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RNA sequencing identified differentially expressed genes in the mesocorticolimbic and nigrostriatal systems of compulsive METH taking rats.

ABSTRACT: Methamphetamine (METH) is an extremely addictive drug which continues to cause significant harm to individuals and communities. Differences in patterns of abuse, amounts of METH taken, and in relapse rates exist among METH users who meet DSM-V criteria for METH use disorder (MUD). We are actively investigating the behavioral and molecular differences between compulsive and non-compulsive METH self-administering (SA) rats in the presence of a foot-shock which serves as an aversive stimulus. In the present study, we used male rats that were trained to self-administer METH (0.1 mg/kg/infusion, IV) on an FR-1 schedule for 20 days using a pattern of three 3-h sessions per day and followed by foot-shocks (0.18mA to 0.36mA) for the next 9 days. All the METH taking rats escalated their drug intake during the 20 days of training phase. During the foot-shock phase, a group of rats continued to self-administer METH in the presence of aversive stimuli and were called shock-resistant (SR, compulsive), whereas others who decreased their intake were termed shock-sensitive (SS, non-compulsive). Animals were euthanized 2 hours after the last SA session and the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (DStr) and midbrain (MBr) were isolated for RNA sequencing. RNA sequencing showed a large number of differentially expressed genes (DEGs) in all the brain regions. Our study supports the notion that studying multiple brain regions is critical for a comprehensive understanding of the interconnected neuroadaptive changes which are associated with substance use disorders (SUDs). The present study is of significant translational importance by further supporting the idea that targeting common DEGs identified across multiple brain regions might lead to the development of effective therapeutic approaches against MUD.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE301346 | GEO | 2025/09/30

REPOSITORIES: GEO

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Project description:Neuroplastic changes in the dorsal striatum participate in the transition from casual drug use to habitual and compulsive drug taking. These alterations might also play a critical role in the development of methamphetamine (METH) addiction. Nevertheless, the molecular substrates that underlie habitual METH consumption have yet to be elucidated. Therefore, in the present study, we examined the influence of METH self-administration on the expression of genes and proteins of interest, as potential substrates of METH-induced neuronal plasticity in the dorsal striatum. Rats self-administered METH (0.1 mg/kg/injection, i.v.) during 15 h sessions for 8 d and were euthanized after 2 h, 24 h, or 1 month of abstinence. Compared to yoked saline control, METH self-administration induced increases in the mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and of the synaptic protein, synaptophysin (Syp) at 2 h after cessation of drug exposure. METH self-administration also caused changes in FosB, BDNF and TrkB protein levels, with increases at 2 and 24 h but decreases observed after 1 month of drug abstinence. Importantly, METH exposure caused increases in the levels of H3K4me3 and pCREB after 2 and 24 h of abstinence. Chromatin immunoprecipitation followed by qPCR was used to clarify the role of these proteins in the regulation of gene expression. We found that METH self-administration caused enrichment of pCREB, but not of H3K4me3, on the promoters of c-fos, fosb, Bdnf and Syp at 2 h after drug cessation. These data indicate that METH-induced activation of their transcription is mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, METH self-administration might trigger epigenetic changes that caused alterations in the expression of genes and proteins serving as substrates for addiction-related synaptic plasticity. Animals were trained to self-administer METH for 8 d as described in the paper, dorsal striata were isolated 2 h, 24 h and 1 month after the final self-administration session. RNA extraction, RNA labeling and microarray hybridization were performed. In brief, total RNA was isolated from the samples using RNeasy Mini Kit (QIAGEN, Valencia, CA). RNA concentration and integrity was determined using Agilent BioAnalyzer (Agilent, Santa Clara, CA). Samples were stored at -80ÂºC. Microarray hybridization was done using RatRef-12 Expression BeadChips arrays (22 523 probes) (Illumina Inc., San Diego, CA). A 600 ng of total RNA from each sample was amplified using Illumina RNA Amplification kit (Ambion, Austin, TX). Single-stranded RNA (cRNA) was generated and labeled by incorporating biotin-16-UTP (Roche Diagnostics, Indianapolis, IN). 750 ng of each cRNA sample were hybridized to Illumina arrays at 55Â°C overnight according to the Gene Expression Protocol for BeadStation (Illumina Inc.). Hybridized cRNA was detected with cyanine3-streptavidin (GE Healthcare, Piscataway, NJ) and quantified using Illumina's BeadStation 500GX scanner.

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RNA sequencing identified differentially expressed genes in the mesocorticolimbic and nigrostriatal systems of compulsive METH taking rats.

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