Homozygous Brattleboro rats display attenuated conditioned freezing responses

Stoehr, James D.; Cheng, Savio W.T.; North, William G.

doi:10.1016/0304-3940(93)90087-2

Cited by 16 publications

(8 citation statements)

References 33 publications

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“…In line with these findings are results from a study using an antisense oligodeoxynucleotide mRNA to the V 1a subtype which showed that intra-septal infusion of the antisense reduced anxiety in the elevated plus-maze [32]. Furthermore, the vasopressin-deficient rats Brattleboro were found to display attenuated conditioning freezing responses [33], while rats with high innate anxiety showed increased levels of vasopressin in the hypothalamus [34]. Interestingly, chronic treatment with the classical antidepressant, paroxetine, normalized hypothalamic vasopressin levels in these latter rats [35].…”

Section: Introductionsupporting

confidence: 69%

Non-Peptide Vasopressin V1b Receptor Antagonists as Potential Drugs for the Treatment of Stress-Related Disorders

Griebel¹,

Stemmelin²,

Gal³

et al. 2005

CPD

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Since vasopressin has been shown to be critical for adaptation of the hypothalamo-pituitary-adrenal axis during stress through its ability to potentiate the stimulatory effect of CRF, it has been hypothesized that this peptide may provide a good opportunity for pharmacological treatment of stress-related disorders. The availability of the first orally active non-peptide V(1b) receptor antagonist, SSR149415, opened a new era for examining the role of vasopressin in animal models of anxiety and depression. In rats, SSR149415 blocked several endocrine (i.e. ACTH release), neurochemical (i.e. noradrenaline release) and autonomic (i.e. hyperthermia) responses following various stress exposures. Moreover, the drug was 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. These latter were highly effective and reliably produced robust effects in most anxiety tests, while SSR149415 showed clear-cut effects only in particularly stressful situations. Experiments with mice or hamsters indicated that V(1b) receptor blockade is associated with reduced aggressiveness, suggesting that SSR149415 could prove useful for treating aggressive behavior. It is important to note that SSR149415 is devoid of adverse effects on motor functions or cognitive processes, and it did not produce tolerance to its anxiolytic- or antidepressant-like activity. Altogether, these findings suggest that V(1b) receptor antagonists represent a promising alternative to agents currently used for the treatment of depression and some forms of anxiety disorders.

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Section: Introductionsupporting

confidence: 69%

Non-Peptide Vasopressin V1b Receptor Antagonists as Potential Drugs for the Treatment of Stress-Related Disorders

Griebel¹,

Stemmelin²,

Gal³

et al. 2005

CPD

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“…A number of studies have indicated that di/di Brattleboro rats exhibit deficits of Pavlovian fear conditioning (Stoehr et al, 1993), spatial working memory (Colombo et al, 1992), and prepulse inhibition (Feifel and Priebe, 2001), with heterozygous (di/+) rats generally showing a partial phenotype. Although these data have been interpreted as evidence that vasopressin plays an important and permissive role in the regulation of cognition, this hypothesis is qualified by our recent observation that di/+ Brattleboro rats exhibit superior visuospatial attention and motor speeding, as assessed by a lateralized reaction time task (Jentsch, 2003).…”

Section: Introductionmentioning

confidence: 99%

Null Mutation of the Arginine-Vasopressin Gene in Rats Slows Attentional Engagement and Facilitates Response Accuracy in a Lateralized Reaction Time Task

Jentsch

Arguello

Anzivino

2003

Neuropsychopharmacol

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The neurophysin vasopressin is thought to play an important role in emotional behavior and aspects of cognition in the rat, and the pathophysiology of this system has been implicated in two neurodevelopmental disorders, namely autism and schizophrenia. Genetic deficiency of vasopressin in rats, resulting from a null mutation of the vasopressin gene, causes alterations of brain development with resulting behavioral and neurochemical phenotypes in adulthood. We previously demonstrated that partial vasopressin deficiency (rats heterozygous for the null mutation) produces enhanced visuospatial attention and motor speeding. Here, the results of studies of homozygous Brattleboro rats that are fully vasopressin deficient are reported. We trained subjects to perform a lateralized reaction time task that measures visuospatial divided attention; in task conditions in which the duration of target stimuli was varied from trial to trial, homozygous Brattleboro rats showed a performance phenotype that consisted of more accurate responding for longer duration, and less accurate responding for briefer duration, target stimuli. No differences in response times were measured. Further experiments revealed that two separate processes produced this complex phenotype: a relatively slowed period of attentional engagement (resulting in compromised detection of fast onset-fast offset stimuli) that only partially masks a generally more accurate pattern of responding. These results, taken with earlier data, indicate that vasopressin plays a critical role in regulating visual attention and cognition, either directly, or via early alterations in neurodevelopment.

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“…There is a genetic animal model, the Brattleboro rat, which fails to produce sufficient AVP due to a single base pair deletion in its AVP gene (Schmale & Richter 1984). Since its discovery about 40 years ago (Valtin et al 1962), the Brattleboro rat has proved to be very useful for studying the physiological consequence of AVP deficiency (Woods & Johnston 1983, Stoehr et al 1993, Walter et al 1996. On the other hand, in some clinical circumstances, inappropriately high plasma AVP results in free water retention and hyponatremia (Bartter & Schwartz 1967).…”

Section: Introductionmentioning

confidence: 99%

Adaptation to sustained high plasma vasopressin in water and electrolyte homeostasis in the rat transgenic for the metallothionein-vasopressin fusion gene

Yokoi

Nagasaki

Tachikawa

et al. 2002

Journal of Endocrinology

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Prolonged exposure of tissues to a receptor agonist often leads to adaptive changes that limit the subsequent responsiveness of the tissue to the same agonist. Recently, we have generated rats transgenic for the metallothionein I-human arginine vasopressin (AVP) fusion gene (Tg), which produced high plasma AVP with relatively preserved renal water excretion, suggesting that there might be adaptive mechanism(s) for maintaining water and electrolyte homeostasis against chronic AVP oversecretion from the earliest stage of life. In this study, to investigate whether down-regulation of AVP V2 receptor (V2R), which could possibly be caused by long-standing high plasma AVP, participates in this adaptive mechanism(s), non-peptidic V2R antagonist OPC31260 was administered to reverse the down-regulation, and water loading was performed after V2R antagonist treatment had been withdrawn. Additionally, to confirm the down-regulation, Northern blotting analysis for V2R mRNA was carried out. Tg rats showed slightly decreased urine volume and water intake with an equivalent plasma [Na + ] level (Tg 140·4 0·6 mEq/l; control 139·3 0·6 mEq/l) under basal conditions. After water loading using a liquid diet containing zinc, which stimulates the promoter region in the transgene, the urine increase showed only limited suppression with a dramatically increased plasma AVP level and mild hyponatremia (135·8 1·8 mEq/l) in Tg rats. When diet containing OPC31260 had been provided for 4 days until the day before the start of water loading, antidiuresis and hyponatremia (125·4 1·4 mEq/l) were significantly potentiated. V2R mRNA expression in kidney was significantly less in Tg rats than in control rats under basal conditions, and this suppression was restored by OPC31260 treatment to levels comparable with those of control rats. These results suggest that long-standing high plasma AVP causes V2R down-regulation, and it may play an important role in the adaptive mechanism(s) for maintaining water and electrolyte homeostasis in chronically AVP-overexpressing rats.

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Homozygous Brattleboro rats display attenuated conditioned freezing responses

Cited by 16 publications

References 33 publications

Non-Peptide Vasopressin V1b Receptor Antagonists as Potential Drugs for the Treatment of Stress-Related Disorders

Non-Peptide Vasopressin V1b Receptor Antagonists as Potential Drugs for the Treatment of Stress-Related Disorders

Null Mutation of the Arginine-Vasopressin Gene in Rats Slows Attentional Engagement and Facilitates Response Accuracy in a Lateralized Reaction Time Task

Adaptation to sustained high plasma vasopressin in water and electrolyte homeostasis in the rat transgenic for the metallothionein-vasopressin fusion gene

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