Differential histone modifications induced by chronic methamphetamine exposure in the rat striatum

Abstract

Methamphetamine (METH) is a very addictive drug. Repeated METH injections cause increases in spine density in striatal medium spiny neurons that receive inputs from corticostriatal glutamatergic projections. We thus undertook the present study to test the possibility that repeated injections of METH might influence the expression of AMPA glutamatergic receptors and of scaffolding proteins. We also measured the effects of METH on the enrichment of acetylated histone 4 on the promoters of AMPA receptors and Homer1. Repeated injections of increasing doses of METH caused significant decreases in the expression of AMPA glutamate receptors (GluA1 and GluA2). There were also METH‐induced decreases in the mRNAs that code for Homer1 and PSD95, proteins that participate in the regulation of the functional effects of glutamate receptors. ChIP‐PCR experiments using antibodies against histone H4 acetylated at lysine 5 (H4K5ac) or lysine 16 (H4K16ac) documented chronic METH‐mediated decreases in the enrichment of H4K5ac and H4K16ac proteins on the promoters of AMPA GluA1 and GluA2 receptors, and on the Homer1 promoter. These results suggest that dynamic regulation of histone H4 acetylation might be involved in the regulation of GluA1 and GluA2. These findings suggest that changes in AMPA receptors might underlie METH‐induced changes in striatal spine density.This work is supported by DHHS/NIH/NIDA/IRP.