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Biol Psychiatry. 2014 Jul 1;76(1):47-56. doi: 10.1016/j.biopsych.2013.09.034. Epub 2013 Oct 16.

Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms.

Author information

1
Molecular Neuropsychiatry Research Branch, US Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse/Intramural Research Program, Baltimore, MD.
2
Synaptic Plasticity Section, US Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse/Intramural Research Program, Baltimore, MD.
3
Molecular Neuropsychiatry Research Branch, US Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse/Intramural Research Program, Baltimore, MD. Electronic address: jcadet@intra.nida.nih.gov.

Abstract

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.

KEYWORDS:

AMPAR; Addiction; CoREST; HDAC2; MeCP2; NMDAR; REST; valproic acid

PMID:
24239129
PMCID:
PMC3989474
DOI:
10.1016/j.biopsych.2013.09.034
[Indexed for MEDLINE]
Free PMC Article

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