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Imipramine Can Be Effective on Depressive-Like Behaviors, but Not on Neurotrophic Factor Levels in an Animal Model for Bipolar Disorder Induced by Ouabain

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Abstract

Introduction

Despite possible risks of mania switching with the long-term use of antidepressants in patients with bipolar disorder (BD), these drugs may help in depressive episodes. Alterations in neurotrophic factor levels seem to be involved in the pathophysiology of BD. The present study aimed to evaluate the effect of acute treatment of imipramine on behavior and neurotrophic levels in rats submitted to the animal model for BD induced by ouabain.

Methods

Wistar rats received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid or ouabain (10−3 M). Following the ICV administration, the rats were treated for 14 days with saline (NaCl 0.9%, i.p.), lithium (47.5 mg/kg, i.p.), or valproate (200 mg/kg, i.p.). On the 13th and 14th days of treatment, the animals received an additional injection of saline or imipramine (10 mg/kg, i.p.). Behavior tests were evaluated 7 and 14 days after ICV injection. Adrenal gland weight and concentrations of ACTH were evaluated. Levels of neurotrophins BDNF, NGF, NT-3, and GDNF were measured in the frontal cortex and hippocampus by ELISA test.

Results

The administration of ouabain induced mania- and depressive-like behavior in the animals 7 and 14 days after ICV, respectively. The treatment with lithium and valproate reversed the mania-like behavior. All treatments were able to reverse most of the depressive-like behaviors induced by ouabain. Moreover, ouabain increased HPA-axis parameters in serum and decreased the neurotrophin levels in the frontal cortex and hippocampus. All treatments, except imipramine, reversed these alterations.

Conclusion

It can be suggested that acute administration of imipramine alone can be effective on depressive-like symptoms but not on neurotrophic factor alterations present in BD.

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Data Availability

All data generated or analyzed during this study are included in the manuscript.

Code Availability

Not applicable.

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Acknowledgements

We would like to acknowledge CNPq, CAPES, FAPESC, and Instituto Cérebro e Mente for the support during the development of the present study.

Funding

Translational Psychiatry Program (USA) is funded by a grant from the National Institute of Health/National Institute of Mental Health (1R21MH117636-01A1, to JQ). Center of Excellence on Mood Disorders (USA) is funded by the Pat Rutherford Jr. Chair in Psychiatry, John S. Dunn Foundation and Anne and Don Fizer Foundation Endowment for Depression Research. Translational Psychiatry Laboratory (Brazil) is funded by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Apoio à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC), and Instituto Cérebro e Mente. JQ and SSV are CNPq Research Fellows.

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Authors and Affiliations

  1. Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    Taise Possamai-Della, Wilson R. Resende, Jorge M. Aguiar-Geraldo, Jefté Peper-Nascimento, João Quevedo & Samira S. Valvassori

  2. Translational Health Research Laboratory, Alto Vale do Rio do Peixe University, Caçador, Brazil

    Gustavo C. Dal-Pont

  3. Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    João Quevedo

  4. Center of Excellence On Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    João Quevedo

  5. Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    João Quevedo

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  1. Taise Possamai-Della
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  2. Gustavo C. Dal-Pont
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Contributions

Samira S. Valvassori and João Quevedo contributed to design and development; methodological design; supervision (responsible for organizing and executing the project); analysis/interpretation and critical review. Jefté Peper-Nascimento, Wilson R. Resende, and Gustavo C. Dal-Pont participated in data collection and processing and biochemical analyses of the samples and performed the statistical analyzes. Taise Possamai-Della and Jorge M. Aguiar-Geraldo performed the statistical analyses and contributed to the analysis/interpretation, literature survey, and writing.

Corresponding author

Correspondence to Samira S. Valvassori.

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Ethics Approval

The experimental procedures followed the terms of the Brazilian Society for Neuroscience and Behavior (SBNeC), as well as the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The local ethics committee Comissão de Ética no Uso de Animais da Universidade do Extremo Sul Catarinense (protocol number #66/2010) approved this study.

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Conflict of Interest

JQ received clinical research support from LivaNova; has speaker bureau membership with Myriad Neuroscience, Janssen Pharmaceuticals, and Abbvie; is consultant for Eurofarma; is stockholder at Instituto de Neurociencias Dr. Joao Quevedo; and receives copyrights from Artmed Editora, Artmed Panamericana, and Elsevier/Academic Press. All the other authors have no conflicts of interest.

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Possamai-Della, T., Dal-Pont, G.C., Resende, W.R. et al. Imipramine Can Be Effective on Depressive-Like Behaviors, but Not on Neurotrophic Factor Levels in an Animal Model for Bipolar Disorder Induced by Ouabain. Mol Neurobiol 59, 7170–7181 (2022). https://doi.org/10.1007/s12035-022-03022-y

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