Repeated exposure to abusive drugs cause long-term alterations in the affective circuits, which is one of the key drives of relapse. Recently environmental events change neuronal plasticity and learning and memory behaviors via inducing DNA methylation, suggesting that DNA methylation may play a critical role in opiates-induced long-term dysfunction of the affective system. The present study proposes to investigate this hypothesis by examining the effects of repeated morphine-induced self-administration on the levels of DNA methylation in key nuclei of the affective regulation and how the latter affects subsequential behavioral reactions of drug and non-drug stimuli in conditioned place preference or aversion. Further, microdialysis-HPLC study will explore the neurotransmitters mediating the morphine-induced alteration of DNA methylation. In vitro electrophysiological recording of slice and behavior-coupled in vivo fluorescent imaging in awake animals will examine the effect of DNA methylation on plasticity and activation of the nuclei. The present proposal will greatly advance the understanding of the mechanisms of environmentally-induced DNA methylation and its effects on brain function.
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