METHAMPHETAMINE AND MODAFINIL EFFECTS ON EPIGENETIC AND FUNCTIONAL MARKERS IN THE MOUSE PREFRONTAL CORTEX

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

Buenos Aires

Congreso; 2nd FALAN Congress; 2016

FALAN

The aim of the present study is to identify differential markers of methamphetamine (METH) and modafinil actions on epigenetic and glutamatergic targets in the medial prefrontal cortex (mPFC), that may help identify pathways associated with addictive vs cognitive enhancing traits of these stimulants. Mice received METH (1 mg/kg), modafinil (90 mg/kg) or vehicle and were sacrificed 1 hr later. We evaluated glutamate synaptic transmission in dopamine receptor 1-expressing layer V pyramidal neurons (whole-cell patch clamp in transgenic BAC-Drd1a-tdTomato) and found that METH induced paired-pulse facilitation of EPSCs, suggesting reduced presynaptic probability of glutamate release onto layer V pyramidal neurons, whereas modafinil did not modify paired-pulse ratios. METH and modafinil had similar effects eliciting increased acetylated histone 3, NMDA GluR1 and HDAC2, and decreased acetylated histone 4 compared to controls. Histone 4 acetylation was blocked by D1 antagonist SCH23390 pretreatment, whereas Histone 3 was not. Also, we found reduced dopamine receptors Drd1a and Drd2 mRNA expression after METH, whereas modafinil showed no differences in Drd1a expression and increased expression of Drd2 compared to controls. These differences could be related to the METH-dependent detrimental effects on mPFC and to pro-cognitive profile induced by modafinil in clinical settings.PICT2012-0924, PICT2012-1769, PICT2015-2594, PICT2014-2499, Argentina/NIH award P20 GM103425 to UAMS, USA.