Rhythmic regulation of DNA methylation factors and core-clock genes in brain structures activated by cocaine or sucrose

Abstract The circadian system interacts with the mesocorticolimbic reward system to modulate reward and memory in a time-of-day dependent manner. The circadian discrimination of reward however remains difficult to address between natural reinforcers and drugs of abuse. Circadian rhythms control cocaine sensitization and conversely cocaine causes long-term alteration in circadian periodicity in part through the serotonergic neurotransmission. Since neural circuits activated by cocaine and natural reinforcers do not completely overlap, we compared the effect of cocaine with that of sucrose, a strong reinforcer in rodents, by using passive chronic administration. The expression of fifteen genes playing a major role in DNA methylation (Dnmts, Tets), circadian rhythms (Clock, Bmal1, Per1/2, Cry1/2, Rev-Erbβ, Dbp1), appetite and satiety (Orexin, Npy) was analyzed in dopamine projection areas like the prefrontal cortex, the caudate putamen, and the hypothalamus interconnected with the reward system. The corresponding proteins of two genes (Orexin, Per2) were examined by IHC. For many factors controlling various biological functions, striking opposite responses were found between the two reinforcers. Global DNA methylation analysis showed that cocaine increased, while sucrose decreased the cytosine methylation content. The data are consistent with a repression of critical core-clock genes by cocaine, suggesting that consequently both agents differentially modulate day/night cycles. Whether cocaine-induced changes are long lasting, or contribute to the establishment of drug addiction requires further neuroepigenetic investigation. Understanding the mechanisms dissociating drugs of abuse from natural reinforcers remains a prerequisite for the design of selective therapeutic tools for compulsive behaviors.