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Mol Neurobiol. 2019 Jan 2. doi: 10.1007/s12035-018-1453-6. [Epub ahead of print]

Regulation of Brain DNA Methylation Factors and of the Orexinergic System by Cocaine and Food Self-Administration.

Author information

1
Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Neuropôle de Strasbourg, Université de Strasbourg, Strasbourg, France.
2
The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands.
3
IGBMC, Inserm U 964, CNRS UMR 7104, University of Strasbourg, Illkirch, France.
4
Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
5
Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Neuropôle de Strasbourg, Université de Strasbourg, Strasbourg, France. anglard@neuro-cnrs.unistra.fr.
6
INSERM, Institut National de la Santé et de la Recherche Médicale, Paris, France. anglard@neuro-cnrs.unistra.fr.

Abstract

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.

KEYWORDS:

Addiction; Cocaine and food self-administration; DNA methylation; Drugs of abuse; Epigenetics; Orexins/hypocretins

PMID:
30603957
DOI:
10.1007/s12035-018-1453-6

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