Abstract
Recent studies have indicated that DNA methylation plays an important role in the development of alcohol abuse. 5-Aza-2’-deoxycytidine (5-Aza-dc), an inhibitor of DNA methyltransferases, was FDA approved for myelodysplastic syndrome treatment. However, it is unclear whether 5-Aza-dc is involved in alcohol abuse. In this study, using a chronic alcohol exposure model in rats, 5-Aza-dc was injected into the medial prefrontal cortex (mPFC). Alcohol-drinking behavior and the anxiety related behavior were evaluated by two-bottle choice and open field test. We found that 5-Aza-dc injection into the mPFC significantly decreased alcohol consumption and alcohol preference in alcohol-exposure rats, corresponding to the reduced blood alcohol levels. Although 5-Aza-dc potentiated the anxiety-like behavior of alcohol-exposure rats, it had no effect on the locomotor activity. Moreover, both of the mRNA and protein levels of DNA Methyltransferase 3A (DNMT3A) and DNMT3B in the mPFC were upregulated after 35 days of alcohol exposure and this upregulation could be reversed by 5-Aza-dc treatment. Additionally, 5-Aza-dc reversed the alcohol-induced downregulation of neurotrophin-3 (Ntf3), correspondingly the expression of its receptor-TrkC was reduced. These findings identified a functional role of 5-Aza-dc in alcohol-related behavioral phenotypes and one of the potential target genes, Ntf3. We also provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcohol abuse.
Highlights
Alcohol abuse is a complex disorder that results in tolerance, withdrawal, relapse and cognitive deficits such as learning and memory impairment[1, 2], which are based on long-lasting gene expression and neuronal synaptic plasticity [3, 4]
We focused on the medial prefrontal cortex because
Repeated measures (RM) two-way analysis of variance (ANOVA) revealed no significant difference in weight gain between the water- and alcohol-exposure groups [F Alcohol (1, 22) = 0.649, p = 0.429]
Summary
Alcohol abuse is a complex disorder that results in tolerance, withdrawal, relapse and cognitive deficits such as learning and memory impairment[1, 2], which are based on long-lasting gene expression and neuronal synaptic plasticity [3, 4]. DNA methylation can maintain long-term stability of related phenotypes by regulating the permanent silencing of specific genes [5, 6]. While several studies support a role of DNA methylation in regulation of alcohol-related behavior [7,8,9], but much less is known about the exact mechanism. The prefrontal cortex (PFC) is associated with the regulation of cognitive, emotional, and motivational processes [10,11,12].
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