Abstract
Rationale
Fas-associated death domain (FADD) is an adaptor of death receptors that can also induce anti-apoptotic actions through its phosphorylated form (p-FADD). Activation of monoamine receptors, indirect targets of classic anti-depressant drugs (ADs), reduced FADD and increased p-FADD and p-FADD/FADD ratio in brain.
Objectives
To ascertain whether ADs, which indirectly regulate monoamine receptors, modulate FADD protein forms to promote anti-apoptotic actions.
Methods
The effects of selected norepinephrine transporter (NET), serotonin transporter (SERT), monoamine oxidase (MAO) inhibitors, atypical ADs, and electroconvulsive shock (ECS) or behavioral procedures (forced swim test, FST) on FADD forms and pro-survival FADD-like interleukin-1β-converting enzyme-inhibitory protein (FLIP-L) and phosphoprotein enriched in astrocytes of 15 kDa (p-PEA-15) contents were assessed in rat brain cortex by western blot analysis.
Results
Acute NET (e.g., nisoxetine) but not SERT (e.g., fluoxetine) inhibitors decreased cortical FADD (up to 37 %) and increased p-FADD/FADD ratio (up to 1.9-fold). Nisoxetine effects were prevented by α2-antagonist RX-821002, suggesting the involvement of presynaptic α2-autoreceptors. Immobility time in the FST correlated with increases of pro-apoptotic FADD and decreases of anti-apoptotic p-FADD. The MAO-A/B inhibitor phenelzine decreased FADD (up to 33 %) and increased p-FADD (up to 65 %) and p-FADD/FADD (up to 2.4-fold). Other MAO inhibitors (clorgyline, Ro 41-1049, rasagiline), atypical ADs (ketamine and mirtazapine), or ECS did not modulate cortical FADD. Chronic (14 days) desipramine and fluoxetine, but not phenelzine, increased p-FADD (up to 59 %), p-FADD/FADD ratio (up to 1.8-fold), and pro-survival p-PEA-15 (up to 46 %) in rat brain cortex.
Conclusions
Multifunctional FADD protein, through an increased p-FADD/FADD ratio, could participate in the mechanisms of anti-apoptotic actions induced by ADs.
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Acknowledgments
This research was funded by Grants SAF2011-29918 (to J.A.G.-S.) and SAF2014-55903-R (to M.J.G.-F.) from Ministerio de Economía y Competitividad (MINECO, Madrid, Spain) and Fondo Europeo de Desarrollo Regional (FEDER). The study was supported in part by Project 2012/011 from Delegación del Gobierno para el Plan Nacional sobre Drogas (Ministerio de Sanidad, Servicios Sociales e Igualdad, Madrid) and by Fundación Alicia Koplowitz (Madrid) both to M. J. G.-F. The authors would like to thank Antonio Crespo for the skillful technical assistance. M. J. G.-F. is a Ramón y Cajal researcher (MINECO-UIB). J. A. G.-S. is a member of the Institut d’Estudis Catalans (Barcelona, Catalonia, Spain).
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The experiments were carried out in accordance with standard ethical guidelines (European Communities Council Directive 86/609/EEC and Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research, National Research Council 2003) and approved by the Local Bioethical Committee (UIB). All efforts were made to minimize the number of rats used and their suffering.
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García-Fuster, M.J., García-Sevilla, J.A. Effects of anti-depressant treatments on FADD and p-FADD protein in rat brain cortex: enhanced anti-apoptotic p-FADD/FADD ratio after chronic desipramine and fluoxetine administration. Psychopharmacology 233, 2955–2971 (2016). https://doi.org/10.1007/s00213-016-4342-6
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DOI: https://doi.org/10.1007/s00213-016-4342-6