title: Methamphetamine causes differential alterations in gene expression and patterns of histone acetylation/hypoacetylation in the rat nucleus accumbens.
abstract: Methamphetamine (METH) addiction is associated with several neuropsychiatric symptoms. Little is known about the effects of METH on gene expression and epigenetic modifications in the rat nucleus accumbens (NAC). Our study investigated the effects of a non-toxic METH injection (20 mg/kg) on gene expression, histone acetylation, and the expression of the histone acetyltransferase (HAT), ATF2, and of the histone deacetylases (HDACs), HDAC1 and HDAC2, in that structure. Microarray analyses done at 1, 8, 16 and 24 hrs after the METH injection identified METH-induced changes in the expression of genes previously implicated in the acute and longterm effects of psychostimulants, including immediate early genes and corticotropin-releasing factor (Crf). In contrast, the METH injection caused time-dependent decreases in the expression of other genes including Npas4 and cholecystokinin (Cck). Pathway analyses showed that genes with altered expression participated in behavioral performance, cell-to-cell signaling, and regulation of gene expression. PCR analyses confirmed the changes in the expression of c-fos, fosB, Crf, Cck, and Npas4 transcripts. To determine if the METH injection caused post-translational changes in histone markers, we used western blot analyses and identified METH-mediated decreases in histone H3 acetylated at lysine 9 (H3K9ac) and lysine 18 (H3K18ac) in nuclear sub-fractions. In contrast, the METH injection caused time-dependent increases in acetylated H4K5 and H4K8. The changes in histone acetylation were accompanied by decreased expression of HDAC1 but increased expression of HDAC2 protein levels. The histone acetyltransferase, ATF2, showed significant METH-induced increased in protein expression. These results suggest that METH-induced alterations in global gene expression seen in rat NAC might be related, in part, to METH-induced changes in histone acetylation secondary to changes in HAT and HDAC expression. The causal role that HATs and HDACs might play in METH-induced gene expression needs to be investigated further.
authors.affiliation: Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, Baltimore, Maryland, United States of America.
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Martin
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Jayanthi
authors.forename: Michael T
authors.initials: MT
authors.lastname: McCoy
authors.forename: Christie
authors.initials: C
authors.lastname: Brannock
authors.forename: Bruce
authors.initials: B
authors.lastname: Ladenheim
authors.forename: Tiffany
authors.initials: T
authors.lastname: Garrett
authors.forename: Elin
authors.initials: E
authors.lastname: Lehrmann
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
mesh_terms: D000107:Acetylation / Q000187:drug effects; D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D000697:Central Nervous System Stimulants; D006657:Histones; D008694:Methamphetamine; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2