oxytocin and Chronic-Disease

Unresolved inflammation represents a central feature of different human pathologies including neuropsychiatric, cardiovascular, and metabolic diseases. The epidemiologic relevance of such disorders justifies the increasing interest in further understanding the mechanisms underpinning the inflammatory process occurring in such chronic diseases to provide potential novel pharmacological approaches. The most common and effective therapies for controlling inflammation are glucocorticoids; however, a variety of other molecules have been demonstrated to have an anti-inflammatory potential, including neuropeptides. In recent years, the oxytocinergic system has seen an explosion of scientific studies, demonstrating its potential to contribute to a variety of physiological processes including inflammation. Therefore, the aim of the present review was to understand the role of oxytocin in the modulation of inflammation occurring in different chronic diseases. The criterion we used to select the diseases was based on the emerging literature showing a putative involvement of the oxytocinergic system in inflammatory processes in a variety of pathologies including neurological, gastrointestinal and cardiovascular disorders, diabetes and obesity. The evidence reviewed here supports a beneficial role of oxytocin in the control of both peripheral and central inflammatory response happening in the aforementioned pathologies. Although future studies are necessary to elucidate the mechanistic details underlying such regulation, this review supports the idea that the modulation of the endogenous oxytocinergic system might represent a new potential pharmacological approach for the treatment of inflammation.

Topics: Animals; Anti-Inflammatory Agents; Chronic Disease; Humans; Inflammation; Oxytocin

Oxytocin is associated with bonding and social deficits in psychiatric disorders and has also been discussed as a potential therapeutic intervention to augment psychotherapy. The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) is a specific form of psychotherapy for chronic depression, an illness in which interpersonal deficits play a major role. In this pilot study, we investigated whether Oxytocin plasma levels predict the clinical outcome of chronic depressive patients after CBASP.. Sixteen patients with chronic depression participated in a 10-week CBASP inpatient program. Oxytocin plasma levels were measured before and after participants played a virtual ball-tossing game (Cyberball) that mimics social exclusion. Clinical outcome after CBASP was evaluated with the Beck Depression Inventory-II (BDI-II) and the 24-item Hamilton Depression Rating Scale (HAMD-24).. After CBASP, depressive symptoms decreased significantly: the response rates were 44% (BDI-II) and 50% (HAMD-24); and the remission rates, 38% (BDI-II) and 44% (HAMD-24). Lower oxytocin plasma levels at baseline correlated with smaller changes in BDI-II scores, but not with the change in HAMD-24 scores.. The limitations of our study were the small sample size, concomitant and non-standardized pharmacotherapy, and lack of a controlled design and a follow-up period.. Our study provides first evidence that oxytocin plasma levels may predict the outcome of psychotherapy in chronic depression. These findings need to be replicated in larger randomized, controlled trials.

Topics: Adult; Chronic Disease; Cognitive Behavioral Therapy; Depression; Female; Humans; Male; Middle Aged; Oxytocin; Pilot Projects; Psychiatric Status Rating Scales; Psychological Distance; Treatment Outcome; Young Adult

Both human and animal studies have suggested that oxytocin may have therapeutic potential in the treatment of schizophrenia. We evaluated the effects of intranasal oxytocin on cognition and its predictive factors in Japanese patients with schizophrenia.. Subjects were 16 chronic schizophrenia patients who underwent intranasal oxytocin treatment for 3 months and were assessed for changes in severity of clinical symptoms and cognitions. Fifteen of the 16 subjects underwent 3-Tesla magnetic resonance imaging.. Oxytocin significantly reduced scores on the positive and negative syndrome scale, especially on the negative symptoms. As for cognition, there was an improvement of the verbal fluency. Furthermore, the change of the negative score in positive and negative syndrome scale showed a negative correlation with the gray matter volumes of the right insula and left cingulate cortex.. Our results indicate that daily administration of intranasal oxytocin may be effective for ameliorating clinical symptoms and cognitive functions in chronic schizophrenia patients, and this improvement may be related to the gray matter volume of the right insula and left cingulate cortex.

Topics: Administration, Intranasal; Adult; Appetite; Brain; Chemotherapy, Adjuvant; Chronic Disease; Cognition; Female; Humans; Male; Middle Aged; Oxytocin; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

The gut microbiota is known to be related to type 2 diabetes (T2D), psychiatric conditions, and opioid use. In this study, we tested the hypothesis that variability in gut microbiota in T2D is associated with psycho-metabolic health.. A cross-sectional study was conducted among African American men (AAM) (n = 99) that were outpatients at a Chicago VA Medical Center. The main outcome measures included fecal microbiota ecology (by 16S rRNA gene sequencing), psychiatric disorders including opioid use, and circulating leptin and oxytocin as representative hormone biomarkers for obesity and psychological pro-social behavior.. The study subjects had prevalent overweight/obesity (78%), T2D (50%) and co-morbid psychiatric (65%) and opioid use (45%) disorders. In the analysis of microbiota, the data showed interactions of opioids, T2D and metformin with Bifidobacterium and Prevotella genera. The differential analysis of Bifidobacterium stratified by opioids, T2D and metformin, showed significant interactions among these factors indicating that the effect of one factor was changed by the other (FDR-adjusted p [q] < 0.01). In addition, the pair-wise comparison showed that participants with T2D not taking metformin had a significant 6.74 log2 fold increase in Bifidobacterium in opioid users as compared to non-users (q = 2.2 x 10-8). Since metformin was not included in this pair-wise comparison, the significant 'q' suggested association of opioid use with Bifidobacterium abundance. The differences in Bifidobacterium abundance could possibly be explained by opioids acting as organic cation transporter 1 (OCT1) inhibitors. Analysis stratified by lower and higher leptin and oxytocin (divided by the 50th percentile) in the subgroup without T2D showed lower Dialister in High-Leptin vs. Low-Leptin (p = 0.03). Contrary, the opposite was shown for oxytocin, higher Dialister in High-Oxytocin vs. Low-Oxytocin (p = 0.04).. The study demonstrated for the first time that Bifidobacterium and Prevotella abundance was affected by interactions of T2D, metformin and opioid use. Also, in subjects without T2D Dialister abundance varied according to circulating leptin and oxytocin.

Topics: Bacteria; Black or African American; Chronic Disease; Cost of Illness; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Humans; Leptin; Male; Metformin; Opioid-Related Disorders; Oxytocin

Chronic depression is characterized by a high degree of early life trauma, psychosocial impairment, and deficits in social cognition. Undisturbed recognition and processing of facial emotions are basic prerequisites for smooth social interactions. Intranasal application of the neuropeptide oxytocin has been reported to enhance emotion recognition in neuropsychiatric disorders and healthy individuals. We therefore investigated whether oxytocin modulates attention to emotional faces in patients with chronic depression.. In this double-blind, randomized, controlled study, 43 patients received a single dose of oxytocin or placebo nasal spray and were tested while fulfilling a facial dot probe task. We assessed reaction times to neutral probes presented at the location of one of two faces depicting happy, angry, or neutral expressions as a prime.. When comparing reaction times to the congruent (prime and probe at the same location) with incongruent presentation of facial emotions, neither the placebo nor oxytocin group showed an attentional preference for emotional facial expressions in terms of a threat bias. However, oxytocin treatment did reveal two specific effects: it generally reduced the allocation of attention towards angry facial expressions, and it increased sustained attention towards happy faces, specifically under conditions of heightened awareness, i.e. trials with longer primes.. We investigated a heterogeneous group of medicated male and female patients. We conclude that oxytocin does modulate basic factors of facial emotion processing in chronic depression. Our findings encourage further investigations assessing the therapeutic potential of oxytocin in chronic depression.. EUDRA-CT 2010-020956-69 . Date registered: 23 February 2011.

Topics: Administration, Intranasal; Anger; Attention; Chronic Disease; Depressive Disorder; Double-Blind Method; Facial Expression; Female; Happiness; Humans; Male; Middle Aged; Oxytocics; Oxytocin; Reaction Time; Social Behavior

Behavioral and neuroplastic changes occurring in the development of addiction parallel those that occur in social bonding. This has led to speculation that drugs of abuse co-opt systems that subserve social attachment to shift attachment to drugs of abuse. Oxytocin, a neuropeptide that is important in social bonding, has been shown in rodents to decrease psychostimulant self-administration, locomotor activity, and conditioned place preference, it is unclear what role it may play in human drug addiction. In this double-blind, placebo-controlled crossover study, 23 cocaine-dependent inpatients in court-ordered treatment completed 4 task sessions measuring desire to use cocaine, cue-induced craving, monetary reward decisions and social cognition. Before each session, subjects administered 24 IU of intranasal oxytocin or placebo. Oxytocin increased desire to use cocaine and cue-induced excitability with no effect on cue-induced desire to use. Oxytocin also removed the effect of state anger on several measures of cue reactivity. Response to monetary reward increased under oxytocin and measures of social cognition worsened. The significant increase in the desire for drug and monetary reward as well as the significant decrease in measures of social cognition was small but warrant further study of the effect of oxytocin׳s effect in cocaine dependent subjects. The effect of oxytocin to modulate the relationship between state anger and cue reactivity should be explored further for potential therapeutic use of oxytocin in cocaine dependent patients. These findings are discussed in light of the human and rodent oxytocin literature.

Topics: Administration, Intranasal; Adult; Analysis of Variance; Antipsychotic Agents; Anxiety; Chronic Disease; Circadian Rhythm; Cocaine-Related Disorders; Cross-Over Studies; Cues; Decision Making; Double-Blind Method; Drug-Seeking Behavior; Female; Humans; Linear Models; Male; Middle Aged; Oxytocin; Pain Measurement; Psychiatric Status Rating Scales; Social Behavior; Surveys and Questionnaires; Young Adult

Oxytocin and its receptor have been found throughout the gastrointestinal (GI) tract, where it affects gut function. Clinically, we have noticed an improvement of bowel habits during lactation in constipated women. The aim of this study was to examine whether oxytocin has an effect on bowel symptoms and psychological well being in women with refractory constipation.. Fifty-nine women with refractory constipation were included in a double blind, multicentre study. After a 2-week run-in period, they were randomly allocated to nasal inhalation of either placebo or oxytocin treatment twice daily for 13 weeks, followed by a 2 weeks, posttreatment period. The patients completed a questionnaire every day concerning bowel habits, abdominal pain and discomfort, and Gastrointestinal Symptoms Rating Scale (GSRS) and Psychological General Well-being (PGWB) twice during the study; namely, during the baseline period and at the end of the treatment period.. Both oxytocin and placebo led to improvement of the constipation according to the GSRS and led to improvement in the sensation of incomplete evacuation and anorectal obstruction, without significant differences between the groups. Abdominal pain and discomfort responded weakly to oxytocin, with no effect of the placebo. In a subgroup of patients with IBS and concomitant depression, a weak improvement in depressed mood was observed after oxytocin administartion.. Nasal administration of oxytocin had no significant advantage over placebo concerning an effect on constipation. However, it seems to have a positive effect on abdominal pain and discomfort and depressed mood. These findings should be further explored.

Topics: Adult; Aged; Anxiety; Chronic Disease; Constipation; Depression; Double-Blind Method; Gastrointestinal Transit; Health Status; Humans; Middle Aged; Oxytocin; Patient Selection; Pilot Projects; Placebos

The results of treatment of 90 patients with diabetes mellitus and pyo-necrotic lesions of the feet were compared. Oxytocin was used in 40 of the patients. It was found that parenteral administration of oxytocin resulted in more favorable course of diabetes mellitus in such patients. The intra-arterial or local use of Oxytocin was found to reliably increase the DNA synthesis by the endothelial cells, fibroblasts and histiocytes, which in its turn creates favorable conditions for the reparative process in the wounds and allows quality of the treatment to be considerably improved.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Chronic Disease; Combined Modality Therapy; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Foot; DNA; Female; Foot; Humans; Male; Middle Aged; Necrosis; Oxytocin

Chronic stress is often associated with a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which can greatly increase risk for a number of stress-related diseases, including neuropsychiatric disorders. Despite a striking sex-bias in the prevalence of many of these disorders, few preclinical studies have examined female subjects. Hence, the present study aimed to explore the effects of chronic stress on the basal and acute stress-induced activity of the HPA axis in the female C57BL/6 mouse. We used a chronic variable stress (CVS) paradigm in these studies, which successfully induces physiological and behavioral changes that are similar to those reported for some patients with mood disorders. Using this model, we found pronounced, time-dependent effects of chronic stress on the HPA axis. CVS-treated females exhibited adrenal hypertrophy, yet their pattern of glucocorticoid secretion in the morning resembled that of controls. CVS-treated and control females had similar morning basal corticosterone (CORT) levels, which were both significantly elevated following a restraint stressor. Although morning basal gene expression of the key HPA-controlling neuropeptides corticotropin releasing hormone (CRH), arginine vasopressin (AVP) and oxytocin (OT) was unaltered within the paraventricular nucleus (PVN) by CVS, CVS altered the PVN OT and AVP mRNA responses to acute restraint. In control females, acute stress decreased AVP, but not OT mRNA; whereas, in CVS females, it decreased OT, but not, AVP mRNA. Unlike the morning pattern of HPA activity, in the evening, CVS-treated females showed increased basal CORT with hypoactive responses of CORT and PVN c-Fos immunoreactivity to restraint stress. Furthermore, CVS elevated evening PVN CRH and OT mRNAs in the PVN, but it did not influence anxiety- or depressive-like behavior after a light/dark box or tail suspension test. Taken together, these findings indicate that CVS is an effective model for HPA axis dysregulation in the female mouse and may be relevant for stress-related diseases.

Topics: Animals; Anxiety; Arginine Vasopressin; Chronic Disease; Corticotropin-Releasing Hormone; Depression; Female; Gene Expression Regulation; Glucocorticoids; Hypothalamo-Hypophyseal System; Mice; Mice, Inbred C57BL; Oxytocin; Paraventricular Hypothalamic Nucleus; Pituitary-Adrenal System; Restraint, Physical; Stress, Psychological

Topics: Adolescent; Adult; Chronic Disease; Cognition Disorders; Female; Humans; Neuropsychological Tests; Oxytocin; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Vasopressins; Young Adult

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

The vasopressin- and oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP) is expressed in various organs including the brain. However, knowledge about its presence in human hypothalamus is fragmentary. Functionally, for a number of reasons (genetic linkage, hydrolysis of oxytocin and vasopressin, its role as angiotensin IV receptor in learning and memory and others) IRAP might play a role in schizophrenia. We studied the regional and cellular localization of IRAP in normal human brain with special emphasis on the hypothalamus and determined numerical densities of IRAP-expressing cells in the paraventricular, supraoptic and suprachiasmatic nuclei in schizophrenia patients and controls. By using immunohistochemistry and Western blot analysis, IRAP was immunolocalized in postmortem human brains. Cell countings were performed to estimate numbers and numerical densities of IRAP immunoreactive hypothalamic neurons in schizophrenia patients and control cases. Shape, size and regional distribution of IRAP-expressing cells, as well the lack of co-localization with the glia marker glutamine synthetase, show that IRAP is expressed in neurons. IRAP immunoreactive cells were observed in the hippocampal formation, cerebral cortex, thalamus, amygdala and, abundantly, hypothalamus. Double labeling experiments (IRAP and oxytocin/neurophysin 1, IRAP with vasopressin/neurophysin 2) revealed that IRAP is present in oxytocinergic and in vasopressinergic neurons. In schizophrenia patients, the numerical density of IRAP-expressing neurons in the paraventricular and the suprachiasmatic nuclei is significantly reduced, which might be associated with the reduction in neurophysin-containing neurons in these nuclei in schizophrenia. The pathophysiological role of lowered hypothalamic IRAP expression in schizophrenia remains to be established.

Topics: Aged; Autopsy; Chronic Disease; Cystinyl Aminopeptidase; Female; Glutamate-Ammonia Ligase; Humans; Hypothalamus; Male; Middle Aged; Neurons; Neurophysins; Oxytocin; Paraventricular Hypothalamic Nucleus; Pituitary Gland, Posterior; Schizophrenia; Suprachiasmatic Nucleus; Vasopressins

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

An increase in the arthritis index as a marker of chronic inflammation and suppression of food intake are observed in adjuvant arthritic (AA) rats. Our previous study demonstrated that central oxytocin (OXT)-ergic pathways were activated potently in AA rats. In the present study, OXT-saporin (SAP) cytotoxin, which chemically disrupts OXT signaling was administered centrally to determine whether central OXT may be involved in the developments of chronic inflammation and alteration of feeding/drinking behavior in AA rats. The arthritis index was significantly enhanced in AA rats pretreated with OXT-SAP administered intrathecally (i.t.) but not intracerebroventricularly (i.c.v.). Suppression of food intake was significantly attenuated transiently in AA rats pretreated with OXT-SAP administered i.c.v. but not i.t. Suppression of drinking behavior was not affected by i.t. or i.c.v. administration of OXT-SAP in AA rats. In addition, intraperitoneal administration of an OXT receptor antagonist did not change the arthritis index or feeding/drinking behavior in AA rats. These results suggest that central OXT-ergic pathways may be involved in anti-inflammation at the spinal level and suppression of feeding behavior at the forebrain-brainstem level in AA rats.

Topics: Animals; Arthritis, Experimental; Chronic Disease; Cytotoxins; Drinking Behavior; Feeding Behavior; Inflammation; Injections, Intraventricular; Male; Mycobacterium; Oxytocin; Rats, Wistar; Receptors, Oxytocin; Ribosome Inactivating Proteins, Type 1; Saporins

Patients with chronic depression (CD) experience a high burden of disease, severe co-morbidity, and increased mortality. Although interpersonal dysfunction is a hallmark of CD, the underlying mechanisms are largely unexplored. Oxytocin (OT) has been proposed to play a crucial role in the social deficits of mental disorders and has been found to be dysregulated after social exclusion (ostracism) in patients with borderline personality disorder. This study investigated how social exclusion affects emotions, OT levels, and cortisol (CT) levels in CD patients.. Twenty-one patients diagnosed with CD and 21 healthy controls (HC) matched for gender, age, and education underwent repeated neuroendocrine measurements in a standardized laboratory setting while playing Cyberball, a virtual ball-tossing game that mimics a social exclusion situation. Emotional reactions, plasma OT and cortisol levels were assessed at baseline and 5, 15, and 40 min after Cyberball.. At baseline, there were no group differences in OT levels. Immediately after playing Cyberball, plasma OT levels showed divergent changes in CD patients and HC; the difference in direction of change was significant with a reduction in CD patients compared to HC (p = .035*); CT levels did not differ between groups at any time point, but decreased over time. Patients showed more threatened emotional needs and increased negative emotions, especially anger and resentment, and showed higher sensitivity to ambiguous threat of social exclusion than healthy controls.. CD patients react to ostracism with pronounced negative emotions. The reduction in OT levels in CD patients after social exclusion may contribute to their interpersonal dysfunction and their difficulty in coping adequately with aversive social cues.

Topics: Adult; Aged; Chronic Disease; Depression; Emotions; Female; Humans; Hydrocortisone; Male; Middle Aged; Oxytocin; Psychological Distance; Psychological Tests; Social Perception; Young Adult

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

Maternal postpartum depression (PPD) carries long-term detrimental effects on children's well-being, yet the mechanisms of transmission remain unclear. One possible pathway of vulnerability involves the oxytocinergic (OT) system, which is transferred from mother to child via sensitive caregiving and is disrupted in PPD.. A large birth cohort (N = 1983) of women were repeatedly assessed for depression from birth to 6 years. Utilizing an extreme case design, two matched cohorts were formed; mothers chronically depressed from birth to 6 years and nondepressed controls (N = 97, depressed = 41, nondepressed; N = 56). At 6 years, mothers and children underwent psychiatric diagnosis, urinary OT was assayed from mother and child before and after social contact, and mother-child interactions were coded.. Baseline OT and OT response of mother and child were interrelated and children of depressed mothers showed low baseline OT and attenuated OT response. Child OT response was negatively predicted by maternal depression, child Axis-I psychopathology, maternal expressed negative affect, and child social withdrawal. Interaction effect of maternal baseline OT and depression emerged. Slope analysis indicated that when maternal OT was medium or low, child OT response was negatively impacted by maternal depression. However, when maternal OT was high, child OT was unaffected, suggesting that maternal OT functionality buffers the effects of depression on the child.. Results suggest involvement of the OT system in the cross-generational transfer of vulnerability, as well as resilience, from depressed mothers to their children. Because the OT system is open to interventions that enhance maternal touch and contact, findings have important implications for targeted early dyadic inventions.

Topics: Adult; Case-Control Studies; Child; Child, Preschool; Chronic Disease; Depression; Depression, Postpartum; Female; Humans; Infant; Infant, Newborn; Male; Maternal Behavior; Mother-Child Relations; Mothers; Oxytocin; Social Behavior; Touch

Poor oral availability and susceptibility to reduction and protease degradation is a major hurdle in peptide drug development. However, drugable receptors in the gut present an attractive niche for peptide therapeutics. Here we demonstrate, in a mouse model of chronic abdominal pain, that oxytocin receptors are significantly upregulated in nociceptors innervating the colon. Correspondingly, we develop chemical strategies to engineer non-reducible and therefore more stable oxytocin analogues. Chemoselective selenide macrocyclization yields stabilized analogues equipotent to native oxytocin. Ultra-high-field nuclear magnetic resonance structural analysis of native oxytocin and the seleno-oxytocin derivatives reveals that oxytocin has a pre-organized structure in solution, in marked contrast to earlier X-ray crystallography studies. Finally, we show that these seleno-oxytocin analogues potently inhibit colonic nociceptors both in vitro and in vivo in mice with chronic visceral hypersensitivity. Our findings have potentially important implications for clinical use of oxytocin analogues and disulphide-rich peptides in general.

Topics: Abdominal Pain; Analgesics; Animals; Chronic Disease; Humans; Magnetic Resonance Spectroscopy; Mice; Oxytocin

Exposure to early life stress causes increased stress responsiveness and permanent changes in the central nervous system. We recently showed that delayed gastric emptying (GE) and accelerated colonic transit (CT) in response to acute restraint stress (ARS) were completely restored following chronic homotypic stress (CHS) in rats via upregulation of hypothalamic oxytocin (OXT) expression. However, it is unknown whether early life stress affects hypothalamic OXT circuits and gastrointestinal motor function. Neonatal rats were subjected to maternal separation (MS) for 180 min/day for 2 wk. Anxiety-like behaviors were evaluated by the elevated-plus-maze test. GE and CT were measured under nonstressed (NS), ARS, and CHS conditions. Expression of corticotropin-releasing factor (CRF) and OXT in the paraventricular nucleus (PVN) of the hypothalamus was evaluated by real time RT-PCR and immunohistochemistry. MS increased anxiety-like behaviors. ARS delayed GE and accelerated CT in control and MS rats. After CHS, delayed GE and accelerated CT were restored in control, but not MS, rats. CRF mRNA expression was significantly increased in response to ARS in control and MS rats. Increased CRF mRNA expression was still observed following CHS in MS, but not control, rats. In response to CHS, OXT mRNA expression was significantly increased in control, but not MS, rats. The number of OXT-immunoreactive cells was increased following CHS in the magnocellular part of the PVN in control, but not MS, rats. MS impairs the adaptation response of gastrointestinal motility following CHS. The mechanism of the impaired adaptation involves downregulation of OXT and upregulation of CRF in the hypothalamus in MS rats.

Topics: Adaptation, Physiological; Animals; Animals, Newborn; Anxiety, Separation; Chronic Disease; Female; Gastrointestinal Motility; Gene Expression Regulation; Hypothalamus; Male; Oxytocin; Rats; Rats, Sprague-Dawley; Stress, Psychological

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 hypothalamic nonapeptide vasopressin is a known player in the pathogenesis of chronic heart failure. According to the large body of clinical evidence, vasopressin has an impact on salt and water imbalance, hyponatremia, and subsequent renal insufficiency - the most common and destructive co-morbidity of patients afflicted with chronic heart failure. Despite the well-documented elevated levels of vasopressin in the blood of such patients, its expression in the magnocellular hypothalamic nuclei and transport to the posterior pituitary has not yet been investigated. In addition, the literature almost lacks the information on the contribution of another member of nonapeptide family, oxytocin, in the pathogenesis of this disease. Here we present a postmortem analysis of vasopressin and oxytocin-immunoreactive neurons and their terminals in the posterior pituitary of 8 male patients (53.8+/-9.3 years) who had died from CHF and 9 male controls (54.6+/-11.8 years). In line with previous clinical reports, our study on hypothalami of chronic heart failure patients revealed a significant increase in the relative profile density (+29%) of vasopressin-positive neurons in the hypothalamic supraoptic nucleus. Consistently we found a significant increase in the relative optic density of vasopressin-immunoreactivity in the posterior pituitary (+33%) of these patients. In contrast, the similar analysis applied for oxytocin neurons revealed no statistically significant differences to controls. In conclusion, our study provides the morphological evidence for activation of vasopressin (but not oxytocin) expression and vasopressin transport to the posterior pituitary in patients with chronic heart failure.

Topics: Cadaver; Chronic Disease; Gene Expression; Heart Failure; Humans; Hypothalamo-Hypophyseal System; Male; Middle Aged; Oxytocin; Vasopressins

The pathogenesis of inflammatory bowel disease is unknown; however, the disorder is aggravated by psychological stress and is itself psychologically stressful. Chronic intestinal inflammation, moreover, has been reported to activate forebrain neurons. We tested the hypotheses that the chronically inflamed bowel signals to the brain through the vagi and that administration of a combination of secretin (S) and oxytocin (OT) inhibits this signaling.. Three daily enemas containing 2,4,6-trinitrobenzene sulfonic acid (TNBS), which were given to rats produced chronic colitis and ongoing activation of Fos in brain neurons.. Fos was induced in neurons in the paraventricular nucleus of the hypothalamus, basolateral amygdala, central amygdala, and piriform cortex. Subdiaphragmatic vagotomy failed to inhibit this activation of Fos, suggesting that colitis activates forebrain neurons independently of the vagi. When administered intravenously, but not when given intracerebroventricularly, in doses that were individually ineffective, combined S/OT prevented colitis-associated activation of central neurons. Strikingly, S/OT decreased inflammatory infiltrates into the colon and colonic expression of tumor necrosis factor-alpha and interferon-gamma.. These observations suggest that chronic colonic inflammation is ameliorated by the systemic administration of S/OT, which probably explains the parallel ability of systemic S/OT to inhibit the colitis-associated activation of forebrain neurons. It is possible that S and OT, which are endogenous to the colon, might normally combine to restrict the severity of colonic inflammatory responses and that advantage might be taken of this system to develop novel means of treating inflammation-associated intestinal disorders.

Topics: Amygdala; Animals; Cerebral Cortex; Chronic Disease; Colitis; Genes, fos; Injections, Intraperitoneal; Injections, Intraventricular; Interferon-gamma; Intestinal Mucosa; Male; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Prosencephalon; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Secretin; Signal Transduction; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha; Vagotomy

Accumulation of continuous life stress (chronic stress) often causes gastric symptoms. Although central oxytocin has antistress effects, the role of central oxytocin in stress-induced gastric dysmotility remains unknown. Solid gastric emptying was measured in rats receiving acute restraint stress, 5 consecutive days of repeated restraint stress (chronic homotypic stress), and 7 consecutive days of varying types of stress (chronic heterotypic stress). Oxytocin and oxytocin receptor antagonist were administered intracerebroventricularly (icv). Expression of corticotropin-releasing factor (CRF) mRNA and oxytocin mRNA in the paraventricular nucleus (PVN) of the hypothalamus was evaluated by real-time RT-PCR. The changes of oxytocinergic neurons in the PVN were evaluated by immunohistochemistry. Acute stress delayed gastric emptying, and the delayed gastric emptying was completely restored after 5 consecutive days of chronic homotypic stress. In contrast, delayed gastric emptying persisted following chronic heterotypic stress. The restored gastric emptying following chronic homotypic stress was antagonized by icv injection of an oxytocin antagonist. Icv injection of oxytocin restored delayed gastric emptying induced by chronic heterotypic stress. CRF mRNA expression, which was significantly increased in response to acute stress and chronic heterotypic stress, returned to the basal levels following chronic homotypic stress. In contrast, oxytocin mRNA expression was significantly increased following chronic homotypic stress. The number of oxytocin-immunoreactive cells was increased following chronic homotypic stress at the magnocellular part of the PVN. Icv injection of oxytocin reduced CRF mRNA expression induced by acute stress and chronic heterotypic stress. It is suggested that the adaptation mechanism to chronic stress may involve the upregulation of oxytocin expression in the hypothalamus, which in turn attenuates CRF expression.

Topics: Animals; Brain; Brain Chemistry; Chronic Disease; Gene Expression Regulation; Hypothalamus; Immunohistochemistry; Injections, Intraventricular; Male; Oxytocics; Oxytocin; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Restraint, Physical; RNA, Messenger; Stress, Physiological

Many psychiatric disorders are a result of a disturbance in or exhaustion of the human stress response system. It is striking that many of these disorders such as depression, anxiety disorders and post-traumatic stress and somatoform and dissociative disorders are more prevalent in women. There are various explanations for this differing prevalence: it can be attributed to molecular, genetic, neurophysiological, relational and neurohormonal differences. Among the topics discussed are differences in exposure to chronic and traumatic stressors, the role of vasopressin and oxytocin in recovery and neurophysiological differences, the differentiating effect of hormones and neuropeptides such as oxytocin and vasopressin, the tend and befriend response and factors such as abuse and attachment disruption in early childhood.

Topics: Anxiety Disorders; Chronic Disease; Depressive Disorder; Dissociative Disorders; Female; Genetic Predisposition to Disease; Humans; Male; Oxytocin; Prevalence; Sex Factors; Stress Disorders, Post-Traumatic; Stress, Psychological; 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

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

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

The contractile activity of the isolated myometrium of pregnant women with mycoplasma, chlamydia and mixed infections has been studied by pharmacological organ bath method. We found that mycoplasma infection decreased while chlamydia or mixed infection increased myometrium contraction evoked by oxytocin or prostaglandin F2alpha. The results of this study could be important for the prediction of possible complications during pregnancy and labour in women with chronic specific urogenital infections.

Topics: Chlamydia Infections; Chronic Disease; Dinoprost; Down-Regulation; Female; Histamine; Humans; Mycoplasma Infections; Myometrium; Organ Culture Techniques; Oxytocin; Potassium Chloride; Pregnancy; Pregnancy Complications, Infectious; Up-Regulation; Uterine Contraction

This study investigated the influence of chronic hyperthyroidism on mammary function in lactating rats and the effects on their pups. Thyroxine-treated (10 microg per 100 g body weight per day; hyperthyroid (HT)) or vehicle-treated rats were mated 2 weeks after the start of treatment and killed with their litters on days 7, 14 and 21 of lactation. Serum concentrations of triiodothyronine (T(3)) and tetraiodothyronine (T(4)) increased in thyroxine-treated rats. In HT mothers, serum prolactin decreased on day 7 and day 14 of lactation, whereas insulin-like growth factor I (IGF-I) and progesterone concentrations decreased, and corticosterone increased on day 7 of lactation. In HT pups, T(4) concentration increased on day 7 and day 14 of lactation, whereas T(3) increased only on day 14 of lactation, and growth hormone increased on day 7 of lactation. Mammary prolactin binding sites did not vary, but there was an increase in the binding sites in the liver on day 14 of lactation in thyroxine-treated rats. In an acute suckling experiment, thyroxine-treated rats released less oxytocin, growth hormone and prolactin and excreted less milk than did control rats. Mammary casein, lactose and total lipid concentrations in thyroxine-treated rats were similar to those of control rats on day 14 of lactation. Histological studies of the mammary glands showed an increased proportion of alveoli showing reduced or no lumina and cells with condensed nuclei on day 14 and day 21 of lactation; the TdT-mediated dUTP nick-end labelling (TUNEL) test revealed an increase in apoptosis in alveolar cells on day 21 of lactation in thyroxine-treated rats. Expression of SGP-2, a gene expressed during mammary involution, increased in thyroxine-treated rats on day 14 and day 21 of lactation, whereas expression of insulin-like growth factor binding protein 5, a proapoptotic signal, was unchanged. Bcl-2, which promotes survival of mammary gland epithelial cells was unchanged, whereas expression of IGF-I, which also promotes survival of mammary gland epithelial cells, increased on day 21 of lactation in thyroxine-treated rats. These results indicate that thyroxine treatment produces some milk stasis as a result of impairments in suckling induced release of oxytocin that may initiate the first stage of mammary involution, increasing apoptosis in a gland that is otherwise actively producing and secreting milk.

Topics: Animals; Animals, Suckling; Apoptosis; Binding Sites; Chronic Disease; Clusterin; Female; Glycoproteins; Growth Hormone; Hyperthyroidism; In Situ Nick-End Labeling; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor I; Liver; Mammary Glands, Animal; Microscopy, Fluorescence; Milk Ejection; Molecular Chaperones; Oxytocin; Pregnancy; Pregnancy Complications; Progesterone; Prolactin; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroxine; Triiodothyronine

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

The neurochemical and behavioural effects of a novel stereotaxic surgical method developed for interrupting the nerve fibres running through the rat pituitary stalk to the posterior pituitary gland was studied. The cerebrospinal fluid (CSF) vasopressin (AVP) and oxytocin (OT) content as well as changes in aggressiveness were measured in rats one week and one month after the surgical intervention. The main results are as follows: (1) the compression of the pituitary stalk elicits a chronic increase in water consumption, as well as in CSF vasopressin and oxytocin content; (2) the surgical intervention increased the frequency of clinch fighting after one week. The increase in aggressiveness accentuated after one month and, in addition, operated animals showed reduced scores of resting while exploratory and social behaviours increased; (3) there was a strong positive correlation between water consumption, vasopressin, and aggressiveness; (4) oxytocin changes showed a positive correlation with variation in social behaviour. The surgical intervention may serve as a model for lesions of the pituitary stalk and formation of ectopic neurohypophyses in humans.

Topics: Aggression; Animals; Behavior, Animal; Chronic Disease; Diabetes Insipidus; Drinking; Male; Nerve Compression Syndromes; Oxytocin; Pituitary Gland; Rats; Rats, Wistar; Social Behavior; Vasopressins

Neonatally handled (H) animals, as adults, exhibit lower ACTH and corticosterone (B) responses to a number of acute stressors compared to their non-handled (NH) counterparts. However, little is known about activity within the hypothalamic-pituitary-adrenal (HPA) axis of H and NH animals under conditions of chronic stress. We, therefore, examined HPA function in adult H and NH rats exposed to chronic intermittent cold stress (4 h of 4 degrees C cold a day for 21 days; H CHR and NH CHR) and in control H and NH (H CTL and NH CTL) rats. H CTL and NH CTL animals displayed comparable ACTH and B responses to a single, acute exposure to cold. We found that H CHR animals exhibited lower levels of ACTH, but not B, during the 21st exposure to cold (the homotypic stressor) compared to the first exposure to cold in H CTL; however, ACTH and B levels in NH CHR were not different from those in NH CTL. In contrast, NH CHR animals hypersecreted ACTH and B in response to restraint (the novel, heterotypic stressor) compared to NH CTL and both H groups, whereas H CHR and H CTL animals did not differ in their responses to restraint. These endocrine responses were associated with increased basal median eminence levels of both CRH and AVP in H CHR and NH CHR relative to their control groups (with NH CHR exhibiting the highest absolute levels of each secretagogue), and with decreased glucocorticoid receptor densities in septum of both H CHR and NH CHR. In addition, the expected lower glucocorticoid receptor density in hippocampus and frontal cortex of NH rats compared to H rats was observed. We believe that the difference in glucocorticoid receptor density between H and NH animals in the hippocampus and frontal cortex and the associated differences in secretagogue content in the median eminence are related to the hypersecretion of ACTH and B in the NH CHR relative to the other groups. Furthermore, we hypothesize that an active inhibitory process is involved in the adaptation of HPA responses of H CHR animals to the homotypic stressor, and present a working model of regulation of activity within the CRH/AVP neurons in the PVN.

Topics: Adrenocorticotropic Hormone; Animals; Arginine Vasopressin; Basal Metabolism; Chronic Disease; Cold Temperature; Corticosterone; Corticotropin-Releasing Hormone; Handling, Psychological; Hypothalamo-Hypophyseal System; Male; Median Eminence; Oxytocin; Pituitary-Adrenal System; Rats; Stress, Physiological

Previous studies have shown that many treatments that stimulate the peripheral secretion of oxytocin (OT) and vasopressin (AVP) from the pituitary simultaneously increase the levels of these peptides in the cerebrospinal fluid (CSF). Since osmotically and nonosmotically stimulated pituitary secretion of OT and AVP is markedly blunted in hyponatremic rats, the present studies evaluated whether central OT and AVP secretion into the CSF is similarly inhibited during sustained hyponatremia. Adult male rats with indwelling cisterna magna cannulae were rendered hyponatremic (plasma [Na+] < 110 mmol/l) by s.c. infusion of desmopressin (dDAVP; 10 ng/h) in combination with ingestion of a liquid diet for 3 days, then subjected to osmotic (i.v. or i.p. injection of 2 M NaCl; HS) or nonosmotic (6 mmol/kg of 0.15 M LiCl i.p.) stimulation. In normonatremic rats both i.v. and i.p. HS caused marked increases in plasma OT and AVP levels 30 min after treatment. Significant elevations of OT, but not AVP, were also present in CSF. Despite similar increases in plasma Na+ concentrations, plasma OT responses in the hyponatremic rats were absent after HS i.v. and were significantly blunted after HS i.p., but neither group had increased plasma AVP. In parallel with the plasma results, CSF OT responses were absent in hyponatremic rats given HS i.v. and significantly blunted in hyponatremic rats given HS i.p., but neither group had increased CSF AVP. Nonosmotic stimulation with isotonic LiCl increased OT levels both in plasma and CSF in normonatremic rats 20 min after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arginine Vasopressin; Brain; Chronic Disease; Hyponatremia; Injections, Intraperitoneal; Injections, Intravenous; Isotonic Solutions; Lithium Chloride; Male; Oxytocin; Rats; Rats, Sprague-Dawley; Reference Values; Saline Solution, Hypertonic

The external zone of the median eminence in rats contains very few oxytocinergic (OT) fibers. However, 6 weeks after lesioning the paraventricular nucleus (PVN) many OT axons can be found in the external zone, possibly as part of a mechanism compensating for the loss of secretion originating from the PVN. In this study, we investigated whether such structural reorganization of the median eminence occurs in chronically hyponatremic rats, which are known to have significantly inhibited OT and vasopressin (AVP) neurosecretory responses to most physiological stimuli. Normonatremic and chronically hyponatremic rats received bilateral PVN lesions using a rotating knife. One week after PVN lesions both vasopressin-neurophysin (AVP-NP) and oxytocin-neurophysin (OT-NP) staining intensities decreased in the internal zone of the median eminence, and AVP-NP immunoreactivity almost entirely disappeared from the external zone. Six weeks after PVN lesions OT-NP but not AVP-NP immunostaining appeared in the external zone of the median eminence in the normonatremic rats. In contrast, no increase in OT-NP staining occurred in the external zone of the median eminence in the hyponatremic rats by six weeks after PVN lesions. These results indicate that chronic hyponatremia inhibits not only synthesis and secretion of AVP and OT, but also impairs cellular processes involved in the sprouting response normally seen following bilateral PVN lesions in rats.

Topics: Animals; Arginine Vasopressin; Axons; Chronic Disease; Drug Implants; Hyponatremia; Immunohistochemistry; Male; Median Eminence; Nerve Regeneration; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley

Topics: Animals; Chronic Disease; Dehydration; Female; Immunohistochemistry; Nerve Endings; Oxytocin; Pituitary Gland, Posterior; Rats; Vasopressins

Acute and chronic pulmonary and systemic hemodynamic responses to arginine vasopressin (AVP) were examined in 4-wk hypoxia-adapted and air control rats. AVP, administered intravenously as bolus injections or sustained infusions, produced major dose-dependent V1-receptor-mediated reductions in mean pulmonary arterial pressure in hypoxia-adapted rats. These effects were comparable in pentobarbital-anesthetized, thoracotomized animals and in conscious, intact rats. Chronic infusions of AVP induced a sustained reduction in mean pulmonary arterial pressure and partially prevented the development of pulmonary hypertension without changing systemic arterial pressure. AVP induced significant decreases in cardiac output in both groups; the cardiac output response was not significantly different in hypoxia-adapted and air control animals. AVP induced almost no change in MPAP in air control rats. Furthermore the systemic pressor effects of AVP were significantly blunted in hypoxia-adapted rats compared with air controls. We conclude that the pulmonary depressor and blunted systemic pressor effects of AVP observed in hypoxia-adapted rats may be related to release of a vasodilator, such as endothelium-derived relaxing factor, vasodilator prostaglandins, or atrial natriuretic peptides. Further study is needed to elucidate these mechanisms and assess the usefulness of AVP and/or its analogues in the treatment and prevention of hypoxia-induced pulmonary hypertension.

Topics: Adaptation, Physiological; Anesthesia; Animals; Arginine Vasopressin; Blood Pressure; Cardiac Output; Chronic Disease; Consciousness; Hemodynamics; Hypoxia; Male; Oxytocin; Pulmonary Artery; Rats; Rats, Inbred Strains

Rats inoculated in the tail-base with killed Mycobacterium butyricum developed an arthritic swelling and inflammation of the limbs accompanied by a hyperalgesia to noxious pressure applied thereto. These changes were maximal at 3 weeks and had subsided by 10 weeks post-inoculation. At 3 weeks, arthritic rats manifested an elevation in levels of immunoreactive (ir)-vasopressin (VP) but not ir-oxytocin (OT) in the midbrain. In contrast, ir-OT was increased in the medulla-pons while ir-VP was unaltered therein. These changes had disappeared by 10 weeks. No other brain region displayed changes. Thus, chronic arthritis is associated with selective and reversible effects upon discrete brain pools of ir-VP and ir-OT. The data clearly demonstrate that pools of ir-VP and ir-OT can be modulated independently of each other in particular brain tissues. Whether the changes are produced by, or reflect a functional response to, the pain rather than other characteristic of the arthritis, remains to be determined.

Topics: Animals; Arthritis; Arthritis, Experimental; Brain Chemistry; Chronic Disease; Male; Oxytocin; Pain; Rats; Rats, Inbred Strains; Stress, Physiological; Vasopressins

Lesions of the hypothalamic paraventricular nucleus depleted immunoreactive (ir)-vasopressin (VP) and -oxytocin (OT) from rat spinal cord but failed to modify nociceptive thresholds. Further, intrathecal introduction of VP and OT into the cord failed either to influence nociceptive thresholds or to modify the antinociceptive action of morphine. However, doses of VP as low as 20 ng caused, in contrast to OT, a hind-limb muscular flaccidity and respiratory disturbances. Rats suffering from chronic arthritis did not, finally, reveal any alterations in levels or ir-VP or ir-OT in the spinal cord. Is is concluded that spinal pools of VP and OT are derived from the paraventricular nucleus and do not play a major role in nociceptive processes in the spinal cord. A role of spinal VP in motor and, possibly autonomic control is, nevertheless, indicated.

Topics: Animals; Arthritis, Experimental; Chronic Disease; Male; Morphine; Oxytocin; Pain; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred Strains; Sensory Thresholds; Spinal Cord; Vasopressins

Sixty-six patients with chronic hypertension were cared for during a total of 72 pregnancies. Patients were treated at home primarily by greater than or equal to 4 hours of bed rest daily in the left recumbent position. Only patients whose diastolic blood pressures remained greater than 110 mmHg were treated with hydralazine (Apresoline, Ciba). With this plan of treatment there were only 3 perinatal deaths for an uncorrected perinatal mortality of 4.1% (1.4% corrected). Twenty-nine percent of the patients had babies that were small for gestational age, 13.8% had positive oxytocin challenge tests, and 36.8% developed superimposed preeclampsia. When compared with the outcome of previous pregnancies, the program of bed rest lowered perinatal mortality from 16.8 to 8.8%. Thus, it is suggested that bed rest together with the avoidance of diuretics and the judicious use of hydralazine results in the most favorable fetal outcome.

Topics: Bed Rest; Birth Weight; Chronic Disease; Female; Fetal Death; Humans; Hydralazine; Hypertension; Infant Mortality; Infant, Newborn; Infant, Small for Gestational Age; Meconium; Oxytocin; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular

Topics: Adult; Antihypertensive Agents; Chronic Disease; Female; Fetal Growth Retardation; Fetus; Growth; Humans; Hydralazine; Hydrochlorothiazide; Hypertension; Infant, Newborn; Methyldopa; Oxytocin; Pregnancy; Pregnancy Complications, Cardiovascular; Prenatal Diagnosis; Ultrasonography

Persistent and complete post-vagotomy gastric atony was treated in 3 patients by intravenous infusion of oxytocin. Despite failure of both conventional treatment with gastric aspiration and intravenous fluids or jejunal feeding, as well as the reported trials with bethanechol chloride and metaclopramide, these patients promptly responded to oxytocin. It appears that the latter may represent a solution to this uncommon but recalcitrant complication of peptic ulcer surgery.

Topics: Chronic Disease; Gastric Emptying; Humans; Male; Oxytocin; Stomach Diseases; Vagotomy

Topics: Acute Disease; Chronic Disease; Estriol; Female; Fetal Distress; Fetal Heart; Fetal Hypoxia; Heart Rate; Humans; Maternal-Fetal Exchange; Oxygen Consumption; Oxytocin; Placenta Diseases; Pregnancy; Prenatal Diagnosis; Ultrasonography; Umbilical Cord

Three cases have been observed over the past 3 years at Los Angeles County-USC Medical Center, Women's Hospital, which have shown an unusual fetal heart rate response to induced uterine contractions during the antepartum period. All 3 cases resulted in perinatal death apparently due to asphyxia. This report describes this unusual pattern and presents a discussion of its possible significance.

Topics: Adult; Chronic Disease; Estriol; Female; Fetal Death; Fetal Heart; Fetus; Gestational Age; Growth; Heart Rate; Humans; Hypertension; Infant, Newborn; Oxytocin; Phonocardiography; Placenta Diseases; Placental Insufficiency; Polyhydramnios; Pregnancy; Pregnancy Complications, Cardiovascular

The purpose of this investigation was to determine whether the oxytocin challenge test (OCT) could serve as the primary method for managing pregnancies characterized by possible placental insufficiency. One hundred and five patients underwent 225 oxytocin challenge tests; no perinatal deaths occurred. Eight tests were positive, 21 suspicious, and 196 negative. Because of data obtained in a preliminary study, all 8 fetuses with positive tests were delivered by cesarean section. Four of the 8 had repetitive suspicious tests prior to a positive test, suggesting that utero-placental function may deteriorate gradually. Urinary excretion of estriol did not decrease significantly in any patient, suggesting that the OCT is a more sensitive indicator of placental function than excretion of estriol. Except for patients with preeclampsia who were induced for maternal indications, all pregnancies with a negative OCT were allowed to terminate spontaneously. Five of the 97 fetuses with negative tests developed late-onset deceleration patterns during labor. This indicates that a negative OCT will not necessarily predict fetal tolerance to labor, contrary to assertions made by some other investigators. It is concluded that the OCT can serve as the primary method for assessing the fetal status in pregnancies characterized by placental insufficiency.

Topics: Chronic Disease; Estriol; Female; Fetus; Gestational Age; Growth; Humans; Hypertension; Infant, Newborn; Oxytocin; Phosphatidylcholines; Placenta Diseases; Placental Function Tests; Placental Insufficiency; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Pregnancy, Prolonged; Risk; Sphingomyelins; Ultrasonography

Topics: Chronic Disease; Female; Fetal Diseases; Fetal Heart; Heart Rate; Humans; Infant, Newborn; Oxytocin; Placenta Diseases; Pregnancy; Prenatal Diagnosis; Umbilical Arteries; Umbilical Veins

Topics: Acidosis; Actinomycosis; Animals; Chronic Disease; Endometritis; Ergotism; Female; Hypocalcemia; Lactation Disorders; Mammary Glands, Animal; Mastitis; Necrosis; Obstetric Labor Complications; Oxytocin; Pregnancy; Swine; Swine Diseases