Global Examination of the Effects of Methamphetamine on Histone Post‐Translational Modifications in the Rat Striatum

Abstract

Methamphetamine (METH) is a highly addictive psychostimulant that has been associated with deleterious physical and social consequences. A variety of factors ranging from life experiences to genetics are believed to play a role in the addiction process. Post‐translational modifications (PTMs) on histone proteins can lead to alterations in the organization of nucleosomal arrays and the accessibility of transcriptional factors to DNA as a form of epigenetic regulation. This study investigated the effects of chronic METH self‐administration in rats on PTMs of histones H3 and H4 in the striatum using liquid chromatography‐mass spectrometry. Chronic METH use induced group downregulation of the following PTMs on histone H3: K9 dimethylation with unmodified S10 and T11 and K14 acetylation; K18 methylation with K23 acetylation; and K79 dimethylation with T80 phosphorylation. Individual economic demand for METH was positively correlated with H3K79 methylation, H3K14 acetylation, H4K5 acetylation, H4K8 acetylation, H4K12 acetylation, and H4K16 acetylation. The significant decrease of H3T80 phosphorylation supports a downregulation of neural progenitor cell proliferation and neurogenesis, which is consistent with previously discovered inhibition of astrocyte and neural progenitor propagation as a result of METH use. Our novel findings, showing correlation between individual demand and the abundance of post‐translational modifications, offer a novel insight into the epigenetic regulation associated with METH use and further the current understanding of the impact of substance use on epigenome remodeling, while also elucidating potential therapeutic targets for future studies. Support or Funding Information This project was funded by the Hamel Center for Undergraduate Research whose financial support made this research possible.