Genetic and Environmental Risk Factors for Cocaine Addiction (COCCAINE)
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PROVIDER: PRJNA532957 | ENA |
REPOSITORIES: ENA
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Project description:Genetic and Environmental Risk Factors for Cocaine Addiction (COCCAINE)
| PRJNA532956 | ENA
Project description:Familial transmission and high heritability of liability for drug abuse has been demonstrated by large scale epidemiological and twin studies, but the role of pre-existing susceptibility to addiction is still not clear. Our data show that F1 and F2 offspring sired by rats with high motivation for drug reinforcement and drug intake during cocaine self-administration maintained their ancestor’s addict-like behavior. This paternal transmission of drug addiction is an acquired trait that is dependent on cocaine induced high motivation in F0. Reduced representation bisulfite sequencing of F0 and F1 sperm DNA reveal a few persistent epigenetic changes in genes that critically regulate early development and morphogenesis. These epigenetic traits may underlie alterations in the neurological basis that lead to the transmission of cocaine motivation. Our results reveal the epigenetic transgenerational inheritance of drug craving and provide a potential etiology in cocaine abuse vulnerability.
2017-03-17 | GSE72401 | GEO
Project description:Epigenetics of Cocaine and Nicotine Addiction
| PRJNA389764 | ENA
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:Environmental enrichment produces a protective addiction phenotype in animal models. Gene transcription is thought to mediate this protective phenotype and has a profound influence on neuronal plasticity and psychiatric disorders. Understanding the molecular and genetic mechanisms underlying environmental enrichment may lead to novel targets for pharmacotherapeutics to treat cocaine addiction. We investigated the differential regulation of transcript levels using RNA sequencing of the rat nucleus accumbens after environmental enrichment/isolation and cocaine/saline self-administration. New functional pathways were also identified for cocaine modulation and environmental enrichment.
2017-02-22 | GSE88736 | GEO
Project description:Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms in the brain that underly long-lasting maladaptive plasticity and addiction-like behaviors. In this study, we leverage a large RNA-sequencing dataset to generate gene co-expression networks across 6 interconnected regions of the brain’s reward circuitry from mice that underwent saline or cocaine self-administration, followed by a 24-hour or 30-day withdrawal period and a saline or cocaine challenge. We identify phosphodiesterase 1b (Pde1b), a Ca2+/calmodulin-dependent enzyme that catalyzes the hydrolysis of cAMP and cGMP, as one of the top hub genes within a nucleus accumbens (NAc) gene module that was bioinformatically associated with addiction-like behavior. Within Drd1- and Drd2-expressing medium spiny neurons (D1 and D2 MSNs) in the NAc, we found that chronic cocaine selectively upregulates Pde1b expression in D2 MSNs. Using a virus-mediated overexpression approach, we demonstrate that Pde1b in the NAc influences cocaine self-administration behavior, locomotor responses, electrophysiological properties of MSNs, and cocaine-induced transcriptomic adaptations in a cell-type- and sex-dependent manner. Together, we identify novel gene modules across the brain’s reward circuitry associated with addiction-like behavior and explore the role of Pde1b in regulating the molecular, cellular, and behavioral response to cocaine.
2024-04-19 | GSE244767 | GEO
Project description:Ovarian Tumor Risk and Environmental and Genetic Factors
| PRJNA302695 | ENA
Project description:By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix microarray suite 4 and microarray suite 5, which use perfect-match-minus-mismatch models, and dchip and rma, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy. Keywords: cocaine addiction
2006-01-26 | GSE3016 | GEO
Project description:The amygdala plays a key role in the negative emotional states associated with the relapse to drug seeking behavior. Neuroanatomical and functional observations have uncovered the role of discrete amygdala subregions in different aspects of these negative affective states. However, the underlying transcriptional regulatory programs driving the function of distinct amygdala cell types remains unknown. We generated an atlas of single nucleus gene expression and chromatin accessibility in the amygdala of rats with low and high cocaine addiction-like behaviors after prolonged abstinence from extended access to cocaine intravenous self-administration. We identified thousands of cell type-specific differentially expressed genes, suggesting that negative affective states are associated with cell type-specific mechanisms which are enriched for molecular pathways, including energy metabolism and GABAergic synapses in excitatory and somatostatin neurons. We demonstrate that higher addiction severity is linked to excessive GABAergic inhibition and, using pharmacological inhibition, we find that addiction-like phenotypes are regulated by the metabolite methylglyoxal which is an agonist at GABA-A receptors. By analyzing differences in chromatin accessibility, we predict upstream transcriptional regulators associated with addiction-like behavior and find discordant regulation of key transcription factors among distinct cell populations. Overall, we provide a comprehensive characterization of cell type-specific transcriptional changes in the amygdala during protracted abstinence and use these insights to identify a novel target for pharmacological intervention.
2023-08-09 | GSE212416 | GEO
Project description:The amygdala plays a key role in the negative emotional states associated with the relapse to drug seeking behavior. Neuroanatomical and functional observations have uncovered the role of discrete amygdala subregions in different aspects of these negative affective states. However, the underlying transcriptional regulatory programs driving the function of distinct amygdala cell types remains unknown. We generated an atlas of single nucleus gene expression and chromatin accessibility in the amygdala of rats with low and high cocaine addiction-like behaviors after prolonged abstinence from extended access to cocaine intravenous self-administration. We identified thousands of cell type-specific differentially expressed genes, suggesting that negative affective states are associated with cell type-specific mechanisms which are enriched for molecular pathways, including energy metabolism and GABAergic synapses in excitatory and somatostatin neurons. We demonstrate that higher addiction severity is linked to excessive GABAergic inhibition and, using pharmacological inhibition, we find that addiction-like phenotypes are regulated by the metabolite methylglyoxal which is an agonist at GABA-A receptors. By analyzing differences in chromatin accessibility, we predict upstream transcriptional regulators associated with addiction-like behavior and find discordant regulation of key transcription factors among distinct cell populations. Overall, we provide a comprehensive characterization of cell type-specific transcriptional changes in the amygdala during protracted abstinence and use these insights to identify a novel target for pharmacological intervention.
2023-08-09 | GSE212415 | GEO