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 biological and cognitive functions, striking opposite responses were found between the two reinforcers, notably for genes controlling DNA methylation/demethylation processes and in global DNA methylation involved in chromatin remodeling. 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 observed cocaine and sucrose-induced changes in DNA methylation in a time dependent manner are long lasting or contribute to the establishment of 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.
Highlights
Drugs of abuse and natural reinforcers such as food or sugar activate some common brain structures of the mesocorticolimbic reward system and can lead to addiction characterized by a compulsive behavior despite the awareness of negative effects
The regulation of methyl-CpG-binding proteins MeCP2 considered as a major epigenetic factor [9] and MBD1 suggested that postmitotic neurons could reinterpret the DNA methylation code they acquired during early development
The present study demonstrates that the response to cocaine and sucrose of many genes in dopamine projection areas and the hypothalamus is regulated in a time-dependent manner
Summary
Drugs of abuse and natural reinforcers such as food or sugar activate some common brain structures of the mesocorticolimbic reward system and can lead to addiction characterized by a compulsive behavior despite the awareness of negative effects. Cocaine was found to regulate DNA methyltransferases (Dnmts) and ten-eleven translocation (Tets) methylcytosine dioxygenases expression controlling DNA methylation and demethylation processes [5,10,11] Consistent with these findings, DNA methylation of genes such as the cyclin-dependent kinase-like 5 [12] involved in the “early-onset seizure” variant of Rett syndrome [13], the memory suppressor gene protein phosphatase-1 [11,14], Homer regulating glutamate signaling and synaptic plasticity [15] and the Orexin receptor-1 gene [5] regulating the reinforcing and rewarding properties of cocaine [16] has been reported to be modulated by cocaine. The orexin system function extends beyond general reward seeking and plays a critical role in expression of the multiphenotype addiction-like state [45]
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