and tail suspension depression-related tasks. BTBR, therefore, exhibited lower depression-like scores than B6 on two standard tests sensitive to antidepressants, did not differ from B6 on two well-validated anxiety-like behaviors, and did not exhibit unusual stress reactivity to sensory stimuli. Our findings support the interpretation that autism-relevant social deficits, vocalizations, and repetitive behaviors are not the result of abnormal stress reactivity in the BTBR mouse model of autism.

Topics: Adaptation, Ocular; Animals; Autistic Disorder; Corticosterone; Corticotropin-Releasing Hormone; Disease Models, Animal; Fever; Hindlimb Suspension; Interpersonal Relations; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Oxytocin; Pain Threshold; Radioimmunoassay; Receptors, Glucocorticoid; Reflex, Acoustic; RNA, Messenger; Stress, Psychological

Gastric electrical stimulation (GES) has been proposed as a therapeutic option for obesity. However, its clinical efficacy is not proven, and its mechanisms remain largely unknown. To compare the peripheral and central neural and behavioral effects in rats of GES with a pulse width currently used in clinical trials (GES-A: 6 mA, 0.3 ms, 40 Hz, 2 s on, 3 s off) and GES with a wider pulse (GES-B: same as GES-A, except that the pulse width is 3 ms). Experiment 1: assessing gastric volume changes as a result of GES. Experiment 2: recording the extracellular potentials of a single neuron in the paraventricular nucleus (PVN) with GES. Experiment 3: determining the effects of GES on oxytocin-immunoreactive (OT-IR) neuron expression in the hypothalamus. Experiment 4: determining the effects of GES on food intake and body weight. GES-B, but not GES-A, significantly increased gastric volume. GES-B activated a higher percentage of gastric distention-responsive neurons in the PVN (93% vs. 81%, P = 0.021) and elicited more intensive neuronal responses than GES-A. The number of OT-IR neurons was significantly increased in the PVN and supraoptic nucleus with both methods of GES compared with control groups. The increase in OT-IR neurons in the PVN was higher with GES-B than with GES-A. A 1-week GES treatment significantly reduced daily food intake and body weight. GES-B was more potent than GES-A in producing weight loss (P < 0.001). The effects of GES depend on the stimulation pulse width. GES with a wider pulse is more effective both peripherally and centrally and more potent in reducing body weight in rats.

Topics: Animals; Disease Models, Animal; Eating; Electric Stimulation Therapy; Equipment and Supplies; Female; Male; Neurons; Obesity; Oligopeptides; Oxytocin; Paraventricular Hypothalamic Nucleus; Pyrrolidonecarboxylic Acid; Rats; Rats, Sprague-Dawley; Stomach; Weight Loss

Spinal long-term potentiation (LTP) elicited by noxious stimulation enhances the responsiveness of dorsal horn nociceptive neurons to their normal input, and may represent a key mechanism of central sensitization by which acute pain could turn into a chronic pain state. This study investigated the electrophysiological and behavioral consequences of the interactions between LTP and descending oxytocinergic antinociceptive mechanisms mediated by the hypothalamic paraventricular nucleus (PVN). PVN stimulation or intrathecal oxytocin (OT) reduced or prevented the ability of spinal LTP to facilitate selectively nociceptive-evoked responses of spinal wide dynamic range (WDR) neurons recorded in anesthetized rats. In a behavioral model developed to study the effects of spinal LTP on mechanical withdrawal thresholds in freely moving rats, the long-lasting LTP-mediated mechanical hyperalgesia was transiently interrupted or prevented by either PVN stimulation or intrathecal OT. LTP mediates long-lasting pain hypersensitivity that is strongly modulated by endogenous hypothalamic oxytocinergic descending controls.

Topics: Analgesia; Analgesics; Animals; Behavior, Animal; Disease Models, Animal; Efferent Pathways; Electric Stimulation Therapy; Hyperalgesia; Injections, Spinal; Long-Term Potentiation; Male; Nociceptors; Oxytocin; Pain Measurement; Pain Threshold; Paraventricular Hypothalamic Nucleus; Posterior Horn Cells; Rats; Rats, Wistar; Spinothalamic Tracts

Anecdotal evidence suggests that chronic bladder pain improves while breastfeeding. The present study sought to identify potential mechanisms for such a phenomenon by investigating the effects of the lactogenic hormones prolactin (PL) and oxytocin (OXY) in a rat model of bladder nociception. Lactating rats were less sensitive to urinary bladder distension (UBD) than controls. In investigating potential antinociceptive and anxiolytic roles for these hormones, we found exposure to a footshock paradigm (STRESS groups) produced bladder hypersensitivity in saline-treated rats, manifested as significantly higher electromyographical (EMG) responses to UBD, compared to rats exposed to a nonfootshock paradigm (SHAM groups). This hypersensitivity was attenuated by the intraperitoneal administration of OXY prior to footshock in the STRESS-OXY group. The administration of PL augmented EMG responses in the SHAM-PL group but had no effect on the responses of the STRESS-PL group. In the absence of behavioral pretreatment, OXY attenuated UBD-evoked responses while PL had no effect. Moreover, OXY-treated rats spent more time in the open arm of an elevated plus maze compared to saline-treated rats suggesting anxiolysis. These studies suggest the potential for systemic OXY, but not PL, as an analgesic and anxiolytic treatment for painful bladder disorders such as interstitial cystitis.. This study presents evidence that systemic oxytocin has both analgesic and anxiolytic properties which may make it a potentially useful agent for patients with stress-exacerbated chronic-pain syndromes such as interstitial cystitis. These studies do not suggest a similar role for prolactin.

Topics: Analgesics; Animals; Anti-Anxiety Agents; Anxiety; Disease Models, Animal; Electric Stimulation; Female; Injections, Intraperitoneal; Lactation; Maze Learning; Neuropsychological Tests; Nociceptors; Oxytocin; Pain, Intractable; Prolactin; Rats; Rats, Sprague-Dawley; Sex Factors; Stress, Psychological; Treatment Outcome; Urinary Bladder; Urinary Bladder, Overactive; Visceral Afferents

Regular physical activity is beneficial in preventing the risk of cardiovascular complications of diabetes. Recent studies showed a cardioprotective role of oxytocin (OT) to induce natriuretic peptides (NPs) and nitric oxide (NO) release. It is not known if the diabetic state is associated with a reduced OT-NPs-NO system and if exercise training improves this system. To address this, we investigated the effects of treadmill running using the db/db mouse model of type 2 diabetes. Eight-week-old db/db mice were subjected to running 5 days per week for a period of 8 weeks. The lean db/+ littermates were used as controls. Sedentary db/db mice were obese and hyperglycaemic, and exercise training was not effective in reducing body weight and the hyperglycaemic state. Compared to control mice, db/db mice had lower heart weight and heart-to-body weight ratios. In these mice, this was associated with augmented cardiac apoptosis, cardiomyocyte enlargement and collagen deposits. In addition, db/db mice displayed significant downregulation in gene expression of OT (76%), OT receptors (65%), atrial NP (ANP; 43%), brain NP (BNP; 87%) and endothelial nitric oxide synthase (eNOS) (54%) in the heart (P < 0.05). Exercise training had no effect on expression of these genes which were stimulated in control mice. In response to exercise training, the significant increment of anti-apoptotic Bcl-2 gene expression was observed only in control mice (P < 0.05). In conclusion, downregulation of the OT-NPs-NO system occurs in the heart of the young db/db mouse. Exercise training was not effective in reversing the defect, suggesting impairment of this cardiac protective system in diabetes.

Topics: Animals; Base Sequence; Cardiomyopathies; Diabetes Complications; Diabetes Mellitus, Type 2; Disease Models, Animal; DNA Primers; Down-Regulation; Genes, bcl-2; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Natriuretic Peptides; Nitric Oxide Synthase Type III; Oxytocin; Physical Conditioning, Animal; Physical Exertion; Receptors, Oxytocin; Risk Factors

We investigated whether postinfarct treatment with oxytocin (OT) improves left ventricular (LV) function and remodeling via cardiac repair of myocardial ischemia-reperfusion injury.. Experiments were performed with 30 minutes of coronary occlusion and 2 or 14 days of reperfusion rabbit model of myocardial infarction. LV function and remodeling were significantly improved in the OT group. The infarct size was significantly reduced in the OT group. The number of CD31-positive microvessels was increased significantly in the OT group. There were no Ki67-positive myocytes in either group. The expression of the OT receptor, phosphorylated (p)-Akt protein kinase, p-extracellular signal-regulated protein kinase, p-enodthelial NO synthase, p-signal transducer and activator of transcription 3, vascular endothelial growth factor, B-cell lymphoma 2, and matrix metalloproteinase-1 (MMP-1) were markedly increased in the OT group days 2 and 14 post myocardial infarction.. Postinfarct treatment with OT reduces myocardial infarct size and improves LV function and remodeling by activating OT receptors and prosurvival signals and by exerting antifibrotic and angiogenic effects through activation of MMP-1, endothelial NO synthase, and vascular endothelial growth factor. These findings provide new insight into therapeutic strategies for ischemic heart disease.

Topics: Animals; Blood Pressure; Cyclin D1; Disease Models, Animal; Echocardiography; Extracellular Signal-Regulated MAP Kinases; Heart; Heart Rate; Male; Matrix Metalloproteinase 1; Microvessels; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Oxytocin; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1; Proto-Oncogene Proteins c-akt; Rabbits; Receptors, Oxytocin; Signal Transduction; STAT3 Transcription Factor; Stroke Volume; Vascular Endothelial Growth Factor A; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

During the brain's innate immune response microglia, astroglia and ependymal cells resolve/repair damaged tissue and control infection. Released interleukin-1beta (IL-1beta) reaching cerebroventricles stimulates circumventricular organs (CVOs; subfornical organ, SFO; organum vasculosum lamina terminalis, OVLT), the median preoptic nucleus (MePO), and magnocellular and parvocellular neurons in the supraoptic (SON) and paraventricular (PVN) nuclei. Hypertonic saline (HS) also activates these osmosensory CVOs and neuroendocrine systems, but, in contrast to IL-1beta, inhibits the peripheral immune response. To examine whether the brain's innate immune response is attenuated by osmotic stimulation, sterile acidic perfusion fluid was microdialyzed (2 microl/min) in the SON area of conscious rats for 6 h with sterile HS (1.5 M NaCl) injected subcutaneously (15 ml/kg) at 5 h. Immunohistochemistry identified cytokine sources (IL-1beta(+); OX-42(+) microglia) and targets (IL-1R(+); inducible cyclooxygenase, COX-2(+); c-Fos(+)) near the probe, in CVOs, MePO, ependymal cells, periventricular hypothalamus, SON, and PVN. Inserting the probe stimulated magnocellular neurons (c-Fos(+); SON; PVN) via the MePO (c-Fos(+)), a response enhanced by HS. Microdialysis activated microglia (OX-42(+); amoeboid/hypertrophied; IL-1beta(+)) in the adjacent SON and bilaterally in perivascular areas of the PVN, periventricular hypothalamus and ependyma, coincident with c-Fos expression in ependymal cells and COX-2 in the vasculature. These microglial responses were attenuated by HS, coincident with activating parvocellular and magnocellular neuroendocrine systems and elevating circulating IL-1beta, oxytocin, and vasopressin. Acidosis-induced cellular injury from microdialysis activated the brain's innate immune response by a mechanism inhibited by peripheral osmotic stimulation.

Topics: Acidosis; Animals; Brain; Disease Models, Animal; Ependyma; Immunity, Innate; Interleukin-1beta; Male; Microdialysis; Microglia; Midline Thalamic Nuclei; Osmosis; Oxytocin; Rats; Rats, Sprague-Dawley; Saline Solution, Hypertonic; Supraoptic Nucleus; Vasopressins

Understanding the early factors affecting obesity development in males and females may help to prevent obesity and may lead to the discovery of more effective treatments for those already obese. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of obesity is characterized by hyperphagia-induced obesity, due to a spontaneous lack of CCK(1) receptors. In the present study, we focused on the behavioral and physiological aspects of obesity development from weaning to adulthood. We examined body weight, feeding efficiency, fat pad [brown, retroperitoneal, inguinal and epydidimal (in males)] weight, inguinal adipocyte size and number, leptin and oxytocin levels, body mass index, waist circumference, and females' estrous cycle structure. In the males, central hypothalamic gene expression was also examined. OLETF rats presented overall higher fat and leptin levels, larger adipocytes, and increased waist circumference and BMI from weaning until adulthood, compared with controls. Analysis of developmental patterns of gene expression for hypothalamic neuropeptides revealed peptide-specific patterns that may underlie or be a consequence of the obesity development. Analysis of the developmental trajectories toward obesity within the OLETF strain revealed that OLETF females developed obesity in a more gradual manner than the males, presenting delayed obesity-related "turning points," with reduced adipocyte size but larger postweaning fat pads and increased adipocyte hyperplasia compared with the males. Intake decrease in estrus vs. proestrus was significantly less in OLETF vs. Long-Evans Tokushima Otsuka females. The findings highlight the importance of using different sex-appropriate approaches to increase the efficacy of therapeutic interventions in the treatment and prevention of chronic early-onset obesity.

Topics: Adipocytes; Adipose Tissue; Age Factors; Aging; Animals; Blood Glucose; Body Mass Index; Body Weight; Chronic Disease; Disease Models, Animal; Disease Progression; Eating; Estrus; Feeding Behavior; Female; Gene Expression Regulation, Developmental; Hyperphagia; Hypothalamus; Leptin; Male; Neuropeptides; Obesity; Oxytocin; Rats; Rats, Inbred OLETF; Receptor, Cholecystokinin A; RNA, Messenger

Osmotic control of arginine vasopressin (AVP) and oxytocin (OXT) release from magnocellular neurosecretory cells (MNCs) of the supraoptic (SON) and paraventricular (PVN) nuclei is essential for body fluid homeostasis. The electrical activity of MNCs, which is regulated by intrinsic and extrinsic osmosensitive factors, is a primary determinant of blood AVP and OXT levels. Although we now understand many of the cellular mechanisms that mediate the osmotic control of electrical activity and secretion from MNCs, further insight is likely to emerge from a molecular analysis of these mechanisms. An important step towards this goal could be made through the use of mouse genetic models. However, the electrophysiological properties of MNCs in mice have not been characterized, making direct comparisons with the rat model somewhat difficult. In this study, we examined the electrical properties of MNCs from the mouse SON. Extracellular recordings from neurons in superfused explants revealed modes of basal and osmotically modulated firing very similar to those observed previously in rats. Recordings in hypothalamic slices confirmed that SON neurons receive kynurenic-acid-sensitive excitatory synaptic inputs from the organum vasculosum laminae terminalis (OVLT). Current-clamp recordings from acutely dissociated SON neurons showed proportional changes in membrane cation conductance during changes in fluid osmolality. We conclude, therefore, that MNCs in the mouse SON display intrinsic osmosensitive properties and firing patterns that are very similar to those reported in the rat. Mouse MNCs therefore represent a useful model for the study of molecular factors contributing to the osmotic control of AVP and OXT release.

Topics: Animals; Arginine Vasopressin; Body Fluids; Calcium; Disease Models, Animal; Exocytosis; Homeostasis; Hypothalamus; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Models, Genetic; Neurons; Neurosecretory Systems; Oxytocin; Supraoptic Nucleus; Water-Electrolyte Balance

Prior research has reliably found high blood (hyperserotonemia) - but low brain - serotonin levels in autistic individuals. At early stages of development, high levels of serotonin in the blood may enter the brain of a developing fetus, causing a loss of serotonin terminals through negative feedback and thus disrupting subsequent serotonergic function. The current study extends earlier findings in a developmental hyperserotonemia (DHS) model of autism in Sprague-Dawley rats by treating 8 dams of developing rat pups with a serotonergic agonist, 5-methoxytryptamine (5-MT; 1 mg/kg) during development (from gestational day 12 to post-natal day 20; PND 20). DHS pups exhibited post-injection seizures, which were non-existent in saline-treated pups (p<0.05). Behavioral results in infancy indicated that DHS pups spent less time with the dam during the active phase on PNDs 15-17 (p<0.05) and experienced decreased maternal bonding in a return to dam task on PND 17 (p<0.05). On subsequent tests, DHS animals exhibited greater gnawing reactions to a novel stimulus (p<0.05), less behavioral inhibition (p<0.05), and had fewer olfactory-based social interactions (p<0.05) and greater non-olfactory mounting (p<0.05). However, there were no changes in anxiogenic behavior using the elevated plus maze (p>0.05). Post mortem analyses revealed that DHS animals had a loss of oxytocin (OT)-containing cells in the paraventricular nucleus in the hypothalamus (PVN; p<0.05) as well as an increase in calcitonin-gene related peptide (CGRP; p<0.05, one tailed) processes in the central nucleus of the amygdala (CeA) on PND 198. These results may correspond to hypothalamic and amygdalar changes in the human condition and suggest that the hyperserotonemia model of autism may be a valid model which produces many of the social, behavioral, and peptide changes inherent to autism.

Topics: Amygdala; Animals; Animals, Newborn; Anxiety Disorders; Autistic Disorder; Behavior, Animal; Brain; Brain Diseases, Metabolic; Calcitonin Gene-Related Peptide; Disease Models, Animal; Exploratory Behavior; Immunohistochemistry; Maternal Behavior; Maze Learning; Neuropeptides; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Receptor Agonists; Social Behavior Disorders

Neuropeptide S (NPS) and its receptor (NPSR) comprise a recently deorphaned G protein-coupled receptor system. Recent reports implicate NPS in the mediation of anxiolytic-like activity in rodents.. To extend the characterization of NPS, the present studies examined the in vitro pharmacology of mouse NPSR and the in vivo pharmacology of NPS in three preclinical mouse models predictive of anxiolytic action: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH). The ability of NPS to produce antidepressant-like effects in the tail suspension test (TST) was also investigated.. In vitro, mouse NPS 1-20 (mNPS 1-20) and the C-terminal glutamine-truncated mouse NPS 1-19 bound mNPSR with high affinity (Ki = 0.203 +/- 0.060, 0.635 +/- 0.141 nM, respectively) and potently activated intracellular calcium release (EC50 = 3.73 +/- 1.08, 4.10 +/- 1.25 nM). NPS produced effects in vivo consistent with anxiolytic-like activity. In FPT, NPS increased punished crossings (minimal effective dose [MED]: mNPS 1-20 = 0.2 microg, mNPS(1-19) = 0.02 microg), similar to the reference anxiolytic, alprazolam (MED 0.5 microg). NPS increased the percentage of time spent in the open quadrants of EZM (MED: mNPS 1-20 = 0.1 microg, mNPS 1-19 = 1.0 microg), like the reference anxiolytic, chlordiazepoxide (MED 56 microg). In SIH, NPS attenuated stress-induced increases in body temperature similar to alprazolam but with a large potency difference between the NPS peptides (MED: mNPS 1-20 = 2.0 microg, mNPS 1-19 = 0.0002 microg) and mNPS 1-20 increased baseline temperature. Unlike fluoxetine, NPS did not effect immobility time in TST, indicating a lack of antidepressant-like activity.. These data provide an important confirmation and expansion of the anxiolytic-like effects of NPS and implicate the NPS system as a novel target for anxiolytic drug discovery.

Topics: Alprazolam; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Arousal; Body Temperature Regulation; Calcium; Cell Line; Chlordiazepoxide; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fear; Fluoxetine; Humans; In Vitro Techniques; Male; Maze Learning; Mice; Motor Activity; Neuropeptides; Oxytocin; Peptide Fragments; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Structure-Activity Relationship

To understand the adaptation to lactation of obese rats, by studying the interplay among the gut hormone cholecystokinin (CCK), the adiposity hormone leptin and the affiliation hormone oxytocin in modulating body mass and fat storage.. Strain differences were examined between Otsuka Long Evans Tokushima Fatty (OLETF) rats lacking expression of functional CCK-1 receptors and Long Evans Tokushima Otsuka (LETO) controls, tested as nulliparous dams, at the 7 and 15th lactation day, at weaning (lactation day 22) or 8 weeks postweaning.. We measured body mass, fat pads (brown, retroperitoneal and inguinal) and inguinal adipocytes. Plasma levels of leptin and oxytocin were determined.. Fat depots of LETO female rats were larger during lactation compared to the levels found in postweaning and nulliparous female rats. LETO female rats gained weight and accumulated fat during pregnancy and lactation, returning to their normal fat levels postweaning. In contrast, OLETF female rats presented lower body weight and fat depots during the lactation period than nulliparous dams, and regained the weight and fat postweaning. Plasma leptin and oxytocin were highly correlated and followed the same pattern. OLETF leptin levels were highly correlated with fat depot and inguinal cell surface. No significant correlation was found for LETO parameters.. Pregnancy and lactation are energy-consuming events, which naturally induce female rats to increase food intake and accumulate fat. When challenged by the demands of rapidly growing preobese OLETF pups, OLETF dams' fat stores are reduced to lean, LETO levels. During lactation, sensitivity of the oxytocinergic neurons descending from the paraventricular nuclei to the nucleus of the solitary tract to CCK is reduced. We theorized that this pathway is not available to OLETF female rats that lack functional CCK-1 receptors to mediate the signal. The current study contributes to the understanding of the female body's adaptation to lactation.

Topics: Adaptation, Physiological; Adipocytes; Adipose Tissue; Animals; Body Weight; Disease Models, Animal; Female; Hypertrophy; Lactation; Leptin; Mutation; Obesity; Oxytocin; Rats; Rats, Inbred OLETF; Receptors, Cholecystokinin; Weaning; Weight Gain

Oxytocin was previously shown to have anti-inflammatory effects in different inflammation models. The major objective of the present study was to evaluate the protective role of oxytocin (OT) in protecting the kidney against ischemia/reperfusion (I/R) injury.. Male Wistar albino rats (250-300 g) were unilaterally nephrectomized, and subjected to 45 min of renal pedicle occlusion followed by 6 h of reperfusion. OT (1 mg/kg, ip) or vehicle was administered 15 min prior to ischemia and was repeated immediately before the reperfusion period. At the end of the reperfusion period, rats were decapitated and kidney samples were taken for histological examination or determination of malondialdehyde (MDA), an end product of lipid peroxidation; glutathione (GSH), a key antioxidant; and myeloperoxidase (MPO) activity, an index of tissue neutrophil infiltration. Creatinine and urea concentrations in blood were measured for the evaluation of renal function, while TNF-alpha and lactate dehydrogenase (LDH) levels were determined to evaluate generalized tissue damage. Formation of reactive oxygen species in renal tissue samples was monitored by chemiluminescence technique using luminol and lucigenin probes.. The results revealed that I/R injury increased (p<0.01-0.001) serum urea, creatinine, TNF-alpha and LDH levels, as well as MDA, MPO and reactive oxygen radical levels in the renal tissue, while decreasing renal GSH content. However, alterations in these biochemical and histopathological indices due to I/R injury were attenuated by OT treatment (p<0.05-0.001).. Since OT administration improved renal function and microscopic damage, along with the alleviation of oxidant tissue responses, it appears that oxytocin protects renal tissue against I/R-induced oxidative damage.

Topics: Animals; Creatinine; Disease Models, Animal; Glutathione; Kidney; Kidney Diseases; L-Lactate Dehydrogenase; Male; Malondialdehyde; Oxytocin; Peroxidase; Protective Agents; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Tumor Necrosis Factor-alpha; Urea

Oxytocin (OT) is a neurosecretory nonapeptide synthesized in hypothalamic cells that project to the neurohypophysis as well as to widely distributed sites in the central nervous system. Central OT microinjections induce a variety of cognitive, sexual, reproductive, grooming and affiliative behaviors in animals. Obsessive-compulsive disorder (OCD) includes a range of cognitive and behavioral symptoms that bear some relationship with OT. Here, we study the neuroanatomical and cellular substrates of the hypergrooming induced by administration of OT in the central nucleus of amygdala (CeA). In this context, this hypergrooming is considered as a model of compulsive behavior. Our data suggest a link between the CeA and the hypothalamic grooming area (HGA). The HGA includes parts of the paraventricular nucleus and the dorsal hypothalamic area. Our data on colocalization of OT (immunohistochemistry for peptide), OT receptor (binding assay) and its retrogradely labeled cells after Fluoro-Gold injection in the CeA suggest that CeA and connections are important substrates of the circuit underlying this OT-dependent compulsive behavioral pattern.

Topics: Amygdala; Animals; Behavior, Animal; Compulsive Behavior; Disease Models, Animal; Grooming; Male; Microinjections; Oxytocics; Oxytocin; Rats; Stilbamidines

Neurodevelopmental changes induced by environmental stress exposure play a significant but poorly defined role in the etiology of schizophrenia. Exposure of pregnant female rats to a series of unpredictable stresses during the final week of pregnancy generates behavioral deficits and molecular changes in the offspring similar to those observed in schizophrenic individuals. We used this rat prenatal stress preparation to investigate social withdrawal behaviors that may have relevance to the negative symptoms of schizophrenia. The cumulative time adult male offspring of stress-exposed pregnant female rats actively interacted with a weight-matched, same-sex peer was decreased approximately 76% relative to non-stress exposed control rats. Prenatal stress exposure also diminished the quality of the social interaction behavior indicative of reduced social drive. Analysis of the oxytocinergic system in the prenatally stressed male rats revealed significantly less oxytocin mRNA in the paraventricular nucleus and increased oxytocin receptor binding in the central amygdala. Moreover, oxytocin, but not vasopressin, administration into the central amygdala reversed the social incompetence of the prenatally stressed rats without increasing behavior in non-stressed control animals. In addition, cross-fostering pups from prenatally stressed mothers to non-stressed mothers failed to improve the social deficit of the prenatally stressed male offspring. Two behavioral assays designed to measure anxiety did not differentiate the prenatally stressed rats from non-stressed controls. These data indicate that prenatal stress may be an etiologically appropriate animal model for some aspects of schizophrenic social withdrawal. Furthermore, unpredictable prenatal stress exposure selectively degrades social interaction behaviors without increasing anxiety measures.

Topics: Amygdala; Animals; Disease Models, Animal; Female; Humans; Hypothalamus; Oxytocin; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Schizophrenic Psychology; Social Behavior; Stress, Physiological

Topics: Animals; Disease Models, Animal; Drug Administration Schedule; Ejaculation; Erectile Dysfunction; Male; Oxytocin; Rats; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Sexual Behavior, Animal

Experiments were performed in C57BL/6J male mice to determine 1) light/dark effects of acute and chronic shaker stress on open field behavioral patterns and 2) light/dark effects of chronic stress on plasma corticosterone and oxytocin. Shaker stress was applied acutely (15 min) or chronically (3 or 7 days). Mice were tested in the open field in the light or dark phase of the circadian cycle. For the endocrine study, mice were exposed to 3 days of intermittent shaker stress and sacrificed after the last stress event (09:00 or 19:00 h). Acute or chronic shaker stress had no significant effects on intensity of motor activity and rearing of mice tested under either light condition. Mice tested in the dark phase had higher motor activity and exhibited lower anxiety-like behavior as expressed by central zone activities and had higher emotionality as expressed by increased defecation. Chronic stress increased corticosterone with a greater absolute increase in the dark period. However, the percentage stress-induced increase was not different between the day and night periods. The oxytocin response to stress was observed only during the light phase with no change seen at dark phase. These results show that there is a marked difference in the light/dark pituitary stress response with no alteration in stress induced behavioral changes. They also suggest that there are circadian interactions in the endocrine stress axis that are without consequences for open field behavior.

Topics: Analysis of Variance; Animals; Chronic Disease; Circadian Rhythm; Corticosterone; Disease Models, Animal; Exploratory Behavior; Male; Mice; Mice, Inbred C57BL; Motor Activity; Oxytocin; Photoperiod; Stress, Physiological; Vibration

Gastrin-releasing peptide (GRP) is a growth factor for small cell lung cancer (SCLC). GRP belongs to the bombesin peptide family and has significant homology to bombesin. We constructed a bispecific molecule, OKT3xAntag2, by conjugating a monoclonal antibody OKT3 (anti-CD3) with a bombesin/GRP antagonist (Antag2) and evaluated cytotoxicity against SCLC cells.. We tested binding of the bispecific molecule to SCLC cell lines and T cells by flow cytometry, antibody-dependent cellular cytotoxicity (ADCC) of SCLC cells in vitro and in a murine SCLC xenograft model. We studied SCLC apoptosis and necrosis during ADCC and the activity and cleavage of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP).. The bispecific molecule functions as a cross-linker between T cells and SCLC cells, induces T cell activation, and mediates ADCC of SCLC cells; 40% to 80% growth inhibition of SCLC cells mediated by the bispecific molecule at low effector to target cell ratios was achieved. Activation of T cells by the bispecific molecule resulted in significant increases in IFNgamma production and apoptosis and necrosis of SCLC cells associated with cleavage of PARP and caspase-3. Targeted immunotherapy with the bispecific molecule-armed human T cells significantly reduced SCLC tumor burdens in a mouse model.. The bispecific molecule OKT3xAntag2 mediates growth inhibition and apoptosis of SCLC cells by activated T cells through activation and cleavage of caspase-3 and PARP in vitro and in vivo. Clinical trials of this bispecific molecule through adoptive transfer of ex vivo activated T cells in GRP receptor-positive tumors, such as SCLC, are warranted.

Topics: Animals; Antibodies, Bispecific; Antibodies, Monoclonal; Antineoplastic Agents; Apoptosis; Binding Sites; Carcinoma, Small Cell; Cell Line, Tumor; Cell Proliferation; Cytotoxicity Tests, Immunologic; Disease Models, Animal; Humans; Immunoconjugates; Immunotherapy; Interferon-gamma; Lung Neoplasms; Mice; Mice, Inbred NOD; Muromonab-CD3; Oxytocin; Receptors, Bombesin; Structure-Activity Relationship; T-Lymphocytes; Transplantation, Heterologous; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Pain during labor is a common and severe phenomenon, but its clinical management remains haphazard because its neurophysiology is poorly understood. In the current study, the authors evaluate the parturient rat as a relevant model to study the pharmacology of labor pain.. Control of birth timing in term pregnant rats was achieved by gavage with RU 486 (5 mg/kg) the day before the expected day of parturition. The behavioral events preceding the expulsion of the first pup were analyzed, and immunodetection of the c-Fos protein was used to evaluate the spinal neuronal activity at the lumbosacral level where genital and perineal inputs terminate.. Hind limb and abdominal stretches occurred during labor (mean number, 57 +/- 10), arbitrarily defined as the time elapsed between the first stretch and the expulsion of the first pup (mean duration, 62 +/- 5 min). Subcutaneous oxytocin increased the frequency of stretches, accounting for the fact that these manifestations are linked to uterine contractions. Finally, epidural morphine (30 microg/10 microl) in oxytocin-treated rats, although resulting in no change of labor duration, significantly decreased the number of stretches (8 +/- 2 vs. 57 +/- 12 for epidural saline) and the number of c-Fos-positive neurons in the lumbosacral spinal segments (80 +/- 25 vs. 165 +/- 17 for epidural saline).. These results indicate that stretches during labor in the rat correspond to a behavioral response to nociception associated with uterine contractions and suggest that parturition in the rat could be a relevant model to investigate nociceptive mechanisms associated with parturition in women.

Topics: Animals; Disease Models, Animal; Female; Morphine; Oxytocin; Pain; Parturition; Pregnancy; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Uterine Contraction

This study examined whether electrolytic ablation of the periventricular anteroventral third ventricle (AV3V) region would affect the hypothalamic activation and the increase of hypophysial hormone secretion induced by systemic injection of lipopolysaccharide (LPS) in rats. LPS significantly increased the number of cells showing Fos immunoreactivity in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus (P<0.05) and also increased plasma levels of vasopressin, oxytocin, adrenocorticotropin and corticosterone (P<0.05). AV3V lesion significantly reduced LPS-induced Fos immunoreactivity (P<0.05) and vasopressin and oxytocin secretion (P<0.05). Elevations in adrenocorticotropin but not in plasma corticosterone after LPS were affected by prior AV3V lesions. These findings demonstrate that LPS-induced Fos expression in the PVN and SON, and hypophysial hormone secretion is dependent on the integrity of the AV3V region.

Topics: Adrenocorticotropic Hormone; Animals; Cardiovascular Physiological Phenomena; Disease Models, Animal; Hypothalamo-Hypophyseal System; Hypothalamus; Inflammation Mediators; Lipopolysaccharides; Male; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Pituitary Hormones; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Shock, Septic; Stress, Physiological; Supraoptic Nucleus; Third Ventricle; Vasopressins; Water-Electrolyte Balance

Social experience influences behavior and the progression of atherosclerosis in the Watanabe Heritable Hyperlipidemic (WHHL) rabbit, such that WHHL rabbits exposed to a consistent, stable social experience exhibited more affiliative social behavior and less aortic atherosclerosis compared to other social groups. Oxytocin (OT) has been implicated in the expression of social behavior, stress responses, and may provide a mechanism by which social experience influences atherogenesis in WHHL rabbits. The current study examined acute and chronic changes in central and peripheral OT before and after WHHL rabbits were exposed to one of three social conditions. Cannula implanted adjacent to the hypothalamic paraventricular nucleus (PVN) allowed chronic sampling of extracellular OT concentration via microdialysis. Rabbits were exposed to one of three social conditions: an Unstable group, with initially unfamiliar rabbits paired daily for 4h during the initial week and similarly paired with a different, unfamiliar rabbit each week; a Stable group; with the same 2 littermates paired daily for 4h the entire study; and an Individually Caged group. Dialysates from the PVN and blood from the marginal ear vein were collected twice, 20 days apart, from rabbits before and after 2h of exposure to their respective social condition. Dialysates were assayed for OT and plasma was assayed for OT, catecholamines and glucocorticoids. There were no changes in PVN OT in any group following the initial social experience. In contrast, after 20 consecutive days of exposure to their respective social condition, PVN OT increased significantly in the Unstable group, but was relatively unchanged in the Stable group following the social experience on day 22. Peripheral OT was not altered in any group following the 2h social experience on day 1 or 22. The concentration of peripheral OT was the highest in the Stable group at all times. The Stable group also exhibited significantly less aortic atherosclerosis, consistent with earlier findings from our laboratory. Data from the present study suggest that the type of social experience WHHL rabbits are exposed influences PVN OT, social behavior and the progression of atherosclerosis in the WHHL rabbit model of disease.

Topics: Analysis of Variance; Animals; Animals, Inbred Strains; Arteriosclerosis; Corticosterone; Disease Models, Animal; Epinephrine; Hydrocortisone; Hyperlipidemias; Microdialysis; Norepinephrine; Oxytocin; Paraventricular Hypothalamic Nucleus; Rabbits; Social Behavior; Social Environment

Preterm labor (PTL) represents a significant unmet clinical need that affects up to 20% of all pregnancies and is a leading cause of preterm delivery and associated neonatal morbidity and mortality. Therapeutic options are limited, with existing drug therapy (tocolytics) compromised by side effects and limited efficacy. Because oxytocin (OT) is likely to be involved causally in PTL, this study compared two OT receptor antagonists, barusiban and atosiban, for their tocolytic effects. OT was given to instrumented pregnant cynomolgus monkeys to induce contractions and simulate PTL. Barusiban or atosiban was then given iv (bolus or infusion) to evaluate inhibitory effects on uterine contractions, measured by telemetric recording of intrauterine pressure. Both antagonists had high efficacy (96-98% inhibition of intrauterine pressure) and rapid onset of action (0.5-1.5 h). Barusiban was three to four times more potent than atosiban, which was attributed to its higher affinity and selectivity for the OT receptor. Barusiban also had a much longer duration of action (>13-15 h, compared with 1-3 h for atosiban). The inhibitory effects of barusiban were reversible within 1.5-2.5 h by high-dose OT infusion. Overall, barusiban's improved potency, long duration of action, and reversibility may provide an improved tocolytic for treatment of PTL.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hormone Antagonists; Macaca fascicularis; Obstetric Labor, Premature; Oxytocin; Pregnancy; Tocolytic Agents; Uterine Contraction; Vasotocin

Recent research points to the connection between behavioral and gut disorders. Early adverse events are associated with inflammatory bowel disease (IBD). In animal models, maternal deprivation and social isolation predispose to gastric erosion and brain pathology. This study examined (1) brain effects of chronic gastrointestinal inflammation in a rat model of acquired IBD and (2) whether such changes are resolved by individual secretin (S) or oxytocin (OT) peptide treatment. Neurological manifestations of IBD were mapped by c-fos gene expression in male Sprague-Dawley rats (n = 10) with trinitrobenzene sulfonic acid (TNBS)-induced IBD vs controls (n = 11). IBD was characterized by moderate/severe infiltration of inflammatory cells 10 d after TNBS infusion. Age-matched pairs were processed for immunocytochemical detection of Fos, expressed when neurons are stimulated. S or OT (100 mg/250 mL saline) or equivolume saline was administered iv by Alzet pump for 20 d after disease onset. Degree of resolution of colitis-induced brain activation was assessed by c-fos expression, and mean numbers of Fos-immunoreactive nuclei for each group were compared using Independent Samples T-test. Chronic IBD activated periventricular gray, hypothalamic/visceral thalamic stress axes and cortical domains, and septal/preoptic/amygdala, brain areas abnormal in autism. Single peptide treatment with S or OT did not alter the effects of inflammation on the brain. Brain areas concomitantly activated by visceral inflammation are those often abnormal in autism, suggesting that IBD could be a model for testing treatments of autism. Other single and combined peptide treatments of IBD should be tested. The clinical implications for treating autism, IBD, and concomitant sickness behaviors with peptide therapy, with or without maternal nurturing as a natural equivalent, are presented.

Topics: Amygdala; Animals; Autistic Disorder; Chronic Disease; Disease Models, Animal; Hypothalamus; Inflammatory Bowel Diseases; Male; Oxytocin; Rats; Rats, Sprague-Dawley; Secretin

Rodent models of schizophrenia provide powerful experimental tools for elucidating certain manifestations of the brain disease. The chakragati (ckr) mouse mutant, for instance, reproduces aberrant neuroanatomical and behavioral phenotypes observed in the corresponding human condition. To further investigate the utility of this mouse in the context of social behavior, we compared spontaneous behavioral activity and social interactions recorded during the subjective night among wild-type, heterozygous, and homozygous ckr mice. We found that both heterozygous and homozygous ckr animals failed to show appropriate norms of social behavior, including proximity, approach, huddling, and anogenital investigation in response to novel conspecifics. We further found that the anatomical distribution, topography, and connectivity of the neuropeptides oxytocin and vasopressin in the anterior hypothalamus did not differ among wild-type, heterozygous, or homozygous ckr animals. These latter findings suggest that although oxytocin and vasopressin influence social behavior, connectivity of such cells may not be phenotypically relevant for the observed social deficits seen in heterozygous and homozygous ckr mice. Collectively, ckr mice and their heterozygote kin are valuable experimental tools for pre-clinical studies involving disruptions of social behavior (e.g., social withdrawal).

Topics: Animals; Arginine Vasopressin; Behavior, Animal; Disease Models, Animal; Female; Heterozygote; Homozygote; Hypothalamus, Anterior; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Neurologic Mutants; Mice, Transgenic; Motor Activity; Mutation; Oxytocin; Schizophrenia; Schizophrenic Psychology; Social Behavior; Stereotyped Behavior; Tissue Distribution

A hypothalamic oxytocinergic-descending pathway that reaches the dorsal horn of the spinal cord has been well documented and recently related to states of pain and analgesia. In order to study the action of the neuropeptide oxytocin (OT) on pain-related responses, we compared dorsal horn neuronal responses to electrical and mechanical stimulation of receptive fields in normal and neuropathic rats. Spinal nerve (L5 and L6) ligation (Chung rats) was used to produce experimental neuropathy. Single unit activity was recorded at the L4-L5 level from neurons identified as wide dynamic range presenting latency responses corresponding to A-beta, A-delta, C fibers and also exhibiting post-discharge, and wind-up. We tested intrathecally applied doses of 0.05, 0.1, 1, 2, 5, 10 I.U. of OT. Minor effects on responses to electrical stimulation were present in normal rats. Mechanical responses evoked by von Frey filaments were slightly reduced in normal animals. In neuropathic rats a dose of 1 I.U. produced a significant reduction in C-fibers and post-discharge activities, and doses of 2 I.U. caused a further, pronounced reduction in post-discharge, wind-up, and input values. However, the most marked change was the post-discharge reduction at 10 and 20 min after OT administration. Mechanical responses were significantly reduced in terms of their discharge rate response in neuropathic rats. The contrasting results obtained in normal and neuropathic rats revealed an important distinction between these animals and indicate that plastic changes occur as a consequence of nerve damage. In neuropathic rats, mechanisms involving ascending noxious information to the paraventricular nuclei and descending OT activities could be altered so sensitizing the OT receptors of the spinal dorsal horn cells and could explain our observations. Our results point out an anti-algesic OT effect in neuropathic rats.

Topics: Action Potentials; Afferent Pathways; Analgesics; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Nerve Fibers, Myelinated; Nerve Fibers, Unmyelinated; Neuralgia; Nociceptors; Oxytocin; Peripheral Nervous System Diseases; Physical Stimulation; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Spinal Nerve Roots; Synaptic Transmission

Intermedin/Adrenomedullin-2 (IMD), a newly described peptide with structural homology to adrenomedullin (AM), is present in brain and pituitary gland and binds to the same receptors as AM and calcitonin gene-related peptide (CGRP). We hypothesized that IMD would exert actions similar to AM and CGRP and previously have demonstrated that indeed IMD, like AM and CGRP, increases sympathetic tone and inhibits feeding and drinking when administered centrally. Here, we extend those observations by demonstrating that like AM, IMD acts in brain to stimulate the secretions of prolactin (PRL) and adrenocorticotropin (ACTH) and to inhibit the secretion of growth hormone (GH) in conscious rats. In addition, in conscious rats, central administration of IMD results in increased plasma levels of oxytocin (OT) and vasopressin (AVP). The ability of IMD to activate the hypothalamo-pituitary-adrenal (HPA) axis can be blocked by intravenous pretreatment with the corticotropin releasing factor (CRF) antagonist, astressin. These results suggest that multiple members of the AM family of peptides may be involved in the cardiovascular, behavioral and neuroendocrine responses to stress.

Topics: Adrenocorticotropic Hormone; Adrenomedullin; Animals; Corticotropin-Releasing Hormone; Disease Models, Animal; Growth Hormone; Hypothalamo-Hypophyseal System; Male; Neuropeptides; Neurosecretory Systems; Oxytocin; Peptide Fragments; Pituitary Hormones; Prolactin; Rats; Rats, Sprague-Dawley; Stress, Physiological; Vasopressins

In addition to investigating sexual function in rats that display normal ejaculatory behaviour, studying rats that are either 'hyposexual' or 'hypersexual' may provide important insights into the aetiology of ejaculatory dysfunctions in men, such as premature and retarded ejaculation. To this end, rats were matched into groups of 'sluggish', 'normal' and 'rapid' ejaculators based on their ejaculation frequencies displayed in a series of weekly sexual behaviour tests. Selecting rats on this parameter revealed large and stable differences in other parameters of sexual behaviour as well, including ejaculation latency and mount frequency but not intromission frequency and mount latency, putative indices of sexual motivation. Neuroanatomically, Fos immunoreactivity as a measure of neuronal activation was increased in rapid ejaculators compared with sluggish ejaculators in ejaculation-related brain areas, presumably associated with the differences in ejaculatory behaviour. Although the total number of oxytocin neurones within subregions of the hypothalamus did not differ between groups, in the supraoptic nucleus of the hypothalamus more oxytocin neurones were activated in rapid ejaculators compared with the other groups. Apart from the differences observed in ejaculatory behaviour, groups did not differ with respect to their locomotor activity and approach-avoidance behaviour as measured in the elevated plus-maze. Finally, apomorphine-induced stereotypy was similar in sluggish and rapid ejaculators, suggesting no large differences in dopamine susceptibility. Altogether, the present results suggest stable differences in male rat ejaculatory behaviour. Further exploring the neurobiological mechanisms underlying these differences may be a promising approach to gain insights into the aetiology of sexual dysfunctions such as premature, retarded or an-ejaculation.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Analysis of Variance; Animals; Apomorphine; Behavior, Animal; Brain; Cell Count; Disease Models, Animal; Dopamine Agonists; Drug Interactions; Ejaculation; Exploratory Behavior; Female; Immunohistochemistry; Male; Maze Learning; Oncogene Proteins v-fos; Oxytocin; Rats; Rats, Wistar; Reaction Time; Serotonin Receptor Agonists; Sexual Behavior, Animal; Sexual Dysfunction, Physiological; Stereotyped Behavior

To model aspects of trait anxiety/depression, Wistar rats were bred for extremes in either hyper (HAB)- or hypo(LAB)-anxiety as measured on the elevated plus-maze and in a variety of additional behavioral tests. Similar to psychiatric patients, HAB rats prefer passive stress-coping strategies, indicative of depression-like behavior, show hyper-reactivity of the hypothalamo-pituitary-adrenal axis, and a pathological response to the dexamethasone/corticotropin-releasing hormone (CRH) challenge test. Here we tested central mRNA expression, release patterns, and receptor binding of neuropeptides critically involved in the regulation of both anxiety-related behavior and the HPA axis. Thus, CRH, arginine-8-vasopressin (AVP), and oxytocin (OXT) were studied in brains of HAB and LAB males both under basal conditions and after exposure to a mild emotional stressor. In HAB rats, CRH mRNA was decreased in the bed nucleus of the stria terminalis only. While no significant difference in CRH1-receptor binding was found in any brain area, CRH2-receptor binding was elevated in the hypothalamic paraventricular nucleus (PVN), the ventromedial hypothalamus, and the central amygdala of HABs compared to LABs. AVP, but not OXT, mRNA expression as well as release of the neuropeptide, were higher in the PVN of HABs, whereas AVP V1a-receptor binding failed to show significant differences in any brain region studied. Remarkably, intra-PVN treatment of HABs with the AVP V1-receptor antagonist d (CH(2))(5) Tyr (Me) AVP resulted in a decrease in anxiety/depression-related behavior. The elevated expression and release of AVP within the PVN of HAB rats together with the behavioral effects of the AVP V1-receptor antagonist suggest a critical involvement of this neuropeptide in neuroendocrine and behavioral phenomena associated with trait anxiety/depression.

Topics: Analysis of Variance; Animals; Antidiuretic Hormone Receptor Antagonists; Anxiety; Autoradiography; Behavior, Animal; Binding Sites; Breeding; Central Nervous System; Corticotropin-Releasing Hormone; Disease Models, Animal; Exploratory Behavior; Gene Expression; Genetics, Behavioral; In Situ Hybridization; Male; Maze Learning; Microdialysis; Neuropeptides; Oxytocin; Protein Binding; Rats; Rats, Inbred Strains; Rats, Wistar; Reaction Time; Receptors, Corticotropin-Releasing Hormone; Receptors, Neuropeptide; RNA, Messenger; Stress, Physiological; Swimming; Time Factors; Vasopressins

The aim of the present investigations was to examine the effects of the states of hypothyroidism or hyperthyroidism on vasopressin (AVP) and oxytocin (OT) release under conditions of equilibrated water metabolism as well as of osmotic stimulation, brought about by the dehydration or hypertonic saline administration. The euhydrated and simultaneously hypothyroid rats showed decreased hypothalamic AVP and OT content and somewhat higher but not significant neurohypophysial AVP content. In these animals the raised OT (but not AVP) plasma level has been observed. In hyperthyroid rats drinking tap water ad libitum the neurohypophysial AVP and OT content significantly diminished; plasma OT concentration (but not AVP) was then elevated. The state of osmotic stimulation was the reason of different response of the hypothalamo-neurohypohysial system function in hypo- or hyperthyroid rats. Significant decreases of neurohypophysial AVP and OT content were found in both hypothyroid dehydrated as well as hypothyroid hypertonic saline-treatment rats as compared with hypothyroid euhydrated ones. On the contrary, in the state of hyperthyroidism AVP content in the neurohypophysis distinctly raised in dehydrated and salt-loaded rats; in these last neurohypophysial OT content increased as well. Plasma OT (but not AVP) distinctly diminished in hyperthyroid and simultaneously dehydrated or hypertonic saline injected rats in relation to hyperthyroid control subgroup. Data from the present study suggest that: 1). altered thyroid gland function affects vasopressin and oxytocin release from the hypothalamo-neurohypophysial system in the state of equilibrated water metabolism; 2). the state of hypo- or hyperthyroidism modifies the response of AVP-ergic and OT-ergic neurons upon the osmoreceptors/osmodetectors stimulation. It may be supposed that OT-ergic neurons display greater than AVP-ergic neurons sensitivity upon the thyroid hormone influence.

Topics: Animals; Disease Models, Animal; Drinking; Hyperthyroidism; Hypothalamo-Hypophyseal System; Hypothyroidism; Male; Oxytocin; Pituitary-Adrenal System; Rats; Rats, Wistar; Vasopressins; Water; Water Deprivation

The aim of the present investigation was to study the structure of reactively modified rat myocardium (experimental heart failure model) during in vitro organotypical culture, including the direct effect of some hypothalamic nonapeptides (oxytocin) and monoamines (dopamine, noradrenalin). Light and electron microscopic methods were used. The major regularities of structural and functional reorganization of myocardium were determined. Multidirectional nature of ultrastructural changes of cardiomyocytes and of cardiac non-muscular cells was found to depend on direct effect of hypothalamic nonapeptides and monoamines upon myocardium. Adaptogenic role of oxytocin in provision of cardiac muscle protection and vitality is discussed.

Topics: Animals; Cardiac Output, Low; Culture Media; Disease Models, Animal; Dopamine; Male; Microscopy, Electron; Myocardium; Myocytes, Cardiac; Norepinephrine; Organ Culture Techniques; Oxytocin; Rats

This paper reviews recent developments in the phenomenology, neurobiology, and genetics of maternal behavior in animal model systems from an evolutionary perspective on psychopathology. Following a review of the phenomenology and neurobiology of maternal behavior, recent studies addressing the role of genetic factors in the maternal behavior of rodents were identified in a search of literature in peer-reviewed journals. Gene knockout studies were evaluated with regard to mouse strain background, method of behavioral phenotyping, and quantification of the behavioral deficits. Gene knockout data were then analyzed using a cluster analysis technique. At least nine genes have been identified that are necessary for the expression of one or more aspects of maternal behavior. These genes encode for three transcription factors: three enzymes, including dopamine beta hydroxylase and neuronal nitric oxide synthase; two receptors, including the prolactin and the estrogen alpha receptor; and one neuropeptide, oxytocin. Cluster analysis suggested possible relationships between specific genes. Gene knockout technology has provided new insights into the molecular basis of maternal behavior that are congruent with the existing neurobiological literature. Future studies of genetic and environmental influences on maternal behavior have the potential to inform models of disease pathogenesis.

Topics: Animals; Autistic Disorder; Behavior, Animal; Biological Evolution; Brain; Cluster Analysis; Disease Models, Animal; Dopamine; Drosophila Proteins; Maternal Behavior; Mice; Mice, Knockout; Muscle Proteins; Nitric Oxide Synthase; Obsessive-Compulsive Disorder; Oxytocin; Phenotype; Prolactin

The effect of oxytocin (1 mg/kg s.c) on gastric acid secretion and on different experimentally induced gastric and duodenal ulcers was studied. The acute gastric ulcer models used were pylorus ligation, indomethacin, ethanol and histamine induced acute gastric ulcers. Chronic gastric ulcers were induced using acetic acid and duodenal ulcers by cysteamine hydrochloride. Oxytocin showed significant antisecretory and antiulcer activity in pylorus ligated rats. Similarly oxytocin reduced the ulcer index in histamine induced gastric ulcers in guinea pigs and cysteamine induced duodenal ulcers in rats. The antiulcer and antisecretory effect was comparable to that of ranitidine (50mg/kg, i.p) though less in intensity. However, it did not show any gastric cytoprotective effect in ethanol and indomethacin induced ulcer models but ranitidine showed protection (p<0.05) in later model. Oxytocin enhanced gastric ulcer healing in acetic acid induced chronic gastric ulcer model. The reversal of oxytocin effect by atosiban, an oxytocin receptor antagonist indicates a role for oxytocin receptors. The antiulcer activity of oxytocin can be attributed to its antisecretory effect.

Topics: Acetic Acid; Acute Disease; Animals; Anti-Ulcer Agents; Chronic Disease; Cysteamine; Disease Models, Animal; Duodenal Ulcer; Duodenum; Ethanol; Female; Gastric Acid; Gastric Mucosa; Guinea Pigs; Histamine; Indomethacin; Male; Oxytocin; Pylorus; Ranitidine; Rats; Rats, Wistar; Stomach; Stomach Ulcer; Vasotocin

Lyprinol exhibits anti-inflammatory activity distinct from that of most NSAIDs, controlling chronic but not acute inflammation. Unlike Cox-1 inhibitors (aspirin, meclofenamic acid) it is not gastro-toxic. Predosing rats with Lyprinol can modify both (i) the spontaneous and (ii) the oxytocin-induced contractions of the uterus. In humans there is anecdotal evidence that Lyprinol can relieve dysmenorrhea. This report explores the concept that the uterotrophic actions of Lyprinol are conditioned by: the intrinsic profile of estrogenic hormones and progestagens and, certain extrinsic stimuli. Evidence from in vitro studies indicates that Lyprinol is not a smooth muscle relaxant and that its uterotrophic mechanism is not that of a cyclo-oxygenase inhibitor, but may mimic that of a leukotriene receptor antagonist.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Bivalvia; Cyclooxygenase Inhibitors; Disease Models, Animal; Drug Evaluation, Preclinical; Dysmenorrhea; Estrus; Female; Gastric Mucosa; Gonadal Steroid Hormones; Hormone Antagonists; Indomethacin; Leukotriene Antagonists; Lipids; Models, Biological; Muscle Relaxation; Myometrium; New Zealand; Ovariectomy; Oxytocin; Rats; Rats, Wistar

Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with considerable clinical variability that is thought in large part to be the result of a hypothalamic defect. PWS results from the absence of paternal expression of imprinted genes localized in the 15q11-q13 region; however, none of the characterized genes has so far been shown to be involved in the etiology of PWS. Here, we provide a detailed investigation of a mouse model deficient for NECDIN: Linked to the mutation, a neonatal lethality of variable penetrance is observed. Viable NECDIN: mutants show a reduction in both oxytocin-producing and luteinizing hormone-releasing hormone (LHRH)-producing neurons in hypothalamus. This represents the first evidence of a hypothalamic deficiency in a mouse model of PWS. NECDIN:-deficient mice also display increased skin scraping activity in the open field test and improved spatial learning and memory in the Morris water maze. The latter features are reminiscent of the skin picking and improved spatial memory that are characteristics of the PWS phenotype. These striking parallels in hypothalamic structure, emotional and cognitive-related behaviors strongly suggest that NECDIN is responsible for at least a subset of the multiple clinical manifestations of PWS.

Topics: Animals; Cognition; Cognition Disorders; Disease Models, Animal; Gonadotropin-Releasing Hormone; Hypothalamus; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurons; Nuclear Proteins; Oxytocin; Prader-Willi Syndrome; Psychomotor Performance

The effect of CCK-8 (50 ng, i.c.v.) on the neurohypophysial vasopressin and oxytocin storage was estimated in haemorrhaged (1 ml per 100 g b.w.) male Wistar rats. In another experimental series rats dehydrated for three days were given CCK-8 in a daily i.c.v. dose of 50 ng. The neurohypophysial vasopressin and oxytocin content was bioassayed by pressor effect following Dekański or milk-ejection activity in vitro following van Dongen and Hays, respectively. The decrease of neurohypophysial vasopressin and oxytocin content, brought about by dehydration, was significantly less marked in animals treated with CCK-8. The depletion of neurohypophysial vasopressin and oxytocin content in haemorrhaged animals could be completely inhibited by earlier i.c.v. administration of CCK-8. It is suggested that hypothalamic cholecystokinin may serve as a modulator of neurohypophysial function.

Topics: Animals; Bloodletting; Dehydration; Disease Models, Animal; Hemorrhage; Injections, Intraventricular; Male; Models, Biological; Oxytocin; Pituitary Gland, Posterior; Rats; Rats, Wistar; Sincalide; Vasopressins

In the behavioral despair test in mice, oxytocin, i.p. injected 60 min before testing, significantly reduced the duration of immobility at doses of 0.250-1.0 mg/Kg; the effect being similar to that of imipramine (7.5-30 mg/Kg i.p.). A more powerful effect was obtained with a 10-day treatment schedule. In the learned helplessness test, oxytocin (0.500 mg/Kg/day i.p. for 8 days) significantly reduced the escape failures and the latency to escape, the effect being even more intense than that of imipramine (20 mg/Kg/day i.p. for 8 days). These results show a new behavioral effect of oxytocin, and further support its role of CNS regulatory peptide.

Topics: Animals; Depression; Disease Models, Animal; Drug Interactions; Escape Reaction; Female; Imipramine; Male; Mice; Motor Activity; Oxytocin; Rats

We attempted to characterize the ability of a new oxytocin derivative, 1-deamino[D-Tyr(Oethyl)2,Thr4,Orn8] vasotocin (ORF 22164), to antagonize the action of oxytocin in several in vitro and in vivo animal models of uterine hyperactivity. In these studies, the derivative was found to be a specific competitive inhibitor of oxytocin-induced contractions of pregnant guinea pig uterus in vitro. In addition, its intravenous administration induced a dose-dependent inhibition of oxytocin-induced uterine contractions in situ. Finally, like ritodrine, the drug induced a dose-dependent delay of ongoing labor in rats. These results suggest that 1-deamino-[D-Tyr(Oethyl)2,Thr4,Orn8] vasotocin, unlike ritodrine, is a potent and specific antagonist of oxytocin-induced uterine contractions and thus may have potential clinical utility in the treatment of preterm labor.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Guinea Pigs; In Vitro Techniques; Obstetric Labor, Premature; Oxytocin; Pregnancy; Rats; Rats, Inbred Strains; Uterine Contraction; Vasotocin

Topics: Animals; Cerebral Angiography; Cerebral Cortex; Cisterna Magna; Disease Models, Animal; Dogs; Hypothalamus; Ischemic Attack, Transient; Male; Oxytocin; Subarachnoid Space; Tissue Extracts; Vasopressins

Topics: Animals; Castration; Disease Models, Animal; Drug Antagonism; Female; Follicle Stimulating Hormone; Gonadotropins, Pituitary; Hypertrophy; Indoles; Melatonin; Mice; Ovarian Diseases; Ovulation; Oxytocin; Physiology, Comparative; Pineal Gland; Rodentia; Serotonin; Tissue Extracts; Vasopressins

Topics: Animals; Diabetes Insipidus; Disease Models, Animal; Female; Kidney Tubules; Male; Mice; Neurosecretion; Organ Size; Oxytocin; Pituitary Gland, Posterior; Rats; Rodent Diseases; Uterus; Vasopressins