METHAMPHETAMINE AND MODAFINIL ELICIT DIFFERENTIAL EPIGENETIC AND FUNCTIONAL PROFILES IN THE MOUSE MEDIAL PREFRONTAL CORTEX

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

Paris

Congreso; ISN-ESN Biennial Meeting; 2017

International Society for Neurochemistry

Methamphetamine (METH) addiction pre­sents with spe­ci­fic be­havioral alterations that sug­gest long-lasting changes in gene regu­lation within brain nuclei of the reward circuitry, including the medial pre­frontal cortex (mPFC). METH negatively impacts the mPFC func­tion, leading to decreased func­tion and longstanding cognitive decline both in humans and animal models. Given the persistence of the addiction phenotype at both be­havioral and trans­criptional levels, in­creasing evidence implicate epige­net­ic mecha­nisms of gene regu­lation behind the neuro­be­havioral adaptions induced by psycho­stimulants. Also, psycho­stimulant drugs are known by their pro-cognitive effects, in part by its ability to in­crease PFC func­tion, such as modafinil. Inter­estingly, modafinil has shown little abuse liability. The aim of the pre­sent study is to iden­ti­fy differential markers of METH and modafinil actions on epige­net­ic and func­tional targets in the mPFC, that may help iden­ti­fy pathways as­so­ci­ated with addictive vs cognitive enhancing traits of these stimulants. Mice received METH (1 mg/kg) or modafinil (90 mg/kg) single dose acute treat­ment (sacrifice 1hr later) or subchronic daily7 days-treat­ment (sacrifice withdrawal day 4). METH single dose treat­ment induced paired-pulse facilitation of EPSCs in D1-ex­pressing layer V pyramidal neu­rons (patch clamp in BAC-Drd1a-tdTomato), sug­gesting re­duced pre­synaptic pro­bability of glu­tam­ate release, whereas modafinil had no effect. We found re­duced dopamine receptors Drd1a and Drd2 mRNA ex­pression after METH, whereas modafinil in­creased ex­pression of Drd2 and c-Fos com­pared to controls. Both stimulants acutely decreased H4ac and in­creased H3ac, HDAC2 and NMDA GluR1, com­pared to controls. H4ac, HDAC2 and GluR1 effects were blocked by D1 antagonist pre­treat­ment, whereas H3ac effect was not. Subchronic METH and modafinil decreased H4ac and GluR1 ex­pression, whereas only METH showed decreased H3ac and HDAC2. These differences could be related to METH-de­pen­dent detrimental effects on mPFC vs the pro-cognitive pro­file induced by modafinil in experimental and clinical settings.