Post-weaning social isolation exacerbates aggression in both sexes and affects the vasopressin and oxytocin system in a sex-specific manner.

Post-weaning social isolation (PWSI) is known to induce exaggerated and abnormal aggression in male rats. Here we aimed to assess the effects of PWSI on aggressiveness and social behavior in both male and female rats. Furthermore, we evaluated how PWSI affects the central oxytocin (OXT) and vasopressin (AVP) systems in both sexes. Wistar rats were isolated (IS) or group housed (GH) in same-sex groups immediately after weaning. After seven weeks, rats underwent an intruder test to assess aggression. In one group, brains were immediately dissected afterwards for in situ hybridization and receptor autoradiography. The other group underwent additional anxiety-like and social behavior tests. PWSI induced increased (abnormal) aggression and impaired social memory in both sexes. Especially IS females exhibited abnormal aggression towards juveniles. Furthermore, PWSI increased OXT mRNA expression in the paraventricular nucleus of the hypothalamus (PVN) and decreased OXTR binding in the anterior portion of the nucleus accumbens (NAcc), independent of the sex. V1a receptor binding was decreased in the lateral hypothalamus (LH) and dentate gyrus (DG) in IS rats, regardless of sex. However, V1a receptor binding in the anterior portion of the bed nucleus of stria terminalis (BNSTa) was decreased in IS females but increased in IS males. Taken together, our data support PWSI as a reliable model to exacerbate aggression not only in male but also in female rats. In addition, OXT receptors in the NAcca and V1a receptors in the LH, DG, and BNSTa may play a role in the link between PWSI and aggression. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

Vasopressin and the Regulation of Thirst.

Recent experiments using optogenetic tools allow the identification and functional analysis of thirst neurons and vasopressin producing neurons. Two major advances provide a detailed anatomy of taste for water and arginine-vasopressin (AVP) release: (1) thirst and AVP release are regulated not only by the classical homeostatic, intero-sensory plasma osmolality negative feedback, but also by novel, extero-sensory, anticipatory signals. These anticipatory signals for thirst and vasopressin release converge on the same homeostatic neurons of circumventricular organs that monitor the composition of the blood; (2) acid-sensing taste receptor cells (which express polycystic kidney disease 2-like 1 protein) on the tongue that were previously suggested as the sour taste sensors also mediate taste responses to water. The tongue has a taste for water. The median preoptic nucleus (MnPO) of the hypothalamus could integrate multiple thirst-generating stimuli including cardiopulmonary signals, osmolality, angiotensin II, oropharyngeal and gastric signals, the latter possibly representing anticipatory signals. Dehydration is aversive and MnPO neuron activity is proportional to the intensity of this aversive state.

Suprachiasmatic vasopressin to paraventricular oxytocin neurocircuit in the hypothalamus relays light reception to inhibit feeding behavior.

Light synchronizes the body's circadian rhythms by modulating the master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. In modern lifestyles that run counter to normal circadian rhythms, the extended and/or irregular light exposure impairs circadian rhythms and, consequently, promotes feeding and metabolic disorders. However, the neuronal pathway through which light is coupled to feeding behavior is less elucidated. The present study employed the light exposure during the dark phase of the day in rats and observed its effect on neuronal activity and feeding behavior. Light exposure acutely suppressed food intake and elevated c-Fos expression in the AVP neurons of SCN and the oxytocin (Oxt) neurons of paraventricular nucleus (PVN) in the hypothalamus. The light-induced suppression of food intake was abolished by blockade of the Oxt receptor in the brain. Retrograde tracer analysis demonstrated the projection of SCN AVP neurons to the PVN. Furthermore, intracerebroventricular injection of AVP suppressed food intake and increased c-Fos in PVN Oxt neurons. Intra-PVN injection of AVP exerted a stronger anorexigenic effect than intracerebroventriclar injection. AVP also induced intracellular Ca2+ signaling and increased firing frequency in Oxt neurons in PVN slices. These results reveal the novel neurocircuit from SCN AVP to PVN Oxt that relays light reception to inhibition of feeding behavior. This light-induced neurocircuit may serve as a pathway for forming the circadian feeding rhythm and linking irregular light exposure to arrhythmic feeding and, consequently, obesity and metabolic diseases.

Serotonin and arginine-vasopressin mediate sex differences in the regulation of dominance and aggression by the social brain.

There are profound sex differences in the incidence of many psychiatric disorders. Although these disorders are frequently linked to social stress and to deficits in social engagement, little is known about sex differences in the neural mechanisms that underlie these phenomena. Phenotypes characterized by dominance, competitive aggression, and active coping strategies appear to be more resilient to psychiatric disorders such as posttraumatic stress disorder (PTSD) compared with those characterized by subordinate status and the lack of aggressiveness. Here, we report that serotonin (5-HT) and arginine-vasopressin (AVP) act in opposite ways in the hypothalamus to regulate dominance and aggression in females and males. Hypothalamic injection of a 5-HT1a agonist stimulated aggression in female hamsters and inhibited aggression in males, whereas injection of AVP inhibited aggression in females and stimulated aggression in males. Striking sex differences were also identified in the neural mechanisms regulating dominance. Acquisition of dominance was associated with activation of 5-HT neurons within the dorsal raphe in females and activation of hypothalamic AVP neurons in males. These data strongly indicate that there are fundamental sex differences in the neural regulation of dominance and aggression. Further, because systemically administered fluoxetine increased aggression in females and substantially reduced aggression in males, there may be substantial gender differences in the clinical efficacy of commonly prescribed 5-HT-active drugs such as selective 5-HT reuptake inhibitors. These data suggest that the treatment of psychiatric disorders such as PTSD may be more effective with the use of 5-HT-targeted drugs in females and AVP-targeted drugs in males.

Arginine vasotocin and androgen pathways are associated with mating system variation in North American cichlid fishes.

Neuroendocrine pathways that regulate social behavior are remarkably conserved across divergent taxa. The neuropeptides arginine vasotocin/vasopressin (AVT/AVP) and their receptor V1a mediate aggression, space use, and mating behavior in male vertebrates. The hormone prolactin (PRL) also regulates social behavior across species, most notably paternal behavior. Both hormone systems may be involved in the evolution of monogamous mating systems. We compared AVT, AVT receptor V1a2, PRL, and PRL receptor PRLR1 gene expression in the brains as well as circulating androgen concentrations of free-living reproductively active males of two closely related North American cichlid species, the monogamous Herichthys cyanoguttatus and the polygynous Herichthys minckleyi. We found that H. cyanoguttatus males bond with a single female and together they cooperatively defend a small territory in which they reproduce. In H. minckleyi, a small number of large males defend large territories in which they mate with several females. Levels of V1a2 mRNA were higher in the hypothalamus of H. minckleyi, and PRLR1 expression was higher in the hypothalamus and telencephalon of H. minckleyi. 11-ketotestosterone levels were higher in H. minckleyi, while testosterone levels were higher in H. cyanoguttatus. Our results indicate that a highly active AVT/V1a2 circuit(s) in the brain is associated with space use and social dominance and that pair bonding is mediated either by a different, less active AVT/V1a2 circuit or by another neuroendocrine system.

Neuropeptide W stimulates adrenocorticotrophic hormone release via corticotrophin-releasing factor but not via arginine vasopressin.

Neuropeptide W (NPW) was isolated as an endogenous ligand for NPBWR1, an orphan G protein-coupled receptor localized in the rat brain, including the paraventricular nucleus. It has been reported that central administration of NPW stimulates corticosterone secretion in rats. We hypothesized that NPW activates the hypothalamic-pituitary-adrenal (HPA) axis via corticotrophin-releasing factor (CRF) and/or arginine vasopressin (AVP). NPW at 1 pM to 10 nM did not affect basal or ACTH-induced corticosterone release from dispersed rat adrenocortical cells, or basal and CRF-induced ACTH release from dispersed rat anterior pituitary cells. In conscious and unrestrained male rats, intravenous administration of 2.5 and 25 nmol NPW did not affect plasma ACTH levels. However, intracerebroventricular (icv) administration of 2.5 and 5.0 nmol NPW increased plasma ACTH levels in a dose-dependent manner at 15 min after stimulation (5.0 vs. 2.5 nmol NPW vs. vehicle: 1802 ± 349 vs. 1170 ± 204 vs. 151 ± 28 pg/mL, respectively, mean ± SEM). Pretreatment with astressin, a CRF receptor antagonist, inhibited the increase in plasma ACTH levels induced by icv administration of 2.5 nmol NPW at 15 min (453 ± 176 vs. 1532 ± 343 pg/mL, p<0.05) and at 30 min (564 ± 147 vs. 1214 ± 139 pg/mL, p<0.05) versus pretreatment with vehicle alone. However, pretreatment with [1-(ß-mercapto-ß, ß-cyclopentamethylenepropionic acid), 2-(Ο-methyl)tyrosine]-arg-vasopressin, a V1a/V1b receptor antagonist, did not affect icv NPW-induced ACTH release at any time (p>0.05). In conclusion, we suggest that central NPW activates the HPA axis by activating hypothalamic CRF but not AVP.

Vasopressin and oxytocin excite MCH neurons, but not other lateral hypothalamic GABA neurons.

Neurons that synthesize melanin-concentrating hormone (MCH) colocalize GABA, regulate energy homeostasis, modulate water intake, and influence anxiety, stress, and social interaction. Similarly, vasopressin and oxytocin can influence the same behaviors and states, suggesting that these neuropeptides may exert part of their effect by modulating MCH neurons. Using whole cell recording in MCH-green fluorescent protein (GFP) transgenic mouse hypothalamic brain slices, we found that both vasopressin and oxytocin evoked a substantial excitatory effect. Both peptides reversibly increased spike frequency and depolarized the membrane potential in a concentration-dependent and tetrodotoxin-resistant manner, indicating a direct effect. Substitution of lithium for extracellular sodium, Na(+)/Ca(2+) exchanger blockers KB-R7943 and SN-6, and intracellular calcium chelator BAPTA, all substantially reduced the vasopressin-mediated depolarization, suggesting activation of the Na(+)/Ca(2+) exchanger. Vasopressin reduced input resistance, and the vasopressin-mediated depolarization was attenuated by SKF-96265, suggesting a second mechanism based on opening nonselective cation channels. Neither vasopressin nor oxytocin showed substantial excitatory actions on lateral hypothalamic inhibitory neurons identified in a glutamate decarboxylase 67 (GAD67)-GFP mouse. The primary vasopressin receptor was vasopressin receptor 1a (V1aR), as suggested by the excitation by V1aR agonist [Arg(8)]vasotocin, the selective V1aR agonist [Phe(2)]OVT and by the presence of V1aR mRNA in MCH cells, but not in other nearby GABA cells, as detected with single-cell RT-PCR. Oxytocin receptor mRNA was also detected in MCH neurons. Together, these data suggest that vasopressin or oxytocin exert a minimal effect on most GABA neurons in the lateral hypothalamus but exert a robust excitatory effect on presumptive GABA cells that contain MCH. Thus, some of the central actions of vasopressin and oxytocin may be mediated through MCH cells.

Involvement of arginine vasopressin and V1b receptor in alcohol drinking in Sardinian alcohol-preferring rats.

BACKGROUND: Recent animal studies have shown that the level of stress-responsive arginine vasopressin (AVP) gene expression in the amygdala is increased during early withdrawal from long-term heroin or cocaine administration. The selective AVP V1b receptor antagonist SSR149415 (capable of exerting antidepressant-like and anxiolytic effects in animal models) also blocked stress-induced reinstatement of drug-seeking behavior. This study was undertaken to investigate the effects of alcohol and to determine whether (i) there are genetically determined differences in basal AVP mRNA levels in the medial/central amygdala (Me/CeA) and medial hypothalamus (MH) between selectively bred Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats; (ii) the AVP mRNA levels are altered by long-term alcohol drinking in sP rats; and (iii) the V1b receptor antagonist SSR149415 alters alcohol drinking in sP rats. METHODS: In Experiment 1, AVP mRNA levels were measured in the Me/CeA and MH of alcohol-naïve sP and sNP rats, and sP rats exposed to the standard, homecage 2-bottle "alcohol versus water" choice regimen 24 h/d for 17 days. In Experiment 2, SSR149415 (0, 3, 10, or 30 mg/kg; intraperitoneal) was acutely administered 30 minutes before lights off to alcohol-experienced sP rats. Alcohol, water, and food intake were monitored 6 and 24 hours later. RESULTS: We found higher basal AVP mRNA levels in both Me/CeA and MH of alcohol-naïve sP than sNP rats; alcohol consumption decreased AVP mRNA levels in both brain regions of sP rats, suggesting genetically determined differences between the 2 rat lines and in the effects of alcohol drinking in sP rats. Acute treatment with SSR149415 significantly reduced alcohol intake of sP rats. CONCLUSION: The stress-responsive AVP/V1b receptor system is 1 component of the neural circuitry underlying high alcohol drinking in sP rats.

Vasopressin cell groups exhibit strongly divergent responses to copulation and male-male interactions in mice.

Arginine vasopressin (AVP) and its nonmammalian homolog arginine vasotocin influence social behaviors ranging from affiliation to resident-intruder aggression. Although numerous sites of action have been established for these behavioral effects, the involvement of specific AVP cell groups in the brain is poorly understood, and socially elicited Fos responses have not been quantified for many of the AVP cell groups found in rodents. Surprisingly, this includes the AVP population in the posterior part of the medial bed nucleus of the stria terminalis (BSTMP), which has been extensively implicated, albeit indirectly, in various aspects of affiliation and other social behaviors. We examined the Fos responses of eight hypothalamic and three extra-hypothalamic AVP-immunoreactive (-ir) cell groups to copulation, nonaggressive male-male interaction, and aggressive male-male interaction in both dominant and subordinate C57BL/6J mice. The BSTMP cells exhibited a response profile that was unlike all other cell groups: from a control baseline of approximately 5% of AVP-ir neurons colocalizing with Fos, colocalization increased significantly to approximately 12% following nonaggressive male-male interaction, and to approximately 70% following copulation. Aggressive interactions did not increase colocalization beyond the level observed in nonaggressive male mice. These results suggest that BSTMP neurons in mice may increase AVP-Fos colocalization selectively in response to affiliation-related stimuli, similar to findings in finches. In contrast, virtually all other cell groups were responsive to negative aspects of interaction, either through elevated AVP-Fos colocalization in subordinate animals, positive correlations of AVP-Fos colocalization with bites received, and/or negative correlations of AVP-Fos colocalization with dominance. These findings greatly expand what is known of the contributions of specific brain AVP cell groups to social behavior.

[Vasopressin and angiogenesis]. / Vasopressine et angiogenèse.

In adult mammals, the CNS vasculature remains essentially quiescent, excepted for specific pathologies. In the seventies, it was reported that proliferation of astrocytes and endothelial cells occurs within the hypothalamic magnocellular nuclei when strong metabolic activation of the vasopressinergic and oxytocinergic neurons was induced by prolonged hyperosmotic stimulation. Using more appropriate techniques, we first demonstrated that in these nuclei, the proliferative response to osmotic stimulus is essentially associated with local angiogenesis. We then showed that hypothalamic magnocellular neurons express vascular endothelial growth factor (VEGF), a potent angiogenic factor, that plays a major rôle in the angiogenesis induced by osmotic stimuli. We then demonstrated a correlation between increased VEGF secretion and local hypoxia. In AVP-deficient Brattleboro rats, the dramatic activation of magnocellular hypothalamic neurons failed to induce hypoxia, VEGF expression or angiogenesis suggesting a major role of hypothalamic AVP. Lastly we showed that 1) hypoxia and angiogenesis were not observed in non-osmotically stimulated Wistar rats in which circulating AVP was increased by the prolonged infusion of exogenous AVP, 2) contractile arterioles afferent to the magnocellular nuclei were strongly constricted by the perivascular application of AVP via V1a receptors (V1a-R) stimulation, and 3) following the intracerebral administration of selective V1a-R antagonist to osmotically stimulated rats, hypothalamic hypoxia and angiogenesis were inhibited. Together, these data strongly suggest that the angiogenesis induced by osmotic stimulation relates to tissue hypoxia resulting from the constriction of local arterioles, via the stimulation of perivascular V1a-R by AVP locally released from dendrites.

Regulatory mechanisms underlying corticotropin-releasing factor gene expression in the hypothalamus.

The hypothalamic-pituitary-adrenal (HPA) axis is activated under various stressors. Corticotropin-releasing factor (CRF) plays a central role in controlling stress response, and regulating the HPA axis. CRF, produced in the hypothalamic paraventricular nucleus (PVN), stimulates adrenocorticotropic hormone (ACTH) production via CRF receptor type 1 (CRF(1) receptor) from the corticotrophs of the anterior pituitary (AP). Cyclic AMP (cAMP)-protein kinase A (PKA) pathway takes a main role in stimulating CRF gene transcription. Forskolin and pituitary adenylate cyclase-activating polypeptide (PACAP) stimulate adenylate cyclase, intracellular cAMP production, and then CRF and arginine vasopressin (AVP) gene expression in hypothalamic 4B cells. Interleukin (IL)-6, produced in the PVN, both directly and indirectly stimulates CRF and AVP gene expression. Estradiol may enhance the activation of CRF gene expression in response to stress. The HPA axis is regulated by a negative feedback mechanism, because glucocorticoids inhibit both CRF production in the hypothalamic PVN and ACTH production in the pituitary. Hypothalamic parvocellular neurons in the PVN are known to express glucocorticoid receptors, and glucocorticoids are able to regulate CRF gene transcription and expression levels directly in the PVN. Glucocorticoids-dependent repression of cAMP-stimulated CRF promoter activity is mainly localized to promoter sequences between -278 and -233 bp. Both negative glucocorticoid regulatory element (nGRE) and serum response element (SRE) are involved in the repression of the CRF gene in the hypothalamic cells.

Cannabinoid-mediated regulation of the hypothalamo-pituitary-adrenal axis in rats: age dependent role of vasopressin.

OBJECTIVE: Adaptation to stress is a fundamental component of life and the hypothalamo-pituitary-adrenocortical axis (HPA) plays a crucial role in it. The place of cannabinoid influence seems to be in the brain, especially where corticotropin releasing hormone and vasopressin (AVP) secreting neurons are located. The role of AVP is considered to be more important in young than in adult rats. Here we addressed the question if cannabinoid-mediated regulation of the HPA involves AVP and if there is any difference between young and adult rats in this process. METHODS: 10-day-old and adult AVP deficient Brattleboro rats were compared with their heterozygous littermates 1h after WIN 55,212-2 (6mg/kg i.p.) injection. RESULTS: In control animals the injection led to elevated adrenocorticotropin (ACTH) and corticosterone hormone levels at both ages without remarkable age difference in ACTH levels while all corticosterone levels of adults was approximately 10-times higher. The ACTH secretion of young AVP deficient rats failed to react to WIN 55,212-2 injection while their corticosterone levels were even higher than their littermates. In contrast in adult the role of AVP was diminished. CONCLUSIONS: We can conclude that the peripheral administration of cannabinoids leads to HPA axis stimulation, which process involves AVP at least in the young rats. The discrepancy between ACTH and corticosterone levels in young rats suggests an alternative adrenal gland regulatory pathway, which might be present in all studied animals. However, it comes to the front just in AVP deficient pups.

Characterization of a novel and selective V1B receptor antagonist.

It has been argued that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a major biological abnormality in patients suffering from psychiatric conditions such as major depression. Both arginine vasopressin (AVP) and corticotrophin releasing factor (CRF) are responsible for stimulating the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. CRF is thought to be the predominant secretagogue under normal conditions but AVP may play a more important role in situations of aberrant/chronic stress. Studies in patients suffering from melancholic depression indicate a hyper-responsiveness to agonism at the vasopressin receptor type 1B (V(1B)); patients display a heightened ACTH release after challenge with the mixed V(1B)/V(2) (vasopressin receptor type 2) agonist desmopressin in comparison to control subjects. A V(1B) antagonist has been developed which has significant selectivity for the human V(1B) receptor over the other members of the vasopressin receptor sub-family. The compound acts as an effective antagonist at both the human recombinant receptor (stably expressed in Chinese hamster ovary (CHO) cells) and the native rat V(1B) receptor (using isolated anterior pituitary cells), blocking the induction of luciferase and the release of ACTH, respectively. In vivo the compound can block the release of ACTH after challenge with a variety of V(1B) agonists. It can also attenuate the ACTH response to acute stressors in rats. Interestingly, this compound does not modulate the activity of the HPA axis under normal basal conditions.

Intrahypothalamic angiogenesis induced by osmotic stimuli correlates with local hypoxia: a potential role of confined vasoconstriction induced by dendritic secretion of vasopressin.

We have previously shown that hyperosmotic stimulation of adult Wistar rats induces local angiogenesis within hypothalamic magnocellular nuclei, in relation to the secretion of vascular endothelial growth factor (VEGF) by the magnocellular neurons. The present study aimed at understanding how osmotic stimulus relates to increased VEGF secretion. We first demonstrate a correlation between increased VEGF secretion and local hypoxia. Osmotic stimulation is known to stimulate the metabolic activity of hypothalamic magnocellular neurons producing arginine vasopressin (AVP) and to increase the secretion of AVP, both by axon terminals into the circulation and by dendrites into the extracellular space. In AVP-deficient Brattleboro rats, the dramatic activation of magnocellular hypothalamic neurons failed to induce hypoxia, VEGF expression, or angiogenesis, suggesting a major role of hypothalamic AVP. A possible involvement of dendritic AVP release is supported by the findings that 1) hypoxia and angiogenesis were not observed in non osmotically stimulated Wistar rats in which circulating AVP was increased by the prolonged infusion of exogenous AVP, 2) contractile arterioles afferent to the magnocellular nuclei were strongly constricted by the perivascular application of AVP via V1a receptors (V1a-R) stimulation, and 3) after the intracerebral or ip administrations of selective V1a-R antagonists to osmotically stimulated rats, hypothalamic hypoxia and angiogenesis were or were not inhibited, respectively. Together, these data strongly suggest that the angiogenesis induced by osmotic stimulation relates to tissue hypoxia resulting from the constriction of local arterioles, via the stimulation of perivascular V1a-R by AVP locally released from dendrites.

Congenital vasopressin deficiency and acute and chronic opiate effects on hypothalamo-pituitary-adrenal axis activity in Brattleboro rats.

A growing body of evidence suggests that vasopressinergic activity in the hypothalamus is important in stress-related behaviors (like drug abuse) in line with a role in the regulation of the hypothalamo-pituitary-adrenal axis (HPA). We hypothesized that in the naturally vasopressin-deficient Brattleboro rat, acute and chronic morphine treatment may lead to reduced HPA axis activity. Rats were treated either with a single dose of morphine (10 mg/kg subcutaneously) and serial blood samples were taken or were treated twice daily with increasing doses of morphine (10-100 mg/kg subcutaneously) for 16 days and animals were killed by decapitation 4 or 16 h after the last injection. Single morphine injection induced a biphasic ACTH and corticosterone elevation with smaller increases in vasopressin-deficient rats. Chronic morphine treatment induced the typical somatic and HPA axis changes of chronic stress; the absence of vasopressin did not prevent these changes. In rats repeatedly treated with morphine plasma, ACTH and corticosterone levels were elevated both 4 and 16 h after the last injection (short and long withdrawal) and the absence of vasopressin attenuated this response. Our data suggest that vasopressin plays a prominent role in morphine treatment and withdrawal-induced acute hormonal changes, but does not affect development of chronic hyperactivity of the HPA axis.

Cardiovascular and endocrine responses to 90 degree tilt during a 35-day saturation dive to 46 and 37 ATA.

INTRODUCTION: Hyperbaria-induced diuresis is accompanied by decreased basal and stimulated release of arginine vasopressin (AVP) and decreased blood volume possibly contributing to the reported orthostatic intolerance. Since hyperosmolality is not a consistent finding, the explanation of blood volume reduction at hyperbaria must involve an osmotic component to the diuresis. Investigations of a possible involvement of atrial natriuretic peptide (ANP) to the hyperbaric diuresis have revealed mixed results. METHODS: Urinary excretion of electrolytes, AVP, and aidosterone were measured in four male subjects studied at 1 atmosphere absolute (ATA) and at 46 and 37 ATA (0.5 atmospheres pressure O2: 5% N2: remainder He) during a 35-d saturation dive. Also, the supine and 90 degrees tilt-stimulated plasma levels of AVP, plasma renin activity (PRA), and aldosterone, and the suppressed responses of ANP and the cardiovascular responses to tilt were determined at these pressures. RESULTS: Tilt-stimulated levels of PRA were increased two- to threefold and the AVP response was eliminated throughout hyperbaria, except in two episodes of tilt-induced syncope where AVP was elevated 10- to 20-fold. This pattern supports most previous reports. Contrary to some reports, both supine and tilt-suppressed levels of ANP were reduced by about 50% at all three tilt experiments conducted at hyperbaria compared to predive control values. DISCUSSION: These results suggest an altered ANP response at pressures of 37 ATA or greater, which is consistent with an appropriate ANP response to blood volume reduction and further suggest that the hyperbaric diuresis is not dependent on increased ANP.

The effects of chronic administration of established and putative antipsychotics on natural prepulse inhibition deficits in Brattleboro rats.

We previously reported that vasopressin deficient Brattleboro (BRAT) rats exhibit deficits in prepulse inhibition (PPI) of the startle reflex that are consistent with PPI deficits exhibited by patients with schizophrenia and other neuropsychiatric disorders. Preliminary evidence indicates that this may be the basis of a predictive model for antipsychotic drug efficacy. Here we report the effects of acute and chronic administration of established and putative antipsychotics on these PPI deficits. BRAT rats, compared to their derivative strain, Long Evans rats, exhibited significantly decreased PPI and startle habituation consistent with patients with schizophrenia and other neuropsychiatric disorders. The second generation antipsychotics, risperidone and clozapine as well as a neurotensin agonist (PD149163) increased BRAT rat PPI, whereas saline, the typical antipsychotic, haloperidol, and a vasopressin analog (1-desamino-D-arginine vasopressin) did not. Similar to their effects in humans, chronic administration of antipsychotic drugs produced stronger effects than acute administration. These results further support the BRAT rat as a model of sensorimotor gating deficits with predictive validity for antipsychotics. The model appears to be able to differentiate first generation from second generation antipsychotics, identify putative antipsychotics with novel mechanisms (i.e., peptides) and reasonably model the therapeutic time course of antipsychotic drugs in humans.

The effects of cross-fostering on inherent sensorimotor gating deficits exhibited by Brattleboro rats.

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating, a process critical to normal cognitive function. Researchers (D. Feifel & K. Priebe, 2001) have identified PPI deficits in the Brattleboro rat, a genetically vasopressin-deficient strain that is derived from the Long Evans rat. The absence of vasopressin, a neuropeptide involved in affiliative behaviors, may adversely affect the rearing of offspring by Brattleboro dams, perhaps accounting for their attenuated PPI. Cross-fostering of Long Evans and Brattleboro pups did not alter the PPI deficits in Brattleboro rats. However, the magnitude and habituation of the startle response, which normally differs between Brattleboro and Long Evans rats, was not different in cross-fostered rats. The authors' results indicated that abnormal rearing by Brattleboro dams may contribute to the startle magnitude and habituation abnormalities in Brattleboro Rats but not to their PPI deficits, suggesting that their sensorimotor gating deficits result from their genetic deviation from Long Evans rats.

Interaction between arginine vasopressin and angiotensin II receptors in the central regulation of sodium balance.

We speculated that the influence of lateral preoptic area (LPO) in sodium balance, involves arginine8-vasopressin (AVP) and angiotensin (ANG II) on Na+ uptake in LPO. Therefore, the present study investigated the effects of central administration of specific AVP and ANG II antagonists (d(CH2)5-Tyr (Me)-AVP (AAVP) and [Adamanteanacetyl1, 0-ET-d-Tyr2, Val4, Aminobutyryl6, Arg(8,9)]-AVP (ATAVP) antagonists of V1 and V2 receptors of AVP. Also the effects of losartan and CGP42112A (selective ligands of the AT1 and AT2 angiotensin receptors, respectively), was investigated on Na+ uptake and renal fluid and electrolyte excretion. After an acclimatization period of 7 days, the animals were maintained under tribromoethanol (200 mg/kg body weight, intraperitonial) anesthesia and placed in a Kopf stereotaxic instrument. Stainless guide cannula was implanted into the LPO. AAVP and ATAVP injected into the LPO prior to AVP produced a reduction in the NaCl intake. Both the AT1 and AT2 ligands administered into the LPO elicited a decrease in the NaCl intake induced by AVP injected into the LPO. AVP injection into the LPO increased sodium renal excretion, but this was reduced by prior AAVP administration. The ATAVP produced a decreased in the natriuretic effect of AVP. The losartan injected into LPO previous to AVP decreased the sodium excretion and the CGP 421122A also decreased the natriuretic effect of AVP. The AVP produced an antidiuresis effect that was inhibited by prior administration into LPO of the ATAVP. The AAVP produced no change in the antidiuretic effect of AVP. These results suggest that LPO are implicated in sodium balance that is mediated by V1, V2, AT1 and AT2 receptors.

Effect of photoperiod on vasopressin-induced aggression in Syrian hamsters.

Syrian hamsters are photoperiodic and become sexually quiescent when exposed to short "winter-like" photoperiods. In short photoperiods, male hamsters display significantly higher levels of aggression than males housed in long photoperiods. Arginine-vasopressin (AVP) within the anterior hypothalamus (AH) has been reported to modulate aggression in hamsters housed in long photoperiods. Previous studies have shown that AVP can facilitate aggression and its effects appear to be mediated by AVP V(1a) receptors (V(1a)R). In the present study, we investigated whether the increased levels of aggression observed after exposure to short photoperiod were the result of an increased responsiveness to AVP within the AH. Injections of AVP into the AH significantly increased aggression in hamsters housed in a long photoperiod, but had no effect in hamsters housed in a short photoperiod. In addition, injection of a V(1a)R antagonist into the AH significantly inhibited aggression in hamsters housed in long photoperiod, but had no effect in hamsters housed in a short photoperiod. These findings indicate that AVP within the AH increases aggression in hamsters housed in long photoperiods, but not in hamsters housed in short photoperiods.