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Background: Bipolar disorder (BD) is a psychiatric disorder with complex therapy, besides the treatment with antidepressants induce a mania switch., Objective: Investigate the effect of the administration of imipramine (IMI) in rats submitted to intracerebroventricular (ICV) administrations of ouabain (OUA)., Methods: Adult Wistar rats (n = 28) were submitted to only one ICV administration of OUA or artificial cerebrospinal fluid. On the 7th and 9th days following the ICV administration, animals were submitted to a behavioral analysis comprising open field task and forced swimming test. Between the 9th and 14th days, the rats received one daily intraperitoneal administration of IMI or saline (Sal). On the 15th day rats were submitted to the last session of behavioral analysis, followed by euthanasia. The frontal cortex and hippocampus were dissected for the subsequent biochemical assessments: oxidative parameters, and Na+/K+-ATPase activity., Results: OUA administration induced a manic-like effect on the 7th day and a depressive-like behavior on the 14th day. In contrast, IMI administration elicited significant mania switch-like effect on this same stage in animals who received OUA. OUA increased oxidative damage and activity of antioxidant enzymes in the brain of rats. IMI potentialized the oxidative damage of OUA. No significant differences between groups were observed in the Na+/K+-ATPase activity., Conclusion: The present study suggests that residual effects from inhibition of the Na+K+ATPase could be involved in the manic-switch observed in bipolar patients. Besides, the OUA model of bipolar disorder could be used to study bipolar disorder in the context of mania switch., (Copyright © 2021. Published by Elsevier B.V.)

In this study, we assessed the oxidative stress parameters in rats submitted to an animal model of mania induced by ouabain (OUA), which included the use of lithium (Li) and valproate (VPA). Li and VPA treatment reversed and prevented the OUA-induced damage in these structures, however, this effect varies depending on the brain region and treatment regimen. Moreover, the activity of the antioxidant enzymes, namely, superoxide dismutase (SOD) and catalase (CAT) was found to be increased and decreased, respectively, in the brain of OUA-administered rats. Li and VPA modulated SOD and CAT activities in OUA-subjected rats in both experimental models. Our results support the notion that Li and VPA exert antioxidant-like properties in the brain of rats submitted to animal model of mania induced by ouabain., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Intracerebroventricular (ICV) injection of ouabain (a potent Na(+)/K(+)-ATPase inhibitor) in rats resulted in manic-like effects. There is an emerging body of data indicating that major neuropsychiatric disorders, such as bipolar disorder and schizophrenia, are associated with increased oxidative stress. In this study, we investigated the effects of ICV ouabain injection on oxidative stress parameters in total tissue of rat brain. Our findings demonstrated that ICV injection increased thiobarbituric acid reactive species levels and protein carbonyl generation in the prefrontal cortex and hippocampus of rats. Moreover, the activity of the antioxidants enzymes catalase and superoxide dismutase was altered in several areas of the rat brain and cerebrospinal fluid of ICV ouabain-subjected rats. These results showed that Na(+)/K(+)-ATPase inhibition can lead to oxidative stress in the brain of rats.

There is an emerging body of data suggesting that bipolar disorder is associated with DNA damage. Intracerebroventricular (i.c.v.) administration of ouabain in rats results in manic-like alterations. We evaluated DNA damage of peripheral blood, cerebrospinal fluid and hippocampus of rats after i.c.v. ouabain injection. Ouabain-induced hyperlocomotion was examined in an open field. Additionally, we used single cell gel electrophoresis (comet assay) to measure early transient damage in cerebrospinal fluid (CSF), hippocampus and blood; and the micronucleus test to measure persistent damage in total blood samples of rats after ouabain administration. Our findings demonstrated that ouabain induced hyperlocomotion in rats, and this response remained up to 7 days following a single i.c.v. injection. In addition, we observed that the persistent increase in the rat spontaneous locomotion is associated with increased hippocampal and peripheral index of early DNA damage in rats. No significant alterations were observed in the micronucleus frequency in total blood samples of the rats after the ouabain i.c.v. injection. These results suggest that ouabain may induce peripheral and central early DNA damage, but this early damage may be repaired., (2010 Elsevier Ireland Ltd. All rights reserved.)

Abstract: There is a body of evidence suggesting that BDNF is involved in bipolar disorder (BD) pathogenesis. Intracerebroventricular (ICV) injection of ouabain (OUA), a specific Na+/K+ ATPase inhibitor, induces hyperlocomotion in rats, and has been used as an animal model of mania. The present study aims to investigate the effects of the lithium (Li) and valproate (VPT) in an animal model of mania induced by ouabain. In the reversal model, animals received a single ICV injection of OUA or cerebrospinal fluid (aCSF). From the day following the ICV injection, the rats were treated for 6days with intraperitoneal (IP) injections of saline (SAL), Li or VPT twice a day. In the maintenance treatment (prevention model), the rats received IP injections of Li, VPT, or SAL twice a day for 12days. In the 7th day of treatment the animals received a single ICV injection of either OUA or aCSF. After the ICV injection, the treatment with the mood stabilizers continued for more 6days. Locomotor activity was measured using the open-field test and BDNF levels were measured in rat hippocampus and amygdala by sandwich-ELISA. Li and VPT reversed OUA-related hyperactive behavior in the open-field test in both experiments. OUA decreased BDNF levels in first and second experiments in hippocampus and amygdala and Li treatment, but not VPT reversed and prevented the impairment in BDNF expression after OUA administration in these cerebral areas. Our results suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania. [Copyright &y& Elsevier]