The Epigenetic Mechanisms of Amphetamine

Abstract

Amphetamine (AMPH) is a psychostimulant and the most prescribed drug to treat attention deficit hyperactive disorder (ADHD). Although therapeutically used doses are generally well tolerated, numerous side effects are still known to occur, such as jitteriness, loss of appetite and psychosis. Moreover, AMPH is liable to be abused by users looking for increased alertness, weight loss or athletic performance. A growing body of evidence indicates that drugs of abuse, including AMPH, control gene expression through chromatin modifications. However, while numerous studies have investigated the molecular mechanisms of AMPH action, only a small number of studies have explored changes in gene expression caused by AMPH. This review examines the epigenetic changes induced by chronic and acute treatments with AMPH and includes, where relevant, data obtained with other psychostimulants such as methamphetamine and cocaine.

Figure 1

Summary of epigenetic modifications induced by amphetamine - Amphetamine (AMPH) has been shown to induce several epigenetic changes. For instance, acute AMPH treatments induce expression of c-fos gene, along with increased histone H4 acetylation at its promoter. On the other hand, chronic exposure reduces histone acetylation and represses c-fos expression by increasing expression of Kmt1a, a histone methyltransferase which increases H3K9 dimethylation at the c-fos promoter. Chronic AMPH treatments have also been shown to increase Dnmt1 expression, which is accompanied by a global increase in DNA methylation. Increased phosphorylation of MeCP2, a protein that associates with methylated DNA, is shown to occur via activation of D1-like dopamine receptors. Finally, several miRNAs are up and down regulated following chronic AMPH use.