Epigenetic Landscape of Methamphetamine Use Disorder

Abstract

The persistence of the addiction phenotype in methamphetamine use disorder (MUD) suggests the potential presence of epigenetic changes and potential structural adaptations that may drive the manifestations of MUD in humans. In the present review, we discuss the evidence that documents the fact that methamphetamine exposure can cause changes in epigenetic modifications, including histone acetylation and methylation, as well as DNA methylation and hydroxymethylation in a complex manner that need to be fully dissected. Nevertheless, our work has demonstrated the existence of correlations between behavioral changes and epigenetic alterations during methamphetamine selfadministration. We found that prolonged methamphetamine self-administration and contingent footshocks resulted in rats with compulsive drug-taking and abstinent phenotypes. In addition, rats that reduce their methamphetamine intake in the presence of punishment showed increased DNA hydroxymethylation in genes encoding potassium channels in their nucleus accumbens. Moreover, altered DNA hydroxymethylation in those genes led to an increase in their mRNA expression. Additional studies revealed decreased mRNA expression of histone deacetylases associated with increased histone acetylation and induced gene expression in the dorsal striatum. These changes were associated with a reduction in methamphetamine intake in response to contingent footshocks. More research is necessary in order to further dissect how pharmacological or genetic manipulations of identified epigenetic alterations and expression of potassium channels can impact methamphetamine-taking behaviors or relapse to methamphetamine-taking after long periods of abstinence. Investigations that use discovery approaches, such as whole-genome sequencing after chromatin immunoprecipitation, should accelerate our efforts to develop epigenetic therapeutic approaches against MUD.

Keywords: DNA hydroxymethylation; DNA methylation; chromatin; epigenetics; gene expression.; histone acetylation; histone methylation; methamphetamine.

Fig. (1)

This schema illustrates, in part, the potential role of histone acetylation and phosphorylation in methamphetamine use disorder. The figure shows the initial steps that may be involved after the release of dopamine (DA) and its interactions with DA D1-like receptors in various brain regions. Subsequent to DA-D1 interactions, there is an activation of protein kinase A and a subsequent cascade that leads to histone phosphorylation and the facilitation of histone acetylation. These biochemical events increase the transcription of immediate early genes and other genes involved in controlling epigenetic events. Together, these events may lead to persistent structural adaptations and associated behavioral changes that are labeled as methamphetamine use disorder. Further elucidation of these molecular events should help to develop a treatment against methamphetamine addiction. (A higher resolution/colour version of this figure is available in the electronic copy of the article).