Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms.
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.
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.
Subramaniam
S
Jayanthi
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.
Michael T
MT
McCoy
Synaptic Plasticity Section, US Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse/Intramural Research Program, Baltimore, MD.
Billy
B
Chen
Synaptic Plasticity Section, US Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse/Intramural Research Program, Baltimore, MD.
Jonathan P
JP
Britt
Synaptic Plasticity Section, US Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse/Intramural Research Program, Baltimore, MD.
Saїd
S
Kourrich
Synaptic Plasticity Section, US Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse/Intramural Research Program, Baltimore, MD.
Hau-Jie
HJ
Yau
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.
Bruce
B
Ladenheim
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.
Irina N
IN
Krasnova
Synaptic Plasticity Section, US Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse/Intramural Research Program, Baltimore, MD.
Antonello
A
Bonci
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.
Jean Lud
JL
Cadet
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D056565:Sirtuin 2 / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology
D004268:DNA-Binding Proteins; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006657:Histones; D008694:Methamphetamine; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D012097:Repressor Proteins; D056564:Sirtuin 1; D056565:Sirtuin 2; D014635:Valproic Acid; C515890:Hdac1 protein, rat; C533426:Hdac2 protein, rat; C104722:glutamate receptor ionotropic, AMPA 2
AMPAR; Addiction; CoREST; HDAC2; MeCP2; NMDAR; REST; valproic acid