Methamphetamine and modafinil differentially alter mRNA expression of epigenetic regulators in the mouse prefrontal cortex.

BETINA GONZALEZ; JAVIER A. MUÑIZ; JEAN LUD CADET; EDGAR GARCIA-RILL; FRANCISCO URBANO; VERONICA BISAGNO

Huerta Grande

Congreso; XXIX Annual Meeting and SAN-ISN Small Conference and Course; 2014

Sociedad Argentina de Investigacion en Neurociencias

Chronic methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and animal models. Modafinil is a wake-promoting compound that is being prescribed off label for the treatment of METH dependence. There is evidence that epigenetic defects play a major role in the pathogenesis of psychiatric disorders. We previously demonstrated that modafinil can rescue METH-induced deficits on memory retention through a mechanism that involves restoration of ERK signaling in the medial prefrontal cortex (mPFC). In this study, we used cPCR to measure mPFC epigenetic regulators of gene expression. These include histone acetyl-transferases (HATs) deacetylases (HDACs), DNA methyltransferases (DNMTs), and methylcytosine dioxygenases (TETs). We also quantified c-Fos expression as a marker of neuronal activation. METH (1 mg/kg, sc) was administered as a single dose or repeatedly (daily for 7 days). Additionally, we evaluated the effects of a single dose of modafinil (90 mg/kg, ip) given alone (MOD) or after METH (METH-MOD). Tissues were collected 1 hr after drug administration. We found that single dose and repeated METH treatments caused increased expression of Tet1 mRNA and decreased Hdac1, Hdac2, Hat1, and Dnmt3A mRNA levels. METH withdrawal also showed decreased expression of Hdac1 and Hdac2. MOD showed decreased Hdac2 and increased c-Fos expression. Interestingly, the METH-MOD group showed a differential expression pattern when compared with METH and MOD alone, with decreased Tet2, and Hdac1 and Hdac2 mRNA levels to even lower values than those obtained with METH. Our results show that METH and modafinil on their own exert differential effects on epigenetic marker expression in the mPFC, with METH altering a larger set of epigenetic regulators than modafinil. These differences could be related to the METH-induced cognitive impairments and mPFC abnormalities.