Title:Epigenetic Landscape of Methamphetamine Use Disorder
Volume: 19
Issue: 12
Author(s): Jean Lud Cadet *Subramaniam Jayanthi
Affiliation:
- Molecular Neuropsychiatry Research Branch, Molecular Neuropsychiatry Section, NIH/NIDA Intramural Research Program, National Institutes of Health; Baltimore, MD,United States
Keywords:
DNA hydroxymethylation, DNA methylation, histone acetylation, histone methylation, epigenetics, methamphetamine,
chromatin, gene expression.
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.
