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It is known that METH negatively impacts the prefrontal cortex (PFC) leading to cognitive decline and addiction whereas modafinil enhances cognition and has a low abuse liability. We investigated if modafinil (90\u00a0mg\/kg) and methamphetmine (METH) (1\u00a0mg\/kg) may differentially influence the acetylation status of histones 3 and 4 (H3ac and H4ac) at proximal promoters of class I, II, III, and IV HDACs. We found that METH produced broader acetylation effects in comparison with modafinil in the medial PFC. For single dose, METH affected H4ac by increasing its acetylation at class I <jats:italic>Hdac1<\/jats:italic> and class IIb <jats:italic>Hdac10<\/jats:italic>, decreasing it at class IIa <jats:italic>Hdac4<\/jats:italic> and <jats:italic>Hdac5<\/jats:italic>. Modafinil increased H3ac and decreased H4ac of <jats:italic>Hdac7<\/jats:italic>. For mRNA, single\u2010dose METH increased <jats:italic>Hdac4<\/jats:italic> and modafinil increased <jats:italic>Hdac7<\/jats:italic> expression. For repeated treatments (4\u00a0d after daily injections over 7\u00a0d), we found specific effects only for METH. We found that METH increased H4ac in class IIa <jats:italic>Hdac4<\/jats:italic> and <jats:italic>Hdac5<\/jats:italic> and decreased H3\/H4ac at class I <jats:italic>Hdac1<\/jats:italic>, <jats:italic>Hdac2<\/jats:italic>, and <jats:italic>Hdac8<\/jats:italic>. At the mRNA level, repeated METH increased <jats:italic>Hdac4<\/jats:italic> and decreased <jats:italic>Hdac2<\/jats:italic>. Class III and IV HDACs were only responsive to repeated treatments, where METH affected the H3\/H4ac status of <jats:italic>Sirt2<\/jats:italic>, <jats:italic>Sirt3<\/jats:italic>, <jats:italic>Sirt7<\/jats:italic>, and <jats:italic>Hdac11<\/jats:italic>. Our results suggest that HDAC targets linked to the effects of modafinil and METH may be related to the cognitive\u2010enhancing vs cognitive\u2010impairing effects of these psychostimulants.<\/jats:p>","DOI":"10.1111\/adb.12737","type":"journal-article","created":{"date-parts":[[2019,2,27]],"date-time":"2019-02-27T20:32:53Z","timestamp":1551299573000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["HDAC superfamily promoters acetylation is differentially regulated by modafinil and methamphetamine in the mouse medial prefrontal cortex"],"prefix":"10.1111","volume":"25","author":[{"given":"Betina","family":"Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones Farmacol\u00f3gicas Universidad de Buenos Aires \u2013 Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas  Buenos Aires 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