ININFA   02677
INSTITUTO DE INVESTIGACIONES FARMACOLOGICAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Modafinil and methamphetamine induce differential effects on mRNA expression of epigenetic regulators in the mouse prefrontal cortex
Autor/es:
B. GONZALEZ; J.A. MUÑIZ; S. JAYANTHI; J. L. CADET; E. GARCIA-RILL; F. J. URBANO; V. BISAGNO
Lugar:
Washington
Reunión:
Congreso; Neuroscience 2014, SfN's 44rd annual meeting; 2014
Institución organizadora:
SFN
Resumen:
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 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 (once 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 withdrawal (METH-MOD). Tissues were collected 1 hr after drug or vehicle 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. The MOD alone group 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 treatments. 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. 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.