Validation of the animal model of bipolar disorder induced by Ouabain: face, construct and predictive perspectives

Samira S Valvassori,Jéssica Lopes-Borges,Wilson R Resende,Gustavo C Dal-Pont,João Quevedo,José Henrique Cararo,Roger B Varela

doi:10.1038/s41398-019-0494-6

Abstract

A particular challenge in the development of a bipolar disorder (BD) model in animals is the complicated clinical course of the condition, characterized by manic, depressive and mixed mood episodes. Ouabain (OUA) is an inhibitor of Na+/K+-ATPase enzyme. Intracerebroventricular (ICV) injection of this drug in rats has been regarded a proper model to study BD by mimic specific manic symptoms, which are reversed by lithium (Li), an important mood stabilizer drug. However, further validation of this experimental approach is required to characterize it as an animal model of BD, including depressive-like behaviors. The present study aimed to assess manic- and depressive-like behaviors, potential alteration in the hypothalamic-pituitary-adrenal (HPA) system and oxidative stress parameters after a single OUA ICV administration in adult male Wistar rats. Moreover, we evaluated Li effects in this experimental setting. Data show that OUA ICV administration could constitute a suitable model for BD since the injection of the drug triggered manic- and depressive-like behaviors in the same animal. Additionally, the OUA model mimics significant physiological and neurochemical alterations detected in BD patients, including an increase in oxidative stress and change in HPA axis. Our findings suggest that decreased Na+/K+-ATPase activity detected in bipolar patients may be linked to increased secretion of glucocorticoid hormones and oxidative damage, leading to the marked behavioral swings. The Li administration mitigated these pathological changes in the rats. The proposed OUA model is regarded as suitable to simulate BD by complying with all validities required to a proper animal model of the psychiatric disorder.

Highlights

Bipolar disorder (BD) is a psychiatric condition marked by aberrant mood swings, including mania, depression, and mixed states
Face validity of the animal model of BD induced by OUA The face validity of an animal model of psychiatric disorder is the ability of the model in mimic the symptoms of the disorder
These results demonstrate that a single injection of OUA induces manic- and depressivelike behaviors in the same animal, contemplating the face validity for a suitable animal model of BD

Summary

Introduction

Bipolar disorder (BD) is a psychiatric condition marked by aberrant mood swings, including mania, depression, and mixed states. Despite its significant impact in the life quality of the patients, both pathophysiology and pathogenesis of this disorder remain unclear[1,2,3]. In this regard, animal models are an essential strategy in search of data on behavioral status, neurotransmitter systems, and mechanisms underlying a particular mental disorder[4,5,6]. It is noteworthy that animal models of mental disorders should comply with the following requirements:[9] Face validity, which indicates whether the model mimics the symptoms of a particular disorder; Construct validity, showing the ability of the model to simulate pathophysiological aspects of the illness; Predictive validity, which assesses whether the drugs included in therapy for the human condition can reverse the symptoms induced in the model

Methods

Results

Conclusion