Differential effects of modafinil and methamphetamine on epigenetic and glutamatergic markers expression in the prefrontal cortex.

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

Cairns

Congreso; ISN 2015 Biennial Meeting; 2015

International Society for Neurochemistry

Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and animal models. Modafinil is a wake-promoting compound approved for the treatment of narcolepsy and being prescribed off label for the treatment of METH dependence. There is increasing evidence that epigenetic defects play a major role in the pathogenesis of psychiatric and substance abuse disorders. Interestingly, several psychotropic drugs in clinical use exhibit epigenetic effects in addition to their commonly understood mechanisms of action. We previously demonstrated that modafinil can rescue METH-induced deficits on visual memory retention through a mechanism that involves restoration of ERK signaling in the medial prefrontal cortex (mPFC). In the present study, we used qPCR to measure mPFC epigenetic regulators of gene expression that modify the local state of chromatin. These include histone deacetylases (Hdac), DNA methyltransferases (Dnmt), and methylcytosine dioxygenases (Tet). We also quantified histone 3 acethylation, glutamate receptor AMPA (Gria) and NMDA (Grin) subunits and c-Fos expression. METH (1 mg/kg, sc) was administered as a single dose or repeatedly (once daily for 7 days and 4 days of withdrawal). Additionally, we evaluated the effects of a single dose of modafinil (90 mg/kg, ip) given alone (MOD) or after METH withdrawal (METH-MOD). Tissues were collected 1 hr after drug or vehicle administration. We found that single dose METH treatments caused increased histone 3 acethylation and expression of Tet1, Gria1 and Gria2 mRNA, together with decreased Hdac1, Hdac2 and Dnmt3A mRNA levels. Repeated METH withdrawal also showed increased expression of Gria1 and decreased expression of Hdac1 and Hdac2, together with increased expression of Grin1 that was not detected when single dose METH was evaluated acutely. The MOD alone group showed decreased Hdac2 and increased c-Fos, Gria1, Gria2, Grin1 and histone 3 acethylation. Interestingly, the METH-MOD group showed a differential expression pattern when compared with METH and MOD alone, with decreased Tet2, Gria1, Gria2 and Grin2a, and Hdac1 and Hdac2 mRNA levels to even lower values than those obtained with METH treatments. Our results show that METH and modafinil 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. Finally, our results suggest that modafinil, given in the presence or absence of METH, appears to initiate differential transcriptional and epigenetic programs that might contribute to its beneficial cognitive effects.