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Acute Regulation of the Arousal-Enhancing Drugs Caffeine and Modafinil on Class IIa HDACs In Vivo and In Vitro: Focus on HDAC7

Abstract

Psychostimulant drugs, such as modafinil and caffeine, induce transcriptional alterations through the dysregulation of epigenetic mechanisms. We have previously demonstrated that acute modafinil administration is accompanied by multiple changes in the expression of histone deacetylases (HDACs) within the mouse medial prefrontal cortex (mPFC). Herein, we compared alterations in class IIa HDACs in the mouse mPFC and dorsal striatum (DS) after a single exposure to each psychostimulant. We treated male C57BL/6 mice with modafinil (90 mg/kg, i.p.), caffeine (10 mg/kg, i.p.), or vehicle and evaluated locomotor activity. Following, we examined hdac4, hdac5, and hdac7 mRNA expression using qRT-PCR and HDAC7, pHDAC7, and pHDACs4/5/7 using Western blot. Last, we explored generalized effects in N2a cell line using modafinil (100 μM and 1 mM) or caffeine (80 μM and 800 μM). Our results indicate that modafinil had greater effects on locomotor activity compared with caffeine. qRT-PCR experiments revealed that modafinil decreased hdac5 and hdac7 mRNA expression in the DS, while caffeine had no effects. In the mPFC, modafinil increased hdac7 mRNA expression, with no effects observed for caffeine. Western blot revealed that within the DS, modafinil induced increases in HDAC7, pHDAC7, and pHDACs4/5/7 protein expression, while, in the mPFC, caffeine induced decreases in HDAC7, pHDAC7, and pHDACs4/5/7 protein levels. In vitro studies revealed that modafinil increased hdac4, hdac5, and hdac7 mRNA levels in N2a, while caffeine only increased hdac5 at a higher dose. These findings support the notion that modafinil and caffeine exert distinct regulation of class IIa HDAC family members and that these transcriptional and translational consequences are region-specific.

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Funding

This work was supported by FONCYT-Agencia Nacional de Promoción Científica y Tecnológica; Tecnológica; Préstamo BID 1728 OC.AR. PICT-2016-1728, and PICT-2018-1744 and UBACYT 2014–2017 #20120130101305BA (to Dr. Urbano); FONCYT-Agencia Nacional de Promoción Científica y Tecnológica; Préstamo BID 1728 OC.AR. PICT 2015–2594 (to Dr. Bisagno)s.

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Authors

Contributions

VB, FJU, and AB were responsible for the study design. AB, MS, and JAM performed the experiments and analyzed data. VB, AB, and OVT wrote the manuscript. VB, FJU, AB, OVT, JLC, and EGR provided critical revision of the manuscript for important intellectual content. All authors have critically reviewed content and approved the final version submitted for publication.

Corresponding author

Correspondence to Veronica Bisagno.

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Principles of animal care were followed in accordance with “Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research” (National Research Council, 2003) and approved by Universidad de Buenos Aires authorities (Protocol Number: A5801-01) using OLAW and ARENA directives (NIH, Bethesda, USA).

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Bernardi, A., Torres, O.V., Sosa, M. et al. Acute Regulation of the Arousal-Enhancing Drugs Caffeine and Modafinil on Class IIa HDACs In Vivo and In Vitro: Focus on HDAC7. Neurotox Res 38, 498–507 (2020). https://doi.org/10.1007/s12640-020-00200-5

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  • DOI: https://doi.org/10.1007/s12640-020-00200-5

Keywords

  • Modafinil
  • Caffeine
  • HDACs
  • mPFC
  • Dorsal striatum
  • N2a cell line