Vasopressinergic System Research Articles

Role of neuronal nitric oxide in the regulation of vasopressin expression and release in response to inhibition of catecholamine synthesis and dehydration

We used neuronal nitric oxide synthase (nNOS) gene knockout mice to study the effects of catecholamines and neuronal nitric oxide on vasopressin expression in the hypothalamic neurosecretory centers. nNOS gene deletion did not change the level of vasopressin mRNA in the supraoptic or paraventricular nuclei. In contrast, vasopressin immunoreactivity was lower in nNOS deficient mice than in wild-type animals. Dehydration increased vasopressin mRNA levels and decreased vasopressin immunoreactivity in both wild-type and nNOS knockout mice, but these responses were more marked in the nNOS knockout mice. Treatment with alpha-mpt, a pharmacologic inhibitor of catecholamine synthesis, resulted in increased vasopressin mRNA levels in wild-type mice and in reduced vasopressin immunoreactivity in both wild-type and nNOS knockout mice. From these results, we conclude: (1) neuronal nitric oxide suppresses vasopressin expression under basal conditions and during activation of the vasopressinergic system by dehydration; (2) catecholamines limit vasopressin expression; (3) nNOS is required for the effects of catecholamines on vasopressin expression.

Effects of intracerebroventricularly-injected morphine on anxiety, memory retrieval and locomotor activity in rats: Involvement of vasopressinergic system and nitric oxide pathway

Morphine has been shown to alter several behavioural processes. We aimed to investigate the effects of intracerebroventricular (i.c.v.) morphine on anxiety, memory retrieval and locomotor activity in rats and to elucidate the possible involvement of the vasopressinergic system and the nitric oxide (NO) pathway in these effects. Rats were pretreated with morphine (0.5, 5, 50 μg/5 μl; i.c.v.) or saline (5 μl; i.c.v.) 30 min before the elevated plus maze test, the probe trial of the Morris water maze and the open field test. Morphine (5 μg/5 μl; i.c.v.) induced significant anxiolytic effects in the elevated plus maze. None of the doses of morphine produced any effects in the probe trial of the Morris water maze and the open field. Pretreatment with an arginine vasopressin (AVP) V 1 receptor antagonist (25, 125 ng/5 μl; i.c.v.), an AVP V 2 receptor antagonist (25, 125 ng/5 μl; i.c.v.), or l-NAME, an NO synthase inhibitor (5, 25 μg/5 μl; i.c.v.) 30 min before morphine significantly prevented the anxiolytic effects of morphine. These results suggest that i.c.v. morphine has significant anxiolytic effects, probably mediated by both vasopressinergic system and NO pathway, but has no effect on memory retrieval or locomotor activity, at least at the applied doses.

Differential roles of amygdaloid nuclei in the anxiolytic- and antidepressant-like effects of the V1b receptor antagonist, SSR149415, in rats

SSR149415 ((2S, 4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide), the first selective nonpeptide vasopressin V1b receptor antagonist has been shown to induce antidepressant-and anxiolytic-like effects following systemic administration, whereas intraseptal infusion of the drug engender antidepressant-but not anxiolytic-like effects. Based on recent evidence that V1b receptors are located within the amygdaloid complex, a structure which is well known for its modulatory role of emotional processes, the possible involvement of the different amygdaloid nuclei in the anxiolytic- and/or antidepressant-like effects of SSR149415 was examined. Male Sprague-Dawley or Wistar rats were infused with SSR149415 into the central (CeA), the basolateral (BlA), or the medial (MeA) nucleus of the amygdala and tested 10 min after microinjection in the elevated plus-maze or the forced-swimming test, two models typically used for assessing the anxiolytic and antidepressant effects of drugs, respectively. Microinjection of SSR149415 into the BlA (1-10 ng), but not into the CeA or the MeA, increased the percentage of time spent in the open arms of the elevated plus-maze, indicating anxiolytic-like effects. Furthermore, in the forced-swimming test, microinjection of the drug into the CeA (1, 10, and 100 ng), BlA (1-10 ng), or MeA (100 ng) decreased immobility, an effect which is indicative of an antidepressant-like action. Together, these findings indicate that while the antidepressant-like effects of SSR149415 are mediated by different amygdaloid nuclei, its anxiolytic-like effects appear to involve only the basolateral nucleus of the amygdala. Moreover, these results add further evidence to the role of extrahypothalamic vasopressinergic systems in the control of emotional responses.

Vasopressinergic system and aging in the female Ts65Dn mouse, a murine model for Down syndrome

Vasopressinergic system and aging in the female Ts65Dn mouse, a murine model for Down syndrome

Hydruric response in Wistar and vasopressin-deficient Brattleboro rats to water load under conditions of increased brain serotonin level

The hydruric response to water load in Wistar rats and homozygous Brattleboro rats with a hereditary defect in the synthesis of vasopressin was studied under conditions of increased brain serotonin level. Serotonin prevented the reduction in reabsorption of osmotically free water in normal rats, but had no effect in vasopressin-deficient Brattleboro rats. Our results suggest that serotonin stimulates vasopressin secretion and interacts with the vasopressinergic system during the realization of osmotic regulation.

Serum vasopressin concentrations in critically ill patients*

To measure arginine vasopressin (AVP) serum concentrations in critically ill patients. Prospective study. Twelve-bed general and surgical intensive care unit in a tertiary, university teaching hospital. Two-hundred-thirty-nine mixed critically ill patients and 70 healthy volunteers. None. Demographic data, hemodynamic variables, vasopressor drug requirements, blood gases, AVP serum concentrations within 24 hrs after admission, multiple organ dysfunction score, and outcome were recorded. Twenty-four hours after admission, study patients had significantly higher AVP concentrations (11.9 +/- 20.6 pg/mL) than healthy controls (0.92 +/- 0.38 pg/mL; p < .001). Males had lower AVP concentrations than females (9.7 +/- 19.5 vs. 15.1 +/- 20.6 pg/mL; p = .014). Patients with hemodynamic dysfunction had higher AVP concentrations than patients without hemodynamic dysfunction (14.1 +/- 27.1 vs. 8.7 +/- 10.8 pg/mL; p = .042). Patients after cardiac surgery (n = 96) had significantly higher AVP concentrations when compared to patients admitted for other diagnoses (n = 143; p < .001). AVP concentrations were inversely correlated with length of stay in the intensive care unit (correlation coefficient, -0.222; p = .002). There was no correlation between serum AVP concentrations and the incidence of shock or specific hemodynamic parameters. Four (1.7%) of the 239 study patients met criteria for an absolute AVP deficiency (AVP, <0.83 pg/mL), and 32 (13.4%) met criteria for a relative AVP deficiency (AVP, <10 pg/mL, and mean arterial pressure, <70 mm Hg). In shock patients, relative AVP deficiency occurred in 22.2% (septic shock), 15.4% (postcardiotomy shock), and 10% (shock due to a severe systemic inflammatory response syndrome) (p = .316). AVP serum concentrations 24 hrs after intensive care unit admission were significantly increased in this mixed critically ill patient population. The lack of a correlation between AVP serum concentrations and hemodynamic parameters suggests complex dysfunction of the vasopressinergic system in critical illness. Relative and absolute AVP deficiency may be infrequent entities during acute surgical critical illness, mostly remaining without significant effects on cardiovascular function.

Effects of spironolactone on sympathetic nerve activity and baroreflex function in patients with early hypertensive heart disease

Activation of the renin-angiotensin-aldosterone system (RAAS) could induce sympathoexcitation mediated by aldosterone in patients with primary hypertension and left ventricular hypertrophy. We hypothesised that aldosterone antagonism may suppress muscle sympathetic nerve activity (MSNA) and improve baroreflex function in subjects with beginning hypertensive heart disease. Eleven patients with mild to moderate primary hypertension and echocardiographic signs of early hypertensive heart disease received either oral spironolactone 25mg/day or placebo for four weeks in a double-blind, cross-over design. On the experimental day, resting biochemical parameters were determined, and MSNA was recorded by microneurography of the peroneal nerve at rest and during intravenous infusion of phenylephrine and nitroprusside. Furthermore, blood pressure (BP) and heart rate were measured non-invasively. Spironolactone increased basal levels of vasopressin, aldosterone and renin. Resting MSNA was higher during treatment with spironolactone compared with placebo (37.0±4.3 vs. 32.4±4.3 bursts/min, p=0.01), while BP and heart rate were not affected. Furthermore, spironolactone altered baroreflex control of MSNA (ΔMSNA / Δdiastolic BP) resulting in higher MSNA levels during nitroprusside infusion (b=-0.57 vs. b=0.05, t-value=2.80, 56 degrees of freedom, p<0.05). However, spironolactone did not affect baroreflex control of MSNA during phenylephrine infusion. Contrary to expectations, spironolactone activates MSNA at rest and during baroreceptor deactivation in patients with early hypertensive heart disease. This sympathoexcitatory effect may be mediated by central mineralocorticoid receptor blockade itself or alternatively, via the RAAS or the vasopressinergic system, which both seem activated during isolated aldosterone antagonism.

Enhanced pressor response to centrally administered vasopressin in WKY rats on high sodium diet

Four week old Wistar-Kyoto (WKY) rats were divided into two groups. The experimental group (n=7) was receiving a high sodium diet (3.28% Na) and the control group (n=7) a normal sodium diet (0.22% Na). After 8 weeks, subjects were chronically implanted with the lateral cerebral ventricle (LCV) cannulas and with the femoral artery catheters. Three series of experiments were carried out on the experimental and control groups. In each series mean arterial pressure (MAP) and heart rate (HR) were recorded for 10 min before and 30 min after the LCV infusion. In series 1 artificial cerebrospinal fluid (aCSF) was administered (2 µl/15 s). In series 2 AVP was infused (20 ng/2 µl aCSF/15 s). In series 3 V1a receptor antagonist (V1 ANT), d(CH2)5[Tyr(Me)2,Ala-NH29]AVP, was applied (80 ng/µl aCSF/15 s). There was no difference in baseline MAP and HR between the experimental and control groups. LCV infusion of aCSF had no effect on MAP and HR. LCV infusion of AVP produced a significant increase of MAP, which was greater in the group on the high sodium diet than in the group on normal sodium diet. The experimental group showed a longer hypertensive effect of centrally applied AVP in comparison to the control. LCV administration of V1 ANT did not exert a significant effect on circulatory parameters. These results suggest that the prolonged high sodium diet does not induce hypertension in WKY rats, but it enhances the pressor function of the central vasopressinergic system.

Effets métaboliques et endocriniens de la privation hydrique et/ou alimentaire chez le rat

We aim at studying the effect of water deprivation, food deprivation and their combination for three days on adrenal cortex, pituitary-thyroid axis and vasopressinergic system activity in rats. Corticosterone level was determined by fluorimetric method. The levels of free thyroxine (FT4) and thyroid stimulating hormone (TSH) were determined by immunoenzymatic assay and vasopressin (AVP) level was determined by radio-immunoassay. In all three groups, basal levels of plasma corticosterone were increased. A thyroid dysfunction was shown after water deprivation, food deprivation and their combination reflected by a significant decrease in FT4 levels. Paradoxically, a significant decrease in TSH level was observed in food-deprived rats and in rats subjected to simultaneous food and water deprivation, while a slight and not significant decrease in TSH level was shown in water-deprived rats. A significant increase in plasma AVP level was observed after water deprivation and simultaneous water and food deprivation, while no change was found after food deprivation. The data indicated that water deprivation, food deprivation and their combination stimulated the adrenal cortex, thereby suggesting a stress state. On the other hand, it seems that nutritional stress modifies the pituitary-thyroid axis through mechanisms different from those of osmotic stress. Moreover, it seems that food deprivation partially prevented the stimulatory effect of water deprivation on vasopressinergic system. To cite this article: A.G. Kasdallah et al., C. R. Biologies 328 (2005).

The Central Vasopressinergic System: Examining the Opportunities for Psychiatric Drug Development

Arginine vasopressin (AVP) is a cyclic nonapeptide synthesized exclusively by neurosecretory cells of the central nervous system (CNS). Two functionally distinct vasopressinergic systems can be defined based on differences in the sites of action and release of AVP. The peripheral vasopressinergic system encompasses the sites of action for AVP released into peripheral circulation (e.g. vascular smooth muscle, liver, kidney) from nerve terminals in the posterior pituitary. Peripherally circulating AVP is responsible for the classic endocrine functions ascribed to this neurohormone (e.g. vasoconstriction, glycogen metabolism, antidiuresis). The central vasopressinergic system, on the other hand, includes the sites of AVP synthesis and release within the CNS, where AVP acts as a neuromodulator/neurotransmitter regulating an array of CNS-mediated functions (e.g. learning and memory, neuroendocrine reactivity, social behaviors, circadian rhythmicity, thermoregulation, and autonomic function). Historically, pharmaceutical interest has focused on drug development efforts that sought to exploit the peripheral effects of AVP. Evidence, however, from clinical studies and animal models of CNS disorders has directly implicated disturbances in vasopressinergic activity in the pathophysiology of a number of human psychiatric disorders (mood, anxiety, and cognitive disorders). This review will examine the available evidence of central vasopressinergic system involvement in psychiatric disorders, and the potential opportunities for development of novel psychopharmaceuticals around this system will be discussed. Specific lines of evidence will be presented which rationalize each AVP receptor subtype (V(1)R or V(1a), V(2)R, V(3)R or V(1b)) as a molecular target for particular psychiatric indications.

Highly selective localization of leukotriene C 4 synthase in hypothalamic and extrahypothalamic vasopressin systems of mouse brain

While leukotriene C 4 (LTC 4) was originally identified as a potent bronchoconstrictor, the compound has versatile biological activities besides inflammatory reactions. Although the high content of LTC 4 has been reported in the hypothalamus and median eminence, the precise localization of the compound remained obscure. To elucidate its possible functions in the neuroendocrine systems, we determined immunohistochemical localization of LTC 4 synthase, a key enzyme to produce LTC 4 using mouse brains. Light microscopy and confocal laser scanning microscopy showed that LTC 4 synthase was selectively localized in the vasopressinergic magnocellular neurons of the hypothalamic paraventricular, supraoptic and suprachiasmatic nuclei and in the retrochiasmatic area, as well as in axons that emanated from these neurons to the pars nervosa of the pituitary gland. At subcellular level, however, LTC 4 synthase and arginine vasopressin appeared to localize differently within individual neurons. LTC 4 synthase immunoreactivity was also observed in the axons of the extrahypothalamic system including the bed nucleus of the stria terminalis, lateral habenular nucleus, midbrain central gray, medial amygdaloid nucleus and ventral septal area, although this immunoreactivity was relatively minor. The other brain regions did not contain LTC 4 synthase immunoreactivity. The distribution of LTC 4 synthase did not overlap with that of either oxytocin or luteinizing hormone releasing hormone. Therefore, LTC 4 is considered to be involved in neural functions of the brain magnocellular vasopressinergic system such as water retention. LTC 4 may also be involved in extrahypothalamic vasopressinergic neural functions including the regulation of learning and memory, social recognition memory, sexual and aggressive behavior, etc.

Mineralocorticoid Treatment Upregulates the Hypothalamic Vasopressinergic System of Spontaneously Hypertensive Rats

Mineralocorticoid effects in the brain include the control of cardiovascular functions, induction of salt appetite, interaction with the vasoactive neuropeptides arginine vasopressin (AVP) and angiotensin II and development or aggravation of hypertension. In this regard, mineralocorticoids may play a pathogenic role in rats with a genetic form of hypertension (spontaneously hypertensive rats, SHR). Our objective was to compare the response of the hypothalamic vasopressinergic system to mineralocorticoid administration in SHR and control Wistar-Kyoto (WKY) rats. Sixteen-week-old male SHR showing a systolic blood pressure of 190 ± 5 mm Hg and normotensive WKY rats (130 ± 5 mm Hg) were treated subcutaneously with oil vehicle or a single 10-mg dose of deoxycorticosterone acetate (DOCA). After 2 h, rats were sacrificed and brains prepared for immunocytochemistry of Fos and vasopressin V1a receptor (V1aR) and for non-isotopic in situ hybridization of AVP mRNA. In the basal state, SHR demonstrated a higher number of AVP mRNA- and V1aR-immunopositive cells in the magnocellular division of the paraventricular hypothalamic nucleus (PVN) than WKY rats. After DOCA injection, SHR responded with a significant increase in both parameters with respect to vehicle-injected SHR. In WKY rats, DOCA was without effect on AVP mRNA although it increased the number of V1aR-positive cells. Changes in the number of Fos-positive nuclei were measured in the PVN, median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT), a circumventricular region showing anatomical connections with the PVN. In vehicle-injected rats, the PVN of SHR showed a higher number of Fos-positive nuclei than in WKY rats, whereas after DOCA treatment, a significant increment occurred in the OVLT but not in the PVN or MnPO of the SHR group only. These data suggest that the enhanced response of the vasopressinergic system to mineralocorticoids may contribute to the abnormal blood pressure of SHR.

Differential regulation of central vasopressin receptors in transgenic rats with low brain angiotensinogen

The consequences of permanent alteration to the brain renin–angiotensin system (RAS) on central vasopressinergic system was studied in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)]. Levels of vasopressin (AVP) and V1a receptor mRNAs were measured by ribonuclease protection assay (RPA) and AVP by radioimmunoassay (RIA). AVP (100 pmol/50nl) was microinjected into the nucleus tractus solitarii (NTS) of urethane-anesthetized TGR(ASrAOGEN) and Sprague–Dawley (SD) rats and the mean arterial pressure (MAP) and heart rate (HR) baroreflex induced by phenylephrine were evaluated. AVP but not its mRNA levels were significantly lower in the hypothalamus and hypophysis of TGR(ASrAOGEN) rats. Brainstem V1a mRNA levels were significantly higher in TGR(ASrAOGEN) in comparison to SD rats (5.2±0.4% vs. 3.3±0.2% of β-actin mRNA, P<0.05). In contrast, the hypothalamic V1a mRNA levels in TGR(ASrAOGEN) were not different from those found in SD rats. AVP microinjections induced a greater decrease in MAP in TGR(ASrAOGEN) in comparison with SD rats (−19.9±5.2 vs. −7.5±0.7 mm Hg, P<0.01). The significantly higher baroreflex sensitivity observed in TGR compared to that of SD rats was normalized after AVP microinjection. The increased brainstem V1a mRNA levels and sensitivity to AVP in TGR(ASrAOGEN) rats indicates a functional upregulation of AVP receptors in the NTS. The fact that the hypothalamic V1a mRNA levels are not altered indicates that these receptors are differentially regulated in different brain regions. This study demonstrates that a permanent deficit in brain angiotensinogen synthesis can alter the functionality of central vasopressinergic system.

Neonatal manipulations of oxytocin alter expression of oxytocin and vasopressin immunoreactive cells in the paraventricular nucleus of the hypothalamus in a gender-specific manner

Early postnatal manipulations of oxytocin have long-term behavioral and physiological consequences; the present study examined the hypothesis that oxytocin or its absence influences the subsequent expression of either oxytocin or arginine vasopressin in the CNS. On postnatal day 1 female and male prairie voles ( Microtus ochrogaster) received a single i.p. injection of oxytocin (3 μg), oxytocin antagonist (0.3 μg), or 50 μl of isotonic saline or were only handled. On postnatal days 1, 8 and 21, brains were fixed, sectioned and stained for oxytocin or vasopressin immunoreactivity and analyzed as a function of age, treatment and sex. Both oxytocin and vasopressin immunoreactivity were observed on day 1 in the supraoptic and paraventricular nuclei (PVN) of the hypothalamus. Numbers of oxytocin and vasopressin neurons increased with age in both nuclei. Females treated on postnatal day 1 with oxytocin or oxytocin antagonist displayed a significant increase in oxytocin immunoreactivity on day 21 in the PVN. In contrast, males treated with antagonist tended to have decreased vasopressin immunoreactivity in the same region. These results revealed that the effects of neonatal manipulation of oxytocin are age-dependent, site-specific and sexually dimorphic. The long-lasting effects of neonatal exposure to exogenous oxytocin and oxytocin antagonist indicate a role for oxytocin in the development of the CNS during the neonatal period, affecting the development of the oxytocinergic system in females and the vasopressinergic system in males. The developmental effects observed suggest one possible mechanism by which neonatal exposure to oxytocin or neonatal inhibition of endogenous oxytocin produces long-lasting behavioral and physiological alterations and could play a role in the development of male- and female-typical behavior.

Regulation of vasopressin secretion by ETA and ETB receptors in compartmentalized rat hypothalamo-neurohypophysial explants.

The endothelins (ET) have been implicated in vasopressin (AVP) release in vivo and in vitro. The effects of ET in this system are complex, and the net AVP secretory response likely depends on a unique combination of ET isoform, ET receptor subtype, and neural locus. The purpose of these studies was to examine the role of ET receptor subtypes at hypothalamic vs. neurohypophysial sites on somatodendritic and neurohypophysial AVP secretion. Experiments were done in cultured explants of the hypothalamo-neurohypophysial system of Long Evans rats. Either the whole explant (standard) or only the hypothalamus or posterior pituitary (compartmentalized) was exposed to log dose increases (0.01-10 nM) of the agonists ET-1 (ET(A) selective), ET-3 (nonselective), or IRL-1620 (ET(B) selective) with or without selective ET(A) (BQ-123, 2-200 nM) or ET(B) (IRL-1038, 6-600 nM) receptor antagonism. In standard explants, ET-1 and ET-3 dose-dependently increased, whereas IRL-1620 decreased net AVP release. Hypothalamic ET(B) receptor activation increased both somatodendritic and neurohypophysial AVP release. At least one intervening synapse was involved, as tetrodotoxin blocked the response. Activation of ET(A) receptors at the hypothalamic level inhibited, whereas ET(A) receptor activation at the posterior pituitary stimulated, neurohypophysial AVP secretion. Antagonism of hypothalamic ET(A) receptors potentiated the stimulatory effect of ET-1 and ET-3 on neurohypophysial secretion, an effect not observed with ET(B) receptor-induced somatodendritic release of AVP. Thus the response of whole explants reflects the net result of both stimulatory and inhibitory inputs. The integration of these excitatory and inhibitory inputs endows the vasopressinergic system with greater plasticity in its response to physiological and pathophysiological states.

Prenatal nicotine exposure and behavior.

Prenatal exposure to nicotine has been associated with changes in behavioral indices in offspring. Flank marking, a scent-marking behavior in golden hamsters, appears to be controlled by arginine vasopressin (AVP) neurons in the hypothalamus. The present study examines the effects of prenatal exposure to nicotine on the vasopressinergic system associated with flank marking behavior.

Effects of intracerebroventricularly injected glucagon-like peptide-1 on cardiovascular parameters; role of central cholinergic system and vasopressin

We aimed to investigate the effects of intracerebroventricularly (i.c.v.) injected glucagon-like peptide-1 (GLP-1) on blood pressure and heart rate, and whether central cholinergic system and vasopressinergic system play roles in these effects. Male Wistar albino rats were used throughout the experiments. Blood pressures and heart rates were observed before and for 30 min following drug injections. I.c.v. GLP-1 (100, 500 and 1000 ng/10 μl) caused a dose-dependent increase in both blood pressure and heart rate. Nicotinic receptor antagonist mecamylamine (25 μg/10 μl, i.c.v.) and muscarinic receptor antagonist atropine (5 μg/10 μl, i.c.v.) prevented the stimulating effect of GLP-1 on blood pressure. The effect of GLP-1 on heart rate was blocked only by mecamylamine. The V 1 receptor antagonist of vasopressin (B-mercapto B, B-cyclopentamethylenepropionyl, O-Me-Tyr,Arg)-vasopressin (10 μg/kg), that was applied intraarterially, only prevented the effect of GLP-1 on blood pressure, but did not show any effect on heart rate. Our data indicate that i.c.v. GLP-1 increases blood pressure and heart rate, and stimulation of central nicotinic and partially muscarinic receptors and vasopressinergic system play a role in the effects of i.c.v. GLP-1 on blood pressure. The effect of GLP-1 on heart rate may be partially due to stimulation of central nicotinic receptors.

Subchronic phencyclidine administration alters central vasopressin receptor binding and social interaction in the rat

Arginine vasopressin (AVP) is a peptide involved in social behaviors in rodents. To investigate the mechanism underlying the deficits in social behavior induced by blockade of N-methyl- d-aspartate (NMDA) receptors, this study examined the effect of noncompetitive NMDA antagonists on AVP receptor binding and social interaction in the rat. Subchronic phencyclidine (PCP) administration (2 mg/kg/day, 14 days, i.p.) significantly reduced the density of V1a receptor binding sites, labeled by an [ 125I]-Linear AVP antagonist, in several brain regions. Subchronic treatment with PCP or MK-801 (0.13 mg/kg/day, 14 days, i.p.) impaired social interactions in rats, as has been previously reported. These results suggest that NMDA antagonists have modulatory effects on the central vasopressinergic system and social interaction.

Effects of Acute Metabolic Stress on the Peripheral Vasopressinergic System in Schizophrenia

Although both vasopressin and stress have been implicated in the course of schizophrenia, it is unknown whether schizophrenic patients have altered stress-induced function of the vasopressinergic system. We examined the effects of acute metabolic stress induced by pharmacological doses (40 mg/kg) of 2-deoxyglucose (2DG) on plasma concentrations of vasopressin in 13 patients with schizophrenia (with no history of polydipsia and hyponatremia) and 12 healthy control subjects. Baseline vasopressin levels were lower in the schizophrenic patients and progressively increased in both groups throughout the 60 min following 2DG administration to a similar absolute amount, thus remaining lower in the schizophrenic group. Concomitantly, patients with schizophrenia had significantly higher 2DG-induced plasma homovanillic acid (HVA) and 5-hydroxyindoleacetic acid levels. Vasopressin responses correlated positively and significantly with the HVA responses in schizophrenics and with the pituitary-adrenal axis responses in controls. These results suggest two different patterns of neuroendocrine alterations in schizophrenia, namely a relatively normal vasopressin response to 2DG despite significantly decreased baseline levels and exaggerated responses of the peripheral dopaminegic and serotonergic systems in the face of normal baseline concentrations.

The vasopressin V1b receptor as a therapeutic target in stress-related disorders.

The complexity of the stress response would appear to provide multiple opportunities for intervention, but treatment strategies are often centered on the improvement of symptoms rather than attempting to "treat" the stress response. However, recent efforts have begun to focus on the development of pharmacological agents that can attenuate the stress response itself, rather than the symptoms associated with stress. Although CRF, which is the main regulator of the stress system, is the focus of current interest, there is an accumulating body of evidence suggesting that the vasopressinergic system may play an equal role in the regulation of the stress response, and that V(1b) receptor antagonists may be of potential therapeutic benefit. The availability of SSR149415, the first selective antagonist for the V(1b) receptor has allowed us to evaluate this hypothesis. SSR149415 is able to attenuate some but not all stress-related behaviors in rodents. While the antidepressant-like activity of the compound was comparable to that of reference antidepressants, the overall profile displayed in anxiety tests was different from that of classical anxiolytics, such as benzodiazepines. The latter were active in a wide range of anxiety models, whereas the V(1b) receptor antagonist showed clear-cut effects only in particularly stressful situations. It is important to note that SSR149415 is devoid of central depressant effects, even at high doses, and does not affect cognitive processes, suggesting a large therapeutic window. Altogether, these findings suggest that V(1b) receptor antagonists might be useful as a treatment for major depression and stress disorders that result from traumatic events.