Peripheral gene expression in cocaine use disorders with low and high anhedonia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA480410 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Treatments for Cocaine Use Disorder (CUD) are variably effective, and there are no FDA-approved medications. One approach to developing new treatments for CUD may be to investigate and target poor prognostic signs. One such sign is anhedonia (i.e. a loss of pleasure or interest in non-drug rewards), which predicts worse outcomes in existing CUD treatments. Inflammation is thought to underlie anhedonia in many other disorders, but the relationship between anhedonia and inflammation has not been investigated in CUD. Therefore, we assessed peripheral genome-wide gene expression in n = 48 individuals with CUD with high (n=24) vs. low (n = 24) levels of anhedonia, defined by a median split of self-reported anhedonia. Our hypothesis was that individuals with high anhedonia would show differential gene expression in inflammatory pathways. No individual genes were significantly different between the low and high anhedonia groups when using t-tests with a stringent false discovery rate correction. However, an exploratory analysis identified 166 loci where t-tests suggested group differences at a nominal p < 0.05. We used DAVID, a bioinformatics tool that provides functional interpretations of complex lists of genes, to examine representation of this gene list in known pathways. It confirmed that mechanisms related to immunity were the top significant associations with anhedonia in the sample. Further, the two top differentially expressed genes in our sample, IRF1 and GBP5, both have primary inflammation and immune functions, and were significantly negatively correlated with total scores on our self-report of anhedonia across all 48 subjects. These results suggest that prioritizing development of anti-inflammatory medications for CUD may pay dividends, particularly in combination with treatment-matching strategies using either phenotypic measures of anhedonia or biomarkers of inflammatory gene expression to individualize treatment.
2018-11-02 | GSE116833 | GEO
Project description:Objective: Cocaine use disorders (CUD) represent a major public health problem in many countries. To better understand the interaction between the environmental modulations and phenotype, the aim of the present study was to investigate the DNA methylation pattern of CUD patients, which were concomitant dependents of cocaine and crack, and healthy controls. Methods: We studied DNA methylation profiles in the peripheral blood of 23 CUD patients and 24 healthy control subjects using the Illumina Infinium HumanMethylation450 BeadChip arrays. Results: Comparison between CUD patients and controls revealed 186 differentially methylated positions (DMPs, adjP<10-5) related to 152 genes, with a subset of CpGs confirmed by pyrosequencing. DNA methylation patterns discriminated CUD patients and control groups. A gene network approach showed that EHMT1, EHMT2, MAPK1, MAPK3, MAP2K1 and HDAC5 genes, which are involved in transcription and chromatin regulation cellular signaling pathways, were also associated with cocaine dependence. Conclusion: The investigation of DNA methylation patterns in CUD patients may contribute to a better understanding of the biological mechanisms involved in cocaine use disorders.
2019-06-30 | GSE77056 | GEO
Project description:Cocaine use disorder (CUD) is an intractable syndrome, and rising overdose death rates represent a significant public health crisis that exacts tremendous personal and financial costs on patients and society. Sharp increases in cocaine use drive the urgent need for better mechanistic insight into this chronic relapsing brain disorder that currently lacks effective treatment options. To investigate the transcriptomic changes involved, we conducted RNA sequencing on two striatal brain regions that are heavily implicated in CUD, the nucleus accumbens and caudate nucleus, from postmortem brains of subjects with CUD and matched control subjects. Weighted gene co-expression analyses identified CUD-specific gene networks enriched in ionotropic receptors and associated with lowered neuroinflammation, contrasting the proinflammatory responses found in opioid use disorder. Integration of comprehensive transcriptomic datasets from mouse cocaine self-administration models revealed evolutionarily conserved gene networks in CUD that implicate especially D1 medium spiny neurons as drivers of cocaine-induced plasticity.
2022-12-19 | GSE214267 | GEO
Project description:MicroRNAs are “master regulators” of gene expression. To investigate microRNAs involved in the incentive motivation for cocaine elicited by exposure to cocaine-associated cues, we conducted NanoString nCounter analyses of microRNA expression in the nucleus accumbens shell of male rats that had been tested for cue reactivity in a previous study. These rats had been trained to self-administer cocaine while living in isolate housing, then during a subsequent 21-day forced abstinence period they either stayed under isolate housing or switched to environmental enrichment (EE), as this EE intervention is known to decrease cocaine seeking. This allowed us to create groups of “high” and “low” cocaine seekers using a median split of cocaine-seeking behavior. We conducted a differential expression analysis across these two groups that identified 33 miRNAs that were differentially altered in the nucleus accumbens shell. Predicted mRNA targets of these microRNAs are implicated in synaptic plasticity and neuronal signaling. Some of these microRNAs have previously been implicated in substance use disorders, while others are predicted to target large numbers of cocaine-related genes. Of the 33 differentially expressed microRNAs, 8 were specifically downregulated in the low-seeking group and another set of 8 had expression levels that were significantly correlated with cocaine-seeking. These findings suggest that processes involved in cocaine-seeking behavior may alter, or be altered by, multiple microRNAs. Further research examining the mechanisms involved in these microRNA changes and their effects on signaling may reveal novel therapeutic targets for attenuating drug craving.
2020-12-25 | GSE153524 | GEO
Project description:Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models
| PRJNA884679 | ENA
Project description:Substance use disorders (SUDs) are associated with disruptions in sleep and circadian rhythms that persist during abstinence and may contribute to relapse risk. Repeated use of substances such as psychostimulants and opioids may lead to significant alterations in molecular rhythms in the nucleus accumbens (NAc), a brain region central to reward and motivation. Previous studies have identified rhythm alterations in the transcriptome of the NAc and other brain regions following the administration of psychostimulants or opioids. However, little is known about the impact of substance use on the diurnal rhythms of the proteome in the NAc. We used liquid chromatography coupled to tandem mass spectrometry-based (LC-MS/MS) quantitative proteomics, along with a data-independent acquisition (DIA) analysis pipeline, to investigate the effects of cocaine or morphine administration on diurnal rhythms of proteome in the mouse NAc. Overall, our data reveals cocaine and morphine differentially alters diurnal rhythms of the proteome in the NAc, with largely independent differentially expressed proteins dependent on time-of-day. Pathways enriched from cocaine altered protein rhythms were primarily associated with glucocorticoid signaling and metabolism, whereas morphine was associated with neuroinflammation. Collectively, these findings are the first to characterize the diurnal regulation of the NAc proteome and demonstrate a novel relationship between phase-dependent regulation of protein expression and the differential effects of cocaine and morphine on the NAc proteome.
2023-07-20 | PXD042043 | Pride
Project description:Gut-microbiota membership is associated with diverse neuropsychological-diseases, including substance use disorders (SUDs). Unravelling mechanistic interactions between gut microbes and the host during psychostimulant use remains challenging. Here we show that cocaine exposure increases intestinal levels of norepinephrine, sensed through the bacterial adrenergic receptor QseC, promoting intestinal colonization of g-Proteobacteria. Gut colonization by g-Proteobacteria depletes the neuroactive metabolite glycine (used as a nitrogen source) both in the gut and cerebrospinal fluid, enhancing host cocaine-induced behaviors. Glycine repletion reversed this response, and intestinal colonization by g-Proteobacteria unable to uptake glycine did not alter the host response to cocaine. Transcriptomic profiling indicates a role of g-Proteobacteria modulated glycine levels in cocaine induced transcriptional plasticity in the nucleus accumbens through the glutamatergic transmission. Altogether, we introduce a mechanism by which intestinal bacteria alter the host’s brain responses to cocaine that could be exploited to modulate reward-related brain circuits that contribute to SUDs.
2022-09-07 | GSE212421 | GEO
Project description:Dopamine (DA) signaling plays an essential role in reward valence attribution and in encoding the reinforcing properties of natural and artificial rewards. The adaptive responses from midbrain dopamine neurons to artificial rewards such as drugs of abuse are therefore important for understanding the development of substance use disorders. Drug-induced changes in gene expression are one such adaptation that can determine the activity of dopamine signaling in projection regions of the brain reward system. One of the major challenges to obtaining this understanding is the inherent cellular heterogeneity in the brain, where each neuron population can be defined by a distinct transcriptional profile. To bridge this gap, we have adapted a virus-based method for labeling and capture of dopamine nuclei, coupled with nuclear RNA-sequencing and bioinformatics analyses, to study the transcriptional adaptations, specifically, of dopamine neurons in the ventral tegmental area (VTA) during cocaine taking and cocaine craving, using a mouse model of cocaine intravenous self-administration (IVSA). Our results show significant changes in gene expression across non-drug operant training, cocaine taking, and cocaine craving, highlighted by an enrichment in expression of repressive epigenetic modifying enzymes during cocaine craving. Immunohistochemical validation further revealed an increase of H3K9me3 deposition in DA neurons during cocaine craving. These results demonstrate that cocaine-induced transcriptional adaptations in dopamine neurons vary by phase of self-administration and suggest that such an approach may be useful in identifying relevant phase-specific molecular targets to alter the behavioral course of substance use disorders.
2024-11-22 | GSE277757 | GEO
Project description:Prior research demonstrated that environmental enrichment creates individual differences in behavior leading to a protective addiction phenotype in rats. Understanding the mechanisms underlying this phenotype will guide selection of targets for much-needed novel pharmacotherapeutics. The current study investigates basal differences in proteome expression in the nucleus accumbens of enriched and isolated rats and the proteomic response to cocaine self-administration using a liquid chromatography mass spectrometry (LCMS) technique to quantify 1917 proteins. Results of complementary Ingenuity Pathways Analyses (IPA) and gene set enrichment analyses (GSEA) demonstrate that cocaine increases vesicular transporters for dopamine and glutamate, as well as increasing proteins in the RhoA pathway. Further, cocaine regulates proteins related to ERK, CREB and AKT signaling. Environmental enrichment altered expression of a large number of proteins with diverse functions, including mood disorders, energy production, ubiquitination, splicing, transport, kinases and neurodegenerative diseases. Most of the biological functions and pathways listed above were also identified in the Cocaine X Enrichment interaction analysis, providing clear evidence that enriched and isolated rats respond quite differently to cocaine exposure. The overall impression of the current results is that enriched saline-administering rats have a unique proteomic complement compared to enriched cocaine-administering rats as well as saline and cocaine-taking isolated rats. These results identify possible mechanisms of the protective phenotype and provide fertile soil for developing novel pharmacotherapeutics.
2014-07-22 | PXD000990 | Pride
Project description:Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an FR1 schedule. However, microbiome-depleted subjects exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.
2024-05-01 | GSE227980 | GEO