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.
Highlights
Addiction to methamphetamine (METH) is an international public health problem with an estimated 15–16 million users worldwide
As an initial step in a program of studies to clarify the molecular bases of METH-induced complex changes in the brain, the present study investigated the time course of potential METH-induced changes in gene expression and histone modifications in the nucleus accumbens (NAC), a structure that is closely tied to the behavioral effects of psychostimulants [30]
We identified corticotropin-releasing factor (Crf) as one gene that was substantially induced in the NAC
Summary
Addiction to methamphetamine (METH) is an international public health problem with an estimated 15–16 million users worldwide. Acute administration of a range of METH doses results in a sense of euphoria, increased energy, and hypersexuality [2]. The drug causes substantial changes in gene expression in some brain regions including the cortex, the dorsal striatum, and the midbrain [8,9,10,11]. These molecular changes include transient increases and decreases in the expression of various transcription factors, neuropeptides, and genes that participate in several biological functions [8,9,10,11,12,13]
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