Regulation of Brain DNA Methylation Factors and of the Orexinergic System by Cocaine and Food Self-Administration
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Inhibitors of DNA methylation and orexin type-1 receptor antagonists modulate the neurobiological effects driving drugs of abuse and natural reinforcers by activating common brain structures of the mesolimbic reward system. In this study, we applied a self-administration paradigm to assess the involvement of factors regulating DNA methylation processes and satiety or appetite signals. These factors include Dnmts and Tets, miR-212/132, orexins, and orx-R1 genes. The study focused on dopamine projection areas such as the prefrontal cortex (PFCx) and caudate putamen (CPu) and in the hypothalamus (HP) that is interconnected with the reward system. Striking changes were observed in response to both reinforcers, but differed depending on contingent and non-contingent delivery. Expression also differed in the PFCx and the CPu. Cocaine and food induced opposite effects on Dnmt3a expression in both brain structures, whereas they repressed both miRs to a different extent, without affecting their primary transcript in the CPu. Unexpectedly, orexin mRNAs were found in the CPu, suggesting a transport from their transcription site in the HP. The orexin receptor1 gene was found to be induced by cocaine in the PFCx, consistent with a regulation by DNA methylation. Global levels of 5-methylcytosines in the PFCx were not significantly altered by cocaine, suggesting that it is rather their distribution that contributes to long-lasting behaviors. Together, our data demonstrate that DNA methylation regulating factors are differentially altered by cocaine and food. At the molecular level, they support the idea that neural circuits activated by both reinforcers do not completely overlap.
KeywordsCocaine and food self-administration Drugs of abuse DNA methylation Epigenetics Orexins/hypocretins Addiction
This work was supported by the CNRS and the Université de Strasbourg, by the Neurotime Erasmus + Mundus program of the European Commission including a doctoral fellowship attributed to Lamis Saad. Sarah Pol Bodetto was a former recipient of a fellowship from the “Ministère de l’Enseignement Supérieur et de la Recherche.” We thank Dr. J. Mendoza for kindly providing orexin A specific antibody and Dr. Katia Befort for comments on the manuscript.
Compliance with Ethical Standards
All procedures involving animal care were conducted in compliance with national laws and policies (Council directive 87848, 1987, Service Vétérinaire de la Santé et de la Protection animale, permission 67-165 to J.Z. and 67-370 to P.R.), with the Ministère de l’Education Nationale de l’Enseignement Supérieur et de la Recherche (project permission number APAFIS#2133-20151 00221 087072 to P.A.) and international guidelines (NIH publication 5586-23, 1985).
Conflict of Interest
The authors declare that they have no conflict of interest.
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