Persistent gene expression changes in NAc, mPFC, and OFC associated with previous nicotine or amphetamine exposure

Abstract

Highly addictive drugs like nicotine and amphetamine not only change an individual's behaviour in the short and long-term, they also induce persistent changes in neuronal excitability and morphology. Although research has started to examine the epigenetic changes that occur immediately after drug exposure, there has been little investigation into the persistent modifications to the epigenome that likely moderate the stable maintenance of the neurological changes. Male Long-Evans rats were administered amphetamine, nicotine, or saline for 14 consecutive days, given a 14 day withdrawal period, and then sacrificed. DNA from the mPFC, OFC, and nucleus accumbens (NAc) was used for global DNA methylation analysis and RNA from the same brain regions was used for gene expression analysis. Following the two-week withdrawal period, exposure to amphetamine or nicotine was associated with a decrease in global DNA methylation in each brain region examined. Previous exposure to nicotine was associated with changes in expression of 16 genes (NAc:6, mPFC:5, OFC:5) whereas exposure to amphetamine was associated with changes in expression of 25 genes (NAc:13, OFC:8, mPFC:4). The persistent epigenetic changes associated with exposure to amphetamine and nicotine were region and drug dependent, and differ from the latent epigenetic changes that occur immediately after drug exposure. The changes in DNA methylation are consistent with the gene expression results and provide further support to the notion that DNA methylation is the key regulatory mechanism for experience dependent changes.