Escalated oxycodone self-administration is associated with activation of specific gene networks in the rat dorsal striatum
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PROVIDER: PRJNA1179446 | ENA |
REPOSITORIES: ENA
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Project description:The number of individuals diagnosed with opioid use disorder (OUD) has risen steeply because of the increased prescribing of opioid drugs like oxycodone for chronic pain relief. OUD is characterized by loss of control of drug taking, continued drug use in the presence of adverse consequences, and repeated relapses to drug taking. Repeated exposure to oxycodone self-administration can lead to addiction in certain rats while others remain unaffected. Understanding the molecular mechanisms between these two groups holds promise for developing strategies to combat addiction. To identify signaling pathways associated with oxycodone addition, this study used male Sprague-Dawley rats to self-administer oxycodone for 20 days according to short-(ShA, 3 h) and long-access (LgA, 9 h) paradigms. Animals were euthanized after 2 hours of self-administration cessation and their dorsal striata were used for RNA sequencing analysis. LgA rats escalated their oxycodone intake and developed into 2 phenotypes, named long-access high (LgA-H, addicted) and long-access lower (LgA-L, non-addicted) rats, based on the level of escalation and drug taken during the self-administration experiment. RNA sequencing revealed many differentially expressed genes in the oxycodone-addicted rats in comparison to other groups. DAVID analysis indicated that some of these genes were involved in potassium transport, ATP binding, and regulation of synaptic processes. Ingenuity pathway analysis (IPA) revealed previous involvement of some genes in OUD and cognitive processes. RNA sequencing and RT-PCR analysis of dorsal striatum samples unveiled a significant upregulation of potassium channel genes Kcnma1, Kcnk9, Kcnq1, Kcnd3, and Kcng3 in LgA-H rats, which was corelated with oxycodone intake. We also identified increased expression for Cldn3, Serping1, and Serpinh1 in ShA rats. Taken together, these observations identified potassium channels as potential targets for the treatment of oxycodone use disorder.
2025-08-20 | GSE280582 | GEO
Project description:Examining changes in gene expression in the dorsal and ventral striatum following chronic oxycodone SA
2019-05-27 | GSE113948 | GEO
Project description:Methamphetamine is a widely abused, highly addictive drug. Regulation of synaptic proteins within the brain’s reward pathway modulates addiction behaviours, the progression of drug addiction and long-term changes in brain structure and function that result from drug use. Therefore, using large scale proteomics studies we aim to identify global protein expression changes within the dorsal striatum, a key brain region involved in the modulation of addiction. We performed LC-MS/MS analyses on rat striatal synaptosomes following 30 days of methamphetamine self-administration (2 hours/day) and 14 days abstinence. We identified a total of 84 differentially-expressed proteins with known roles in neuroprotection, neuroplasticity, cell cytoskeleton, energy regulation and synaptic vesicles. We identify significant expression changes in stress-induced phosphoprotein and protein Tppp, which have not previously been associated with addiction. In addition, we confirm the role of amphiphysin and phosphatidylethanolamine binding protein in addiction. This approach has provided new insight into the effects of methamphetamine self-administration on synaptic protein expression in a key brain region associated with addiction, showing a large set of differentially-expressed proteins that persist into abstinence.
2015-05-06 | PXD001443 | Pride
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 -80ºC. 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 55°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.
2012-05-31 | E-GEOD-38223 | biostudies-arrayexpress
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.
2012-06-01 | GSE38223 | GEO
Project description:We performed discovery-based proteomic profiling of synaptoneurosomes (SNs), subcellular fractions of brain tissue containing both pre- and post-synaptic components, isolated from the dorsal striatum of rats following methamphetamine (Meth) administration to investigate how methamphetamine exposure alters the synaptic proteome. Using tandem mass tag (TMT)-based multiplexed quantification with high-resolution mass spectrometry (HRMS), we identified 6094 proteins and quantified 4583 in 3 out 5 biological replicates. Comparative analysis between Meth-treated and control rats revealed differential regulation for 147 proteins. These proteins were enriched in synaptic, mitochondrial, and proteasomal pathways.
2025-11-19 | PXD066175 | Pride
Project description:Significant methamphetamine (METH)-induced behavioral differences exist between the two sexes of humans and other animals. These dissimilarities may be related to sexual dimorphism in baseline molecular and biochemical mechanisms in brain reward neuroanatomical pathways. As a first step towards identifying sex-based differences in methamphetamine-induced transcriptional signatures, we used RNA sequencing analysis to measure genome-wide changes in gene expression in the dorsal striatum of rats that had self-administered METH. We trained rats to self-administer METH (0.1 mg/kg/infusion, i.v.) using two 3-hr daily sessions (with 30 minutes time out between session) for 20 days. Control rats self-administered saline under similar conditions. This was followed by drug seeking tests on withdrawal days 3 (WD3) and 30 (WD30). Behavioral results show that male rats took more METH than female rats. In both male and female rats, some animals escalated (high-takers) whereas others did not escalate (low-takers) their METH intake during the behavioral experiment. Rats were euthanized 24 hours after the second drug seeking test. RNA was extracted from the dorsal striatum (dSTR) and used in RNA sequencing analysis. The data identified substantial baseline differences in gene expression between female and male control rats. In addition, METH use and withdrawal were associated with significant sex-related differences in changes in striatal gene expression, with minimal overlaps of altered mRNAs. Thus, the present results provide further supporting evidence for sexually dimorphic responses to METH exposure. These observations support the notion of sex-specific approaches to the treatment of patients who suffer from METH use disorder.
2025-06-16 | GSE280589 | GEO
Project description:TRAP translational profiling is a method that allows investigators to genetically characterize specific cell types in complex tissues such as mouse brain. Using this technique we obtained RNA-Seq data from actively translating transcripts present in medium spiny neurons in the dorsal striatum of adult Drd1-EGFP/Rpl10a (CP73) mice that were administered either saline or cocaine under long access conditions
2019-12-16 | GSE141624 | GEO
Project description:TRAP translational profiling is a method that allows investigators to genetically characterize specific cell types in complex tissues such as mouse brain. Using this technique we obtained RNA-Seq data from actively translating transcripts present in medium spiny neurons in the dorsal striatum of adult Drd2-EGFP/Rpl10a (CP101) mice that were administered either saline or cocaine under long access conditions
2019-12-13 | GSE141899 | GEO
Project description:Long-access cocaine intravenous self-administration transcriptional profiling of medium spiny neurons in the dorsal striatum of Drd1-TRAP (CP73) mice
| PRJNA594200 | ENA