Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms

Subramaniam Jayanthi, Michael T. McCoy, Billy Chen, Jonathan P. Britt, Saïd Kourrich, Hau Jie Yau, Bruce Ladenheim, Irina N. Krasnova, Antonello Bonci, Jean Lud Cadet

Research output: Contribution to journalArticlepeer-review

97 Scopus citations


Background Chronic methamphetamine (METH) exposure causes neuroadaptations at glutamatergic synapses. Methods To identify the METH-induced epigenetic underpinnings of these neuroadaptations, we injected increasing METH doses to rats for 2 weeks and measured striatal glutamate receptor expression. We then quantified the effects of METH exposure on histone acetylation. We also measured METH-induced changes in DNA methylation and DNA hydroxymethylation. Results Chronic METH decreased transcript and protein expression of GluA1 and GluA2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and GluN1 N-methyl-D-aspartate receptor subunits. These changes were associated with altered electrophysiological glutamatergic responses in striatal neurons. Chromatin immunoprecipitation-polymerase chain reaction revealed that METH decreased enrichment of acetylated histone H4 on GluA1, GluA2, and GluN1 promoters. Methamphetamine exposure also increased repressor element-1 silencing transcription factor (REST) corepressor 1, methylated CpG binding protein 2, and histone deacetylase 2 enrichment, but not of sirtuin 1 or sirtuin 2, onto GluA1 and GluA2 gene sequences. Moreover, METH caused interactions of REST corepressor 1 and methylated CpG binding protein 2 with histone deacetylase 2 and of REST with histone deacetylase 1. Surprisingly, methylated DNA immunoprecipitation and hydroxymethylated DNA immunoprecipitation-polymerase chain reaction revealed METH-induced decreased enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at GluA1 and GluA2 promoter sequences. Importantly, the histone deacetylase inhibitor, valproic acid, blocked METH-induced decreased expression of AMPAR and N-methyl-D-aspartate receptor subunits. Finally, valproic acid also attenuated METH-induced decrease H4K16Ac recruitment on AMPAR gene sequences. Conclusions These observations suggest that histone H4 hypoacetylation may be the main determinant of METH-induced decreased striatal glutamate receptor expression.

Original languageEnglish (US)
Pages (from-to)47-56
Number of pages10
JournalBiological Psychiatry
Issue number1
StatePublished - Jul 1 2014


  • Addiction
  • CoREST
  • HDAC2
  • MeCP2
  • REST
  • valproic acid

ASJC Scopus subject areas

  • Biological Psychiatry


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