Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are major physiological stimulators of adrenocorticotropin (ACTH) secretion from the pituitary gland, while glucocorticoids act as inhibitors. In addition to acting alone, CRH, AVP and glucocorticoids interact with each other to regulate ACTH release in response to stress. Prolonged or repeated stimulus results in attenuated ACTH responsiveness, a process termed as desensitization. The aim of this study was to investigate the effects of interactions between CRH, AVP and steroids on desensitization of the ACTH response to AVP. Perifused ovine anterior pituitary cells were stimulated with three 5-min pulses of 100 nM AVP at 120, 200 and 280 min, and were continuously exposed to CRH (0.2 nM) from 80 min and/or cortisol (10-500 nM) from 0 min onwards. Desensitization was induced by a 15 min pre-treatment with 5 nM (0.5 nM for CRH alone) AVP immediately preceding the second AVP pulse. When CRH was absent, pre-treatment with 0.5 nM AVP did not influence the ACTH response to the second AVP pulse. In the presence of CRH, the response to the second AVP pulse was reduced to 66.7±2.2% of control (n=6, P<0.0001, t-test). On the other hand, following 5 nM AVP pre-treatment, continuous perifusion with cortisol (100 nM) results in a significantly smaller reduction in the response to the second AVP pulse compared with that seen in its absence (78.4±1.7% c.f. 66.7±1.9% of control; n=10, P<0.001, t-test). In contrast to this, following 5 nM AVP pre-treatment, continuous CRH and cortisol in combination results in a greater reduction in the response to the second AVP pulse compared with that obtained in the absence of these two hormones (46.5±1.7% c.f. 66.2±1.7 of control; n=8, P<0.0001, t-test). Taken together, these data suggest that desensitization of the ACTH response to AVP can be modulated by CRH and/or cortisol: CRH or CRH and cortisol in combination amplify this desensitization, whereas cortisol reduces it.

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Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are major physiological stimulators of adrenocorticotropin (ACTH) secretion from the pituitary gland, while glucocorticoids act as inhibitors. In addition to acting alone, CRH, AVP and glucocorticoids interact with each other to regulate ACTH release in response to stress. Prolonged or repeated stimulus results in attenuated ACTH responsiveness, a process termed as desensitization. The aim of this study was to investigate the effects of interactions between CRH, AVP and steroids on desensitization of the ACTH response to AVP. Perifused ovine anterior pituitary cells were stimulated with three 5-min pulses of 100 nM AVP at 120, 200 and 280 min, and were continuously exposed to CRH (0.2 nM) from 80 min and/or cortisol (10-500 nM) from 0 min onwards. Desensitization was induced by a 15 min pre-treatment with 5 nM (0.5 nM for CRH alone) AVP immediately preceding the second AVP pulse. When CRH was absent, pre-treatment with 0.5 nM AVP did not influence the ACTH response to the second AVP pulse. In the presence of CRH, the response to the second AVP pulse was reduced to 66.7±2.2% of control (n=6, P<0.0001, t-test). On the other hand, following 5 nM AVP pre-treatment, continuous perifusion with cortisol (100 nM) results in a significantly smaller reduction in the response to the second AVP pulse compared with that seen in its absence (78.4±1.7% c.f. 66.7±1.9% of control; n=10, P<0.001, t-test). In contrast to this, following 5 nM AVP pre-treatment, continuous CRH and cortisol in combination results in a greater reduction in the response to the second AVP pulse compared with that obtained in the absence of these two hormones (46.5±1.7% c.f. 66.2±1.7 of control; n=8, P<0.0001, t-test). Taken together, these data suggest that desensitization of the ACTH response to AVP can be modulated by CRH and/or cortisol: CRH or CRH and cortisol in combination amplify this desensitization, whereas cortisol reduces it.

Aggressive behavior in dogs poses public health and animal welfare concerns, however the biological mechanisms regulating dog aggression are not well understood. We investigated the relationships between endogenous plasma oxytocin (OT) and vasopressin (AVP)-neuropeptides that have been linked to affiliative and aggressive behavior in other mammalian species-and aggression in domestic dogs. We first validated enzyme-linked immunosorbent assays (ELISAs) for the measurement of free (unbound) and total (free + bound) OT and AVP in dog plasma. In Experiment 1 we evaluated behavioral and neuroendocrine differences between a population of pet dogs with a history of chronic aggression toward conspecifics and a matched control group. Dogs with a history of aggression exhibited more aggressive behavior during simulated encounters with conspecifics, and had lower free, but higher total plasma AVP than matched controls, but there were no group differences for OT. In Experiment 2 we compared OT and AVP concentrations between pet dogs and a population of assistance dogs that have been bred for affiliative and non-aggressive temperaments, and investigated neuroendocrine predictors of individual differences in social behavior within the assistance dog population. Compared to pet dogs, assistance dogs had higher free and total OT, but there were no differences in either measure for AVP. Within the assistance dog population, dogs who behaved more aggressively toward a threatening stranger had higher total AVP than dogs who did not. Collectively these data suggest that endogenous OT and AVP may play critical roles in shaping dog social behavior, including aspects of both affiliation and aggression.

The concept that the renal excretion of water and electrolytes is partly governed by the volume in some fluid compartment of the body is one which has received some experimental verification. Attempts to define a mechanism sensitive to changes in some fluid compartment of the body have provided support both for and against the theory that stimulation of sensory nerve endings in the intrathoracic circulation sets up afferent impulses in the vagus nerves which diminish the release of antidiuretic hormone from the neurohypophysis and so cause diuresis. Evidence which supports the theory comes from experiments in which atrial distension has been associated with a reduction of antidiuretic activity in the circulating blood. Evidence which does not support the theory comes from experiments in which the diuretic response to left atrial distension has been demonstrated during infusion of vasopressin at rates adequate to completely inhibit water diuresis in conscious dogs (0.025 m-u./kg./min.). A series of experiments has been carried out in an attempt to define the role of antidiuretic hormone in the diuretic response to left atrial distension. In one series, experiments were designed to test the effects of different doses of vasopressin upon the diuretic response to left atrial distension. The results of this series showed that the diuretic response to left atrial distension was composed of an increase in solute excretion and an increase in water excretion. At a rate of infusion of vasopressin of 0.4 m-u./kg./min. or above the increase in water excretion was abolished while the increase in solute excretion was unaffected. In another series, experiments were designed to test the renal response to large changes in vasopressin concentration. The concentrations of vasopressin used (0.4 m-u./kg./min. and 0.04 m-u./kg./min.) completely inhibited water diuresis in conscious dogs. The results of this series indicated that in the hydrated anaesthetized dog, a change from the high concentration of vasopressin to the lower concentration may cause a transient dilute diuresis. These results support the view that a decrease in the circulating concentration of antidiuretic hormone is one mechanism which may produce a diuretic response to left atrial distension. The results will be reported in a condensed form (Mason and Ledsome, 1971; Ledsome and Mason, 1971). / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

The mechanisms which control the accumulation and circulation of the amniotic fluid are poorly understood. Earlier studies had made the tentative suggestion that vasopressin, which is important in the control of water balance in adults, might play a role in the regulation of amniotic fluid turnover. In the work reported here, attempts were made to detect and measure the vasopressin levels in the amniotic fluid of guinea pigs, sheep and humans. Unconcentrated amniotic fluid samples from the guinea pig, sheep and human were assayed using the water-loaded, alcohol-anesthetized rat antidiuretic preparation. If vasopressin is present in the fluid of these animals, it would be at a concentration below the detectable limits of the assay, which were found to be 10 to 15 microunits/ml. Only 4 out of 36 experiments on guinea pig amniotic fluid gave even a suggestion of a response, with 3 of these being too small to be quantified accurately. No sheep or human samples produced an antidiuresis. An attempt was made to dehydrate the maternal guinea pigs, as it. was thought that this would create an osmotic stress in the fetus which might result in increased output of vasopressin. In 29 experiments with fluid of fetuses whose mothers had been without water for 24 or 48 hours prior to collection, 27 gave no response. The responses to the two injections that did indicate activity were too low for accurate quantification. However, these experiments were not considered conclusive, and more extended investigation is needed. Seven human amniotic fluid samples were concentrated on CM-25 Sephadex columns, along with three standard vasopressin loads. The standards showed recoveries of 80% to 90% under optimal conditions. An antidiuretic substance was found in fractions from all of these samples, and it eluted at a similar pH and molarity to the standard vasopressin. This material measured approximately 200 micro-units/ml, and was relatively consistent in all of the samples tested. The amniotic fluid antidiuretic substance (AFAS) appeared to respond with an antidiuresis similar to that of vasopressin on the assay preparation. However, further work suggested that the AFAS could not be identified as vasopressin. Although the pattern of antidiuretic responses were similar, there were marked changes in the sensitivity of the bioassay preparation to the unknown material during periods of little change in the responses to vasopressin itself. A similar contrast was found between different experiments. Sodium thioglycollate incubation also failed to deactivate the active AFAS fractions, whilst control volumes of vasopressin lost apparently all activity following this procedure. The stability characteristics were also dissimilar to those of vasopressin, as the fractions remained active for up to five weeks when stored at neutral pH at 4° C. Optimum pH conditions for the storage of vasopressin are between 3.0 and 5.0. An attempt was made to identify the AFAS as angiotensin II. However, the response pattern on the records of the antidiuretic assay were dissimilar. Further comparisons with combinations of vasopressin and angiotensin II in varying concentrations also failed to mimic the responses to the AFAS. It was concluded that the antidiuretic activity found in the human amniotic fluid was not attributable to vasopressin, angiotensin II, or to a combination of these two hormones, at the levels tested. The nature of the AFAS is at present unknown. Further studies are needed to identify the unknown antidiuretic agent extracted from human amniotic fluid, and the possible mechanisms of its release, and its potential physiological functions, are still unknown. / Science, Faculty of / Zoology, Department of / Graduate

The vertebrate hypothalamus is a central node within multiple interwoven neural networks that integrate external and internal cues to control homeostasis, endocrine functions and social behavior. The neuropeptide hormone arginine-vasopressin (AVP) is produced in both the supraoptic and paraventricular nuclei of the hypothalamus. Expression within these nuclei is conserved across species, and species differences in the expression of AVP and its cognate receptors correlate with differences in social behavior. As a central node within the social behavior network, chemogenetic manipulation of AVP+ cells in the paraventricular nucleus (pvn) of the hypothalamus provides a unique opportunity to investigate the relationship between social behavior and the regulation of stress responses. Here, we show that reversibly inducing excitatory activity in vasopressin neurons in the PVN results in reduced motivation for social interaction and increased grooming behavior in males. Chronic activation of PVN AVP neurons reduced social motivation in male mice that persisted even without CNO administration. These results highlight the role PVN AVP+ neurons play in the modulation of male social motivation.

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