Mimicking Substance Use Disorders in Animal Models. Distinctive effects of modafinil and caffeine on the regional expression of histone deacetylases in the brain

BISAGNO, V.

New Orleans

Simposio; 2022 Society for Biological Psychiatry Annual Meeting; 2022

Distinctive effects of modafinil and caffeine on the regional expression of histone deacetylases in the brainVeronica Bisagno, Ph. D.ININFA (UBA-CONICET), University of Buenos Aires, Junin 956, Buenos Aires, Argentina.Background: Psychostimulants produce different behavioral and neurobiological profiles. For example, some stimulants cause neuroplastic changes leading to addiction and cognitive deficits while others enhance cognition. Epigenetic mechanisms are known contributory factors to drug-induced neuroadaptations. These epigenetic changes include dysregulation of histone deacetylases (HDACs) proposed to participate in maintaining aberrant transcriptional programs associated with altered cognitive functions and behaviors. MethodsWe compared changes in class IIa HDACs in the mouse mPFC and dorsal striatum (DS) after a single exposure to psychostimulants. We treated male C57BL/6 mice with modafinil (90 mg/kg), caffeine (10 mg/kg) or vehicle and evaluated locomotor activity. Following, we examined hdac4, hdac5, hdac7 mRNAs expression using qRT-PCR and HDAC7, pHDAC7, pHDACs4/5/7 by WB. Last, we explored generalized effects in N2a cell line using modafinil (100 µM and 1 mM) or caffeine (80 µM and 800 µM).ResultsModafinil decreased hdac5 and hdac7 mRNAs expression in the DS, while caffeine had no effect. 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, pHDACs4/5/7 protein expression. While, in the mPFC, caffeine induced decreases in HDAC7, pHDAC7, pHDACs4/5/7 protein levels. In vitro studies revealed that modafinil increased hdac4, hdac5, hdac7 mRNA levels in N2a, while caffeine only increased hdac5 at a higher dose.ConclusionTaken together, our results support the notion that modafinil exert distinct regulation of class IIa HDAC family members and that these transcriptional and translational consequences are region-specific and probably linked to modafinil pro-cognitive profile.Acknowledgement: This work is supported by FONCYT-Agencia Nacional de Promoción Científica y Tecnológica; Tecnológica; Argentina.