Neurobiological aspects of the ouabain-induced animal model of bipolar disorder: A narrative review.

Animal models are important tools for investigating the neurobiological mechanisms underlying psychiatric disorders, particularly given the methodological limitations associated with human studies. In bipolar disorder (BD), the development of animal models with adequate translational relevance remains challenging due to the heterogeneous and multifactorial nature of the condition. Among the available models, intracerebroventricular (ICV) administration of ouabain (OUA), an endogenous cardiac steroid and Na+/K+-ATPase inhibitor, has been extensively used to investigate behavioral and molecular alterations in BD. This review summarizes recent evidence on the molecular alterations in the OUA-induced animal model of BD and discusses how these changes may contribute to the behavioral outcomes observed in this model. The available literature indicates that OUA administration induces both manic-like and depressive-like behaviors and, in some cases, mixed states. Also, the model shows a pharmacological response to established treatments, although the effects of antidepressants are more complex. At the molecular level, OUA inhibits Na+/K+-ATPase activity, which could disrupt ionic homeostasis and modulate intracellular signaling pathways. However, alterations in Na+/K+-ATPase activity appear to be region-dependent, with conflicting findings reported in some brain areas (e.g., the hippocampus). Other pathways impacted by OUA include glycogen synthase kinase-3 (GSK-3), protein kinase C (PKC), and extracellular signal-regulated kinase (ERK), although some heterogeneity has been reported, particularly regarding GSK-3 signaling. In addition, OUA administration is associated with alterations in neurotransmitter and neurotrophic signaling, inflammatory mediators, oxidative stress parameters, and cell death-related pathways. In contrast, current evidence does not indicate significant effects on epigenetic enzyme activity, with limited evidence. Taken together, these findings support the utility of the OUA model as an experimental approach to investigating biological mechanisms underlying the pathophysiology of BD.