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Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms.
- Source :
-
Biological psychiatry [Biol Psychiatry] 2014 Jul 01; Vol. 76 (1), pp. 47-56. Date of Electronic Publication: 2013 Oct 16. - Publication Year :
- 2014
-
Abstract
- Background: Chronic methamphetamine (METH) exposure causes neuroadaptations at glutamatergic synapses.<br />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.<br />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.<br />Conclusions: These observations suggest that histone H4 hypoacetylation may be the main determinant of METH-induced decreased striatal glutamate receptor expression.<br /> (Published by Society of Biological Psychiatry on behalf of Society of Biological Psychiatry.)
- Subjects :
- Acetylation drug effects
Animals
Corpus Striatum metabolism
Corpus Striatum physiology
DNA Methylation drug effects
DNA-Binding Proteins metabolism
Histone Deacetylase 1 antagonists & inhibitors
Histone Deacetylase 1 metabolism
Histone Deacetylase 2 antagonists & inhibitors
Histone Deacetylase 2 metabolism
Histones metabolism
Male
Neurons drug effects
Neurons physiology
Rats
Receptors, AMPA biosynthesis
Receptors, N-Methyl-D-Aspartate biosynthesis
Repressor Proteins metabolism
Sirtuin 1 metabolism
Sirtuin 2 metabolism
Valproic Acid pharmacology
Corpus Striatum drug effects
Down-Regulation drug effects
Epigenesis, Genetic drug effects
Methamphetamine pharmacology
Receptors, AMPA genetics
Receptors, N-Methyl-D-Aspartate genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2402
- Volume :
- 76
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Biological psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 24239129
- Full Text :
- https://doi.org/10.1016/j.biopsych.2013.09.034