Cocaine vs natural reinforcers Alteration in the expression of genes involved in DNA methylation and circadian rhythms

The regulation of genes involved in DNA methylation, circadian rhythmicity, appetite, satiety and some microRNAs were investigated in a passive and voluntary administration paradigm for cocaine and natural reinforcers. Drugs of abuse and natural reinforcers activate common brain structures of the mesocorticolimbic reward system and we provide evidence at the molecular level that neural circuits activated by both reinforcers do not completely overlap. The effect of natural reinforcers such as food and sucrose relative to cocaine was compared in the prefrontal cortex, the caudate putamen and the lateral hypothalamus by analyzing gene and protein expression and DNA methylation. Genes or factors analyzed include those involved in DNA methylation (DNMTs, Tets), circadian rhythms (CGs), appetite and satiety (Orx, Npy), and microRNAs either playing a role in cocaine intake or ‘supposed’ to control our genes of interest. In a first publication, we demonstrated that the regulation of brain DNA methylation factors and the orexinergic system by cocaine and food self-administration is different. Similarly, in a second publication, when comparing passive sucrose vs cocaine administration, we highlighted the rhythmic regulation of DNA methylation factors and core-clock genes and the potential role of chromatin remodelling providing evidence that neuroepigenetics participates in the establishment of addiction to drugs of abuse. Altogether, our data contribute to a better understanding of the etiology and pathology of psychiatric disorders related to drug addiction. Understanding the mechanisms dissociating drugs of abuse from natural reinforcers remains a prerequisite for the design of selective therapeutic tools for compulsive behaviours.