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

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.

Intracerebroventricular injection of ouabain causes mania-like behavior in mice through D2 receptor activation

“…In the rat model, increased locomotor activity 16 and cognitive flexibility impairment 24 were demonstrated as characteristics reflecting the mania-like phase. In a recent study, both the mania-like and the depressive phase were demonstrated in rats, along with the accompanying oxidative stress and Na, K-ATPase dysfunction, the same way as they appear in patients with bipolar disorder 23 . In our mice model of ouabain-induced mania, the mania-like phase is illustrated with hyperlocomotion, stereotyped behavior, and a lessened degree of anxiety.…”

“…In this model intracerebroventricular (ICV) injection of ouabain instantly caused hyperactivity in rats 21 . The ouabain-induced model of mania-like behavior in rats is recognized among the employed pharmacological models of mania 22,23 . Also, ICV ouabain administration has an effect on cognitive flexibility and reversal learning in rats 24 .…”

Using mitochondrial respiration inhibitors to design a novel model of bipolar disorder-like phenotype with construct, face and predictive validity

“…Another BD-like model has recently been described, based on chronic ouabain treatment 53 . We contend that Valvassori et al's claimed construct and face validity is weaker than ours: decreased Na + /K + -ATPase activity vs. MD in BD (constract); dichotomic use of tests for either mania-or depression-associated behaviors vs. demonstrating both behavioral poles in the same tests (face).…”

Role of endogenous ouabain in the etiology of bipolar disorder

“…Direct ICV ouabain administration will reduce sodium pump activity in the brain (Hamid et al 2009 ), induce both depressive and manic symptoms which can be treated and prevented with lithium (Valvassori et al 2019 ; El-Mallakh et al 1995 ; Li et al 1997 ). The model attempts to mimic the reduced sodium pump activity that has been reported in bipolar illness, not changes in endogenous ouabain.…”

“…A similar conclusion is reached when genome wide association studies (GWAS) are explored (Judy and Zandi 2013 ). The only animal models of bipolar illness that meet all validity criteria create ion transport abnormalities (Mack et al 2019 ; Valvassori et al 2019 ). Additionally, nearly all interventions that are effective in mania or mood stabilization reduce intracellular sodium either directly or indirectly (El-Mallakh and Huff 2001 ; El-Mallakh and Paskitti 2001 ; Roberts et al 2010 ).…”