Transcriptional profile of brain region involved in habitual learning following methamphetamine self-administration and dopamine receptor antagonist
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE200564 | GEO | 2025/04/02
REPOSITORIES: GEO
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Project description:Methamphetamine (METH) is a powerful stimulant that has caused addiction (compulsive drug seeking and taking behavior) in millions of people world-wide. METH abuse is also associated with negative impact on the brain. One feature of addiction is uncontrollable drug seeking despite adverse consequences and becomes habitual. To mimic this in a rat model, rats with a history of METH use are given the opportunity to earn METH accompanied by aversive shocks on their feet. Rats that continue to take METH are shock-resistant (SR) and rats that reduce their METH intake are shock-sensitive (SS ).Rats that self-administered saline are controls (CT). In addition, we used controls for shock paradigm. For this purpose, when METH SA rat received a shock, the saline SA rat was also shocked. The separate groups of rats that were yoked (Y) to the corresponding METH shock-resistant (SR) and shock-sensitive (SS) rats are termed YSR and YSS, respectively.
2023-02-01 | GSE203268 | GEO
Project description:Methamphetamine (METH) use disorder (MUD) is a neuropsychiatric disorder with loss of self-control over drug intake despite of negative consequences. The behavioral consequences of long-term METH intake on compulsive and non-compulsive individuals remain unclear. Herein we trained rats to self-administered METH 1st for 22 days than 8 days of foot-shock and 15 days of abstinence. Which was followed by 12 days of reinstatement to METH self-administration then 3 days of foot-shock and 15 days of abstinence. After 1st foot-shock phase we found two phenotypes based on their METH intake i.e., shock resistance (SR, compulsive), and shock sensitive (SS, non-compulsive). Interestingly during reinstatement of METH self-administration then foot-shock, some (resurgent shock resistance, RSR) non-compulsive rats, displayed compulsive METH intake behavior. During both abstinence period rats were tested for drug seeking behavior and SR rats displayed higher METH seeking then RSR and SS. 24 hour after 2nd withdrawal day testing, we compared transcriptional and epigenetic changes in dorsal striatum.
2024-09-25 | GSE220896 | GEO
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: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:MicroRNAs (miRNAs) regulate many basic aspects of cell biology including neuronal plasticity, but little is known of their roles in drug addiction. Extended access to cocaine can trigger the emergence of compulsive drug-seeking behaviors, but molecular mechanisms regulating this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with extended access to cocaine. Striatal overexpression of miR-212 decreases, whereas its inhibition increases cocaine intake in rats with extended but not restricted drug access, suggesting that miR-212 serves as a protective factor against the development of compulsive drug seeking. The transcription factor CREB (cAMP response element-binding protein) is considered a core regulator of cocaine reward. We show that miR-212 controls responsiveness to cocaine by dramatically amplifying striatal CREB signaling. This action occurs through miR-212-enhanced Raf-1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (Transducer of Regulated CREB; also known as CRTC). Our findings suggest that striatal miR-212 signaling plays a key role in vulnerability to addiction, and that noncoding RNAs such as the miRNAs may serve as novel targets for the development of anti-addiction therapeutics. To identify potential targets for miR-212, we transfected cells with a vector to overexpress miR-212 or an empty vector. We then analyzed profiled gene expression using Affymetrix arrays.
2010-07-08 | GSE21901 | GEO
Project description:Methamphetamine (Meth) seeking progressively increases after withdrawal (incubation of Meth craving), but the transcriptional mechanisms that contribute to this incubation are unknown. Here we used RNA-sequencing to analyze transcriptional profiles associated with incubation of Meth craving in central amygdala (CeA) and orbitofrontal cortex (OFC), two brain areas previously implicated in relapse to drug seeking. We trained rats to self-administer either saline (control condition) or Meth (10 days; 9 h/day, 0.1 mg/kg/infusion). Next, we collected brain tissue from CeA and OFC on withdrawal day 2 (when Meth seeking is low and non-incubated) and on day 35 (when Meth seeking is high and incubated), for subsequent RNA-sequencing. In CeA, we identified 10-fold more differentially expressed genes (DEGs) on withdrawal day 35 than day 2. These genes were enriched for several biological processes, including protein ubiquitination and histone methylation. In OFC, we identified many fewer expression changes than in CeA. Interestingly, there were more DEGs on withdrawal day 2 than on day 35. Several genes in OFC showed opposing expression changes on withdrawal day 2 (increase) when compared to withdrawal day 35 (decrease), which was further validated by qPCR. Our analyses highlight the CeA as a key region of transcriptional regulation associated with incubation of Meth seeking. In contrast, transcriptional regulation in OFC may contributes to Meth seeking during early withdrawal. Overall, these findings provide a unique resource of gene expression data for future studies examining transcriptional mechanisms in CeA that mediate Meth seeking after prolonged withdrawal.
2018-12-26 | GSE111243 | GEO
Project description:Addiction to psychostimulants is associated with neuroadaptive changes in various brain regions. In this experiment we use a model of methamphetamine self-administration during which we use footshocks as adverse consequences to divide rats into animals that continue to press an active lever to get the drug (shock-resistant) whereas other rats stop or significantly reduce pressing the lever (shock-sensitive) in the presence of these adverse consequences. To investigate potential molecular bases for the divergent phenotype, we performed a whole rat transcriptome study using Affymetrix rat arrays that cover more than 24,000 coding transcripts. The array experiments revealed that there were 24 differentially expressed genes between the resistant and sensitive rats, with 15 up- and 9 downregulated transcripts. Ingenuity pathway analysis revealed that these transcripts belong in a network of genes involved in nervous system development and function, cell signaling, behavior, and disorders of the basal ganglia. These genes included proenkephalin (PENK) and prodynorphin (PDYN), among others. Because PDYN and PENK are expressed in dopamine D1- and D2-containing NAc neurons, respectively, these findings suggest that mechanisms that impact both cell types may play a role in the regulation of compulsive methamphetamine taking by rats.
2016-09-02 | GSE86329 | GEO
Project description:MicroRNAs (miRNAs) regulate many basic aspects of cell biology including neuronal plasticity, but little is known of their roles in drug addiction. Extended access to cocaine can trigger the emergence of compulsive drug-seeking behaviors, but molecular mechanisms regulating this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with extended access to cocaine. Striatal overexpression of miR-212 decreases, whereas its inhibition increases cocaine intake in rats with extended but not restricted drug access, suggesting that miR-212 serves as a protective factor against the development of compulsive drug seeking. The transcription factor CREB (cAMP response element-binding protein) is considered a core regulator of cocaine reward. We show that miR-212 controls responsiveness to cocaine by dramatically amplifying striatal CREB signaling. This action occurs through miR-212-enhanced Raf-1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (Transducer of Regulated CREB; also known as CRTC). Our findings suggest that striatal miR-212 signaling plays a key role in vulnerability to addiction, and that noncoding RNAs such as the miRNAs may serve as novel targets for the development of anti-addiction therapeutics. To identify potential targets for miR-212, we transfected cells with a vector to overexpress miR-212 or an empty vector. We then analyzed profiled gene expression using Affymetrix arrays. Human Affymetrix Study: Cells were transfected with a vector to overexpress miR-212 or an empty vector. We then analyzed profiled gene expression using Affymetrix arrays. The complete, unfiltered set of signal intensity data for Samples miR-212 and pMIF, including miR-212/pMIF ratios, are in the supplementary file at the foot of the record. Probes excluded from analysis (pMIF intensity <100) are indicated in the supplementary file by a no in the far-right column, 'Passed data filtering and included in analysis: no/yes'. Probes that were included in the analyses (pMIF intensity >100) are indicated in the supplementary file by a yes in the 'Passed data filtering and included in analysis: no/yes' column. Rat miRNA Study: Rats were permitted access to intravenous cocaine self-administration (0.5 mg/kg/infusion) for 7 consecutive days during restricted (1-h) or extended (6-h) daily sessions. Control rats remained coaine-naïve throughout. 24-h after the last session the dorsal striatum from each rats was removed, and RNA extracted for microarray profiling. There was a total of n=6 rats per access condition. RNA from 2 rats per access condition were pooled on to arrays, for a total of 3 arrays per access condition, and 9 arrays in total.
2010-07-08 | E-GEOD-21901 | biostudies-arrayexpress
Project description:Methamphetamine (METH) is a drug with high abuse potential that directly affects the central nervous system. METH use leads not only to detrimental health for the user but also to potential risks and costs for society. Impaired cognition has been shown to exist in individuals with long-term METH dependence, and this impairment may be the main cause of impulsive drug taking and high relapse rate. However, the molecular mechanisms underlying METH addiction and METH-induced cognitive decline remain unknown. To investigate potential molecular mechanisms of METH addiction, we compared serum protein expression levels by using label-free quantitative proteomics in 12 long-term METH users and 12 healthy control participants. In total, 23 differentially expressed proteins were found between the two groups. Bioinformatics analyses were used to identify functional networks and protein-protein interactions. The differentially expressed proteins were related to cognitive dysfunction, inflammation of the nervous system, immune system decline, energy metabolism, and calcium binding and regulation. Thus, these 23 proteins may be closely associated with the damage caused by METH to the nervous, immune, and metabolic systems. The results of this study provide additional insights into the molecular mechanisms of METH addiction and potential prevention and treatment options for METH-dependent individuals.
2023-02-14 | PXD040112 |
Project description:Nowadays, drug abuse and addiction are serious public health problems in the USA. Methamphetamine (METH) is one of the most abused drugs, which is known to cause brain damage from repeated exposure on human. Herein, a proteomic study was applied to evaluate METH-induced brain protein dynamics following a two-week chronic regimen of escalating dose of METH exposure. Proteins were extracted from rat brain hippocampal and olfactory bulb tissues and subjected to liquid chromatography-mass spectrometry (LC-MS/MS) analysis. Both shotgun and targeted proteomic analysis were performed. Protein quantitation was initially based on comparing the spectral counts between METH exposed animals and their control counterparts. Quantitative differences were further confirmed through multiple reaction monitoring (MRM) LC-MS/MS experiments. According to the quantitative results, the expression of 18 proteins (11 in hippocampal proteome, 7 in olfactory bulb proteome) were shown a significant alteration as a result of exposure of rats to METH. 13 of these proteins were up-regulated after METH exposure while 5 of were down-regulated. The altered proteins belonging to different structural and functional families were involved in processes such as cell death, inflammation, oxidation, and apoptosis.
2016-04-21 | PXD000915 | Pride