Dataset Information

Methamphetamine leads to the alterations of microRNA profiles in the nucleus accumbens of rats.

ABSTRACT:

Context

MicroRNA (miRNA) is an important regulator of gene expression. Methamphetamine (METH) induces a variety of alterations in different systems by affecting gene expression, but the effects of METH on miRNA profiles need to be elucidated.

Objectives

This study develops a rat model of METH addiction, and analyzes the expression profile alterations of miRNA in nucleus accumbens (NAc) of the METH-addicted rats.

Materials and methods

Sprague-Dawley rats were administered 10 mg/kg METH or vehicle twice a day for 4 weeks. The addictive behaviour of rats was estimated by CPP test. The pathological changes of brain tissues were then observed by HE and Glee silver staining. The miRNA profile analysis of the NAc of the rats was performed using an Illumina HiSeq™ 2500 sequencing system.

Results

CPP test indicated that METH significantly prolonged the residence time of the rats in the drug box (from 307 ± 97 to 592 ± 96 s). The pathological staining showed the distorted axons, and fewer polarized neurons in the METH-treated rats. We further identified 40 differential miRNAs (17 up- and 23 down-regulated) and three novel miRNAs (novel 237, 296 and 501) that responded to METH. The bioinformatic analysis for the potential targets of the differential miRNA suggests that the downstream were concentrated in the Wnt signalling pathway, tuberculosis, toxoplasmosis, spliceosome, lysosome, and axon guidance.

Discussion and conclusions

A number of miRNAs responding to METH were identified in the NAc of rats. These METH-regulated miRNAs provide a new perspective for revealing the molecular mechanisms of METH addiction.

SUBMITTER: Yang J

PROVIDER: S-EPMC8641683 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.