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.

Differential effects of cocaine on histone posttranslational modifications in identified populations of striatal neurons

“…Additional differences were noted for acetylation of H4 on K 8 and K 12 . AcK 5 H4 and to a lesser degree acK 8 H4 were persistent marks that increased in D1 neurons 24 h after single or repeated cocaine injections, in agreement with a previous report (37). It is important to note that the turnover of most acetyl groups is usually high, with reported half-lives of a few minutes (38).…”

Methamphetamine abstinence induces changes in μ-opioid receptor, oxytocin and CRF systems: Association with an anxiogenic phenotype

“…CRF mRNA levels are increased in Acb following a single METH injection (Martin et al, 2012). Likewise, increased CRF levels were observed in the amygdala and plasma of rats undergoing withdrawal from METH selfadministration (Nawata et al, 2012).…”

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

“…20 Some of the long-term effects of this drug may be the results of molecular events that occur in the rodent striatum and NAc after either contingent or noncontingent administration of the drug. [20][21][22][23] In addition to changes in the expression of immediate early genes, 4,22 METH can also alter the expression of several neuropeptides including prodynorphin in the METH SA model. 23 Nevertheless, experimental approaches that use all rats that self-administer a drug to measure biochemical or physiological consequences of drugs do not strictly model human conditions [24][25][26] because not all humans who use rewarding drugs become addicted to them.…”