The prepulse inhibition deficit appearance is largely independent on the circadian cycle, body weight, and the gender of vasopressin deficient Brattleboro rat

Objective. A disturbance of sensorimotor gating measured by prepulse inhibition of acoustic startle (PPI) is one of the best tests of the schizophrenia-like behavior. Vasopressin was implicated in the development of schizophrenia; therefore, the naturally occurring vasopressin-deficient Brattleboro rat has been suggested to be a reliable non-pharmacological animal model. However, previous studies focusing on PPI deficit did not use proper control and despite clear gender differences in the development of the disorder, the effect of gender has been mostly neglected.Methods. First, we compared the „noise” and „tone” type prepulse at 73-77-81 dB intensity during the light or dark phase using small (~150 g) or big (~500 g) Wistar rats. The test parameters were validated by a pharmacological schizophrenia model (30 mg/kg ketamine i.p.). Than male, female, and lactating vasopressin-deficient animals were compared with +/+ ones.Results. We established that the prepulse “noise” type is not optimal for PPI testing. The cycle of the day as well as the body weight had no effect on PPI. Even if we compared vasopressin-deficient animals with their closely related +/+ controls, the PPI deficiency was visible with more pronounced effect at 77 dB prepulse intensity similarly to pharmacological schizophrenia model. Despite our expectation, the gender as well as lactation had no effect on the vasopressin-deficiency induced PPI deficit.Conclusions. The present data confirmed and extended our previous studies that vasopressin-deficient rat is a good model of schizophrenia. It seems that female as well as lactating Brattleboro rats are useful tools for testing putative novel antipsychotics in line with special attention required for schizophrenic women.

Tolvaptan as a tool in renal physiology

For decades, the Brattleboro rat has been a useful model in kidney physiology. These animals manifest central diabetes insipidus (lack of circulating vasopressin) due to a mutation in the vasopressin-neurophysin gene. V2 receptor-mediated vasopressin actions in the kidney can be assessed in these animals by infusing the V2-selective vasopressin analog 1-desamino-8-d-arginine vasopressin (dDAVP). However, the major commercial supplier in the United States has ceased production, creating the need for another reliable experimental model of V2 receptor-mediated vasopressin action in rodents. We designed an in vivo protocol to investigate vasopressin responses in the rat kidney using osmotic minipumps loaded with tolvaptan, a nonpeptide competitive inhibitor of the vasopressin V2 receptor. Tolvaptan-infused rats had a mean urinary osmolality of <300 vs. >2,000 mosmol/kgH2O in vehicle-infused rats. The tolvaptan infusion produced large decreases in the renal abundance of aquaporin-2 (AQP2), aquaporin-3 (AQP3), the β-subunit of the epithelial sodium channel (β-ENaC), and γ-ENaC that were comparable to the differences seen in vehicle-infused vs. vasopressin-infused Brattleboro rats. Thus we conclude that tolvaptan infusion in rats provides an additional model (besides dDAVP-infusion in the Brattleboro rat) for the assessment of V2 receptor-mediated vasopressin actions in the kidney. We also provide ancillary in vitro data in rat inner-medullary-collecting-duct suspensions showing that tolvaptan can block vasopressin's effects on phosphorylation of the water channel AQP2 in vitro. Specifically, tolvaptan almost completely inhibited the ability of vasopressin to increase AQP2 phosphorylation at Ser256, Ser264, and Ser269, while strongly inhibiting a vasopressin-induced decrease in AQP2 phosphorylation at Ser261.