Vasopressin as a Possible Link between Sleep-Disturbances and Memory Problems.

Normal biological rhythms, including sleep, are very important for a healthy life and their disturbance may induce-among other issues-memory impairment, which is a key problem of many psychiatric pathologies. The major brain center of circadian regulation is the suprachiasmatic nucleus, and vasopressin (AVP), which is one of its main neurotransmitters, also plays a key role in memory formation. In this review paper, we aimed to summarize our knowledge on the vasopressinergic connection between sleep and memory with the help of the AVP-deficient Brattleboro rat strain. These animals have EEG disturbances with reduced sleep and impaired memory-boosting theta oscillation and show memory impairment in parallel. Based upon human and animal data measuring AVP levels, haplotypes, and the administration of AVP or its agonist or antagonist via different routes (subcutaneous, intraperitoneal, intracerebroventricular, or intranasal), V1a receptors (especially of hippocampal origin) were implicated in the sleep-memory interaction. All in all, the presented data confirm the possible connective role of AVP between biological rhythms and memory formation, thus, supporting the importance of AVP in several psychopathological conditions.

Ameliorating schizophrenia-like symptoms in vasopressin deficient male Brattleboro rat by chronic antipsychotic treatment.

Due to its various function vasopressin has been associated with many psychiatric disorders, including schizophrenia. Our previous study confirmed that vasopressin-deficient (di/di) Brattleboro rat can be a good genetic model for schizophrenia. Our present aim was to confirm whether the treatment effects of marketed antipsychotics are similar in di/di rats to those seen in human schizophrenic patients. Chronic subcutaneous administration of aripiprazole (5 mg/kg), clozapine (1 mg/kg), haloperidol (0.1 mg/kg), olanzapine (0.3 mg/kg) or risperidone (0.25 mg/kg) was used for 15 days in control (+/+ Brattleboro) and di/di rats. Social discrimination, social avoidance and prepulse inhibition tests were conducted on day 1, 8 and 15 of the treatment. Vasopressin-deficient rats showed social memory- and sensorimotor gating deficit. All used antipsychotics successfully normalized the reduced prepulse inhibition of di/di animals. However, most were effective only after prolonged treatment. Aripiprazole, clozapine, and olanzapine normalized the social memory deficit, while the effects of haloperidol and risperidone were not unequivocal. All drugs reduced social interest to some extent both in control and in di/di animals, aripiprazole being the less implicated in this regard during the social avoidance test. The restoration of schizophrenia-like behavior by antipsychotic treatment further support the utility of the vasopressin-deficient Brattleboro rat as a good preclinical model. Reduced social interest might be a general side-effect of antipsychotics, and aripiprazole has the most favorable profile in this regard.

The Effect of Vasopressin Antagonists on Maternal-Separation-Induced Ultrasonic Vocalization and Stress-Hormone Level Increase during the Early Postnatal Period.

In adults, vasopressin exerts an anxiogenic effect, but less is known about the perinatal period. As a sign of distress, rat pups emit ultrasonic vocalizations when they are separated from their mothers, known as maternal separation-induced ultrasonic vocalization (MS-USV). Previously, reduced MS-USV was reported in 7-8-day-old genetically vasopressin-deficient Brattleboro rats. Here, we aimed to examine the contributing vasopressin receptor (VR) subtypes using Wistar pups. MS-USV was recorded for 10 min, 30 min after vasopressin (V) 1aR, V1bR or V2R antagonist treatment (SR49059, SSR149415, SR121463B; 3, 10 and 30 mg/kg, intraperitoneal). Sedation was studied by the righting reflex and negative geotaxis, and finally, the stress hormone levels were measured by radioimmunoassay. The vasopressin-deficient pups showed decreased MS-USV and adrenocorticotropin levels even after a saline injection, with unchanged corticosterone levels. Thirty mg/kg of V1aR-antagonist increased the corticosterone levels. All V1bR antagonist doses decreased the MS-USV and adrenocorticotropin, while 10 + 10 mg/kg of V1aR and V1bR antagonists decreased MS-USV without influencing the stress hormones. Three mg/kg of V2R antagonist enhanced MS-USV, while 30 mg/kg increased the stress hormone levels. We confirmed that vasopressin deficiency already caused anxiolytic effects in pups. V1bRs are the most important player in connection with their adrenocorticotropin (ACTH)-regulatory role, but a combination of V1aR and V1bR antagonists might be also beneficial through other mechanisms, reducing the possibility of side effects. In contrast, antagonizing the V2Rs may be stressful due to an induction of imbalance in saltwater homeostasis.

Colocalized neurotransmitters in the hindbrain cooperate in adaptation to chronic hypernatremia.

Chronic hypernatremia activates the central osmoregulatory mechanisms and inhibits the function of the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline (NE) release into the periventricular anteroventral third ventricle region (AV3V), the supraoptic (SON) and hypothalamic paraventricular nuclei (PVN) from efferents of the caudal ventrolateral (cVLM) and dorsomedial (cDMM) medulla has been shown to be essential for the hypernatremia-evoked responses and for the HPA response to acute restraint. Notably, the medullary NE cell groups highly coexpress prolactin-releasing peptide (PrRP) and nesfatin-1/NUCB2 (nesfatin), therefore, we assumed they contributed to the reactions to chronic hypernatremia. To investigate this, we compared two models: homozygous Brattleboro rats with hereditary diabetes insipidus (DI) and Wistar rats subjected to chronic high salt solution (HS) intake. HS rats had higher plasma osmolality than DI rats. PrRP and nesfatin mRNA levels were higher in both models, in both medullary regions compared to controls. Elevated basal tyrosine hydroxylase (TH) expression and impaired restraint-induced TH, PrRP and nesfatin expression elevations in the cVLM were, however, detected only in HS, but not in DI rats. Simultaneously, only HS rats exhibited classical signs of chronic stress and severely blunted hormonal reactions to acute restraint. Data suggest that HPA axis responsiveness to restraint depends on the type of hypernatremia, and on NE capacity in the cVLM. Additionally, NE and PrRP signalization primarily of medullary origin is increased in the SON, PVN and AV3V in HS rats. This suggests a cooperative action in the adaptation responses and designates the AV3V as a new site for PrRP's action in hypernatremia.

Mutation in the vasopressin gene eliminates the sex difference in social reinforcement in adolescent rats.

The neuropeptide, arginine vasopressin (AVP), is thought to contribute to sex differences in normative and pathological social development by regulating social motivation. Recent studies using Brattleboro rats that have a mutation in the Avp gene, however, have suggested that AVP impacts adolescent social behaviors of males and females in a similar manner through actions on behavioral state (i.e., arousal). In the present study, we made use of a recently developed operant conditioning paradigm to test whether the chronic, lifelong AVP deficiency caused by the Brattleboro mutation impacts the reinforcement value of social stimuli during adolescence. Operant responding for access to a familiar conspecific was assessed in male and female adolescent wild type (WT; normal AVP), heterozygous Brattleboro (HET), and homozygous Brattleboro (HOM) rats. Following the social reinforcement test, rats were tested in the same operant paradigm except that the social reinforcer was replaced with a light reinforcer to determine whether effects of the Brattleboro mutation were specific to social stimuli or a general characteristic of operant conditioning. WT males directed a greater proportion of their responding toward the social and light stimuli than WT females; only males exhibited a preference for these reinforcers over unreinforced ports. The sex difference in social reinforcement was absent in HOM rats, whereas the sex difference in light reinforcement was present in all genotypes. These data indicate that adolescent males are more sensitive to the reinforcing properties of social and light stimuli, and that the sex difference in social, but not light, reinforcement depends upon normal levels of AVP. These findings support the hypothesis that AVP plays a critical role in sex differences in social development by acting on factors that influence social motivation.

Investigation of social, affective, and locomotor behavior of adolescent Brattleboro rats reveals a link between vasopressin's actions on arousal and social behavior.

Arginine vasopressin (AVP) has recently been implicated in juvenile and adolescent social development. How AVP influences social development, however, is not understood. Adolescent homozygous Brattleboro rats (Hom), which lack AVP due to a mutation in the Avp gene, exhibit fewer active social behaviors (e.g., social play) but more passive social behaviors (e.g., huddling) than their wild type and heterozygous (Het) littermates, raising the possibility that AVP impacts social development through an arousal mechanism. Here, we test whether the atypical social phenotype of adolescent Hom rats is associated with altered behavioral arousal, social approach, or affective behaviors and whether Brattleboro mothers impact these behavioral phenotypes. Male and female Het and Hom adolescents born to Het or Hom mothers were tested in social interaction, open field, novelty-seeking, social approach, and marble burying tests. As reported previously, Hom rats played less and emitted fewer 50 kHz ultrasonic vocalizations while huddling more than their Het littermates. No genotype differences were detected in novelty seeking or social approach, nor were consistent differences found between offspring from Het and Hom mothers. However, Hom rats were less active in the open field and buried fewer marbles than Het rats indicating a hypoaroused, low anxiety phenotype. Open field activity correlated with levels of social play indicating that the effects of the Brattleboro mutation on arousal and social behavior are linked. These data demonstrate that chronic AVP deficiency impacts behavioral arousal during adolescence and support the hypothesis that AVP influences adolescent social development, in part, through its regulation of arousal.

Dissociation of adrenocorticotropin and corticosterone as well as aldosterone secretion during stress of hypoglycemia in vasopressin-deficient rats.

AIMS: In vasopressin-deficient rat pups stressor-induced adrenocorticotropin (ACTH) and corticosterone elevations markedly dissociate. We have shown recently that during the postnatal period mineralocorticoid secretion is more sensitive to stressor exposure than that of glucocorticoids. We have therefore hypothesized that in vasopressin-deficient pups during hypoglycemia, a stressor triggering aldosterone release mainly via ACTH, aldosterone release will change in parallel with ACTH. An additional aim was to reveal at which stage of the development occurs the shift from aldosterone to corticosterone as primarily stressor-induced adrenocortical hormone. MAIN METHODS: Vasopressin-deficient (di/di) and control Brattleboro rats were used both postnatally (10-day-old rats) and in adulthood. KEY FINDINGS: Hypoglycemia induced similar ACTH elevations in pups and adults with significantly lower levels in di/di rats. In contrast, vasopressin-deficiency resulted in elevated resting aldosterone and stressor-induced corticosterone levels in pups without genotype differences in adults. Thus, aldosterone levels also dissociated from ACTH secretion. During stress, pups showed only minimal corticosterone increase, with relatively high aldosterone elevation. Resting levels of gluco- and mineralocorticoid receptor mRNA were smaller, while corticosterone-deactivating enzyme (11ß-HSD2) mRNA level were higher in the hippocampus of 10-day-old rats compared to adults. SIGNIFICANCE: AVP does not seem to substantially regulate the stressor-induced aldosterone production, but both hormones contribute to salt-water regulation. Postnatally higher stressor-induced aldosterone than corticosterone production was still detectable in 40-day-old rats, although to a lesser extent, supporting a shift in the balance between stressor-induced glucocorticoid and mineralocorticoid hormone release throughout the development occurring in rats after postnatal day 40.

Animal models of Central Diabetes Insipidus: Human relevance of acquired beyond hereditary syndromes and the role of oxytocin.

The aim of this study was to review different animal models of Central Diabetes Insipidus, a neurobiological syndrome characterized by the excretion of copious amounts of diluted urine (polyuria), a consequent water intake (polydipsia), and a rise in the serum sodium concentration (hypernatremia). In rodents, Central Diabetes Insipidus can be caused by genetic disorders (Brattleboro rats) but also by various traumatic/surgical interventions, including neurohypophysectomy, pituitary stalk compression, hypophysectomy, and median eminence lesions. Regardless of its etiology, Central Diabetes Insipidus affects the neuroendocrine system that secretes arginine vasopressin, a neurohormone responsible for antidiuretic functions that acts trough the renal system. However, most Central Diabetes Insipidus models also show disorders in other neurobiological systems, specifically in the secretion of oxytocin, a neurohormone involved in body sodium excretion. Although the hydromineral behaviors shown by the different Central Diabetes Insipidus models have usually been considered as very similar, the present review highlights relevant differences with respect to these behaviors as a function of the individual neurobiological systems affected. Increased understanding of the relationship between the neuroendocrine systems involved and the associated hydromineral behaviors may allow appropriate action to be taken to correct these behavioral neuroendocrine deficits.

Vasopressin signaling at brain level controls stress hormone release: the vasopressin-deficient Brattleboro rat as a model.

The nonapeptide arginine vasopressin (AVP) has long been suggested to play an important role as a secretagogue for triggering the activity of the endocrine stress response. Most recent studies employed mutant mice for analyzing the importance of AVP for endocrine regulation under stress. However, it is difficult to compare and draw overall conclusions from all these studies as mixing the genetic material from different mouse strains has consequences on the individual's stress response. Moreover, mice are not ideal subjects for several experimental procedures. Therefore, to get more insight, we used a rather old mutant rat model: the AVP-deficient Brattleboro rat. The present short review is aimed at providing the most interesting results of these studies within the last 8 years that allowed gaining new insights in the potential signal function of AVP in stress and endocrine regulation.

The effects of vasopressin deficiency on aggression and impulsiveness in male and female rats.

The role of vasopressin in aggression received much attention in recent years. However, vasopressin has complex roles on social behavior, which are affected by social experience, motivation and hormonal background, suggesting that its effects depend on the condition of subjects. This hypothesis was tested here by studying the impact of vasopressin deficiency on aggressiveness in reproductively naive and reproductively experienced males, as well as in lactating females, with special reference to the patterns and contexts of attack behavior. We also studied effects on impulsiveness, a behavioral feature strongly related to aggression. Vasopressin deficiency did not affect aggressiveness in reproductively experienced males, decreased the share of violent attacks in reproductively inexperienced males without affecting total attack counts, and suppressed maternal aggression in both early and late phases of lactation; violent forms of attack were decreased in the latter but not the former phase. Changes in aggression appeared unrelated to general changes in maternal behaviors. Impulsivity in the delay discounting task was markedly decreased by vasopressin deficiency in lactating females but not males. Taken together, our findings confirm that vasopressin has an impact on aggressiveness, but show that this impact depends on the condition of subjects, and suggest that the effects of vasopressin on maternal aggression develop in conjunction with impulsivity. Interestingly, overall effects on aggression and specific effects on violent attacks dissociated in both males and females, which hints to the possibility that vasopressin has distinct roles in the development of escalated forms of aggression.

Assessment of attention in male and female Brattleboro rats using a self-paced five-choice serial reaction time task.

The Brattleboro rat is a mutant variation of the Long-Evans strain that exhibits negligible central nervous system levels of vasopressin, a neuropeptide that may influence behavioral and cognitive processes. Compared to Long-Evans rats, Brattleboro rats exhibit diminished fear conditioning and have impairments in spatial memory and sensory gating. The present study sought to further evaluate the cognitive profile of vasopressin-deficient rats by studying attention in male and female Brattleboro and heterozygous rats using a self-paced version of the five-choice serial reaction time task. Male Brattleboro rats required significantly more sessions to meet the training criteria than those by heterozygotic and Long-Evans (wild type) rats. Female Brattleboro rats displayed significantly poorer attention accuracy compared to heterozygotic and Long-Evans rats. Taken together, the present findings add further evidence that vasopressin deficiency diminishes cognitive functioning.

Significance of Renal Evaluation of Vasopressin-Deficient Brattleboro and Wistar Rats by Using Different Concentrated Gadolinium Diethylenetetramine Pentaacetic Acid Dynamic Enhanced Magnetic Resonance Imaging / 实用儿科临床杂志

ObjectiveTo explore the renal functions of vasopressin-deficient Brattleboro(BB) rats by using different concentrated Gadolinium-diethylenetetramine pentaacetic acid(Gd-DTPA) dynamic enhanced magnetic resonance imaging(MRI).MethodsThe study included 14 BB rats(male rats of 3 month-old) and 14 normal male Wistar rats used as control group.Dynamic MRI was performed by using either a low dosage(0.05 mmol/kg) or a high dosage of Gd-DTPA(0.5 mmol/kg).Data of 0-60 min renal cortex,medulla and pelvic were obtained after using contrast medium.MRI of kidneys at different time was analyzed and the mean relative signal intensity(RSI) was measured.Then the RSI curves of different groups were marked.Data of each group were caculated separately by SPSS 11.0 software.ResultsThe findings demonstrated that RSI curves of the vasopressin-deficient kidneys showed different patterns as compared with those of the control group(P