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Fluoxetine reverses behavior changes in socially isolated rats: role of the hippocampal GSH-dependent defense system and proinflammatory cytokines

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Abstract

Exposure of an organism to chronic social isolation (CSIS) has been shown to have an important role in depression. Fluoxetine (Flx) is a first-line treatment for depression; however, its downstream mechanisms of action beyond serotonergic signaling remain ill-defined. We investigated the effect of 3 weeks of Flx (15 mg/kg/day) treatment on behavioral changes and protein expression/activity of the GSH-dependent defense system, including reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GLR), and glutathione S-transferase (GST), as well as catalase (CAT), in the hippocampus of rats exposed to 6 weeks of CSIS. The subcellular distributions of nuclear factor-κB (NF-κB), as well as, cytosolic IL-1β and IL-6 protein expression, were also determined. CSIS induced depressive- and anxiety-like behaviors, evidenced by a decrease in sucrose preference and an increase in the number of buried marbles. Moreover, CSIS compromised redox homeostasis, targeting enzymes such as GPx, CAT, GST, and caused NF-κB nuclear translocation with a concomitant increase in IL-6 protein expression, without an effect on IL-1β. Flx treatment reversed CSIS-induced depressive- and anxiety-like behaviors, modulated GSH-dependent defense by increasing GLR and GST activity, and suppressed NF-κB activation and cytosolic IL-6 protein expression in socially isolated rats. The present study suggests that changes in the GSH-dependent defense system, NF-κB activation and increased IL-6 protein expression may have a role in social isolation-induced changes in a rat model of depression and anxiety, and contributes to our understanding of the mechanisms that underlie the antidepressant and anti-inflammatory activity of Flx in socially isolated rats.

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Acknowledgements

This work was supported by the Grant of Ministry of Education, Science and Technological Development of the Republic of Serbia (173044) to I.P., A.S. and D.F, and Grant from the Deutsche Forschungsgemeinschaft (SFB636-TP3) to P.G. We gratefully thank the staff from Faculty of Medicine, University of Belgrade, for using Chemidoc-MP System (Bio-Rad).

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  1. Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences “Vinča”, University of Belgrade, P. O. Box 522-090, 11001, Belgrade, Serbia

    Ivana Perić, Andrijana Stanisavljević & Dragana Filipović

  2. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159, Heidelberg, Germany

    Peter Gass

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  1. Ivana Perić
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Perić, I., Stanisavljević, A., Gass, P. et al. Fluoxetine reverses behavior changes in socially isolated rats: role of the hippocampal GSH-dependent defense system and proinflammatory cytokines. Eur Arch Psychiatry Clin Neurosci 267, 737–749 (2017). https://doi.org/10.1007/s00406-017-0807-9

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