Effect of chronic oxycodone self administration (SA) on gene expression in the adult male mouse brain
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE113948 | GEO | 2019/05/27
REPOSITORIES: GEO
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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.
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Project description:Effect of chronic oxycodone self administration (SA) on gene expression in the adult male mouse brain
| PRJNA454578 | ENA
Project description:Escalated oxycodone self-administration is associated with activation of specific gene networks in the rat dorsal striatum
| PRJNA1179446 | ENA
Project description:Global changes in gene expression that underlie the circuit and behavioral dysregulation associated with cocaine addiction remain incompletely understood. Here, we determined how a history of cocaine self-administration (SA) “re-programs” transcriptome-wide responses at baseline and in response to cocaine re-exposure after prolonged withdrawal (WD). We assigned male mice to one of six groups: saline or cocaine SA + 24 hr WD; or saline/cocaine SA + 30 d WD + an acute saline/cocaine challenge within the previous drug-paired context. RNA-seq was then conducted on six interconnected brain reward regions. We focused on patterns of gene expression that were altered by cocaine SA, in particular, molecular targets that show priming or desensitization upon re-exposure to cocaine. Genes that were affected uniquely by acute cocaine after cocaine SA+WD displayed region-specific regulation. The greatest number of regulated genes were seen in nucleus accumbens, dorsal striatum, and basolateral amygdala. Further analysis revealed several transcription factors as key upstream regulators in these three regions, including several not previously implicated in cocaine action. Regulation of subsets of these primed and desensitized genes correlated robustly with SA behavior displayed by individual mice. For example, analysis of transcriptome-wide expression changes revealed that genes associated with cocaine intake respond to contextual information in a region-specific manner. This comprehensive picture of transcriptome-wide regulation by cocaine SA and WD throughout the brain’s reward circuitry provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.
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Project description:Prenatal stress is a risk factor for neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). However, how early stress modification of brain development contributes to this pathophysiology is poorly understood. Ventral forebrain regions such as dorsal striatum are of particular interest: dorsal striatum modulates movement and cognition, is altered in NDDs, and has a primarily GABAergic population. Here, we examine effects of prenatal stress on adult movement, cognition, and dorsal striatum neurobiology in mice using striatal-dependent behavioral assays, immunohistochemistry, embryonic ventral forebrain transcriptomics, and placental transcriptomics. We found prenatal stress affected adult procedural, habit, and reversal learning in sex-specific ways. Stress also increased adult dorsal striatal GABAergic neurons – an effect largely driven by males. We sought to examine the developmental origins of these adult brain changes. We found similar sex-specific dorsal striatal cellular changes in earlier points of development. The dorsal striatum primordium--embryonic ventral forebrain—showed that prenatal stress increased DNA replication and cell cycle pathways in male but not female transcriptomics and cellular biology. Unique signatures may have arisen from male-female placental differences. Stress-induced placental transcriptomics showed upregulated morphogenesis pathways in males while females downregulated morphogenic, hormonal, and cellular response pathways. Our findings suggest that prenatal stress could affect placenta function and also alter the GABAergic population of dorsal striatum differentially between the sexes.
2025-06-20 | GSE287771 | GEO
Project description:The development of physical dependence and addiction disorders due to misuse of opioid analgesics is a major concern with pain therapeutics. In this study, we developed a mouse model of oxycodone exposure to gain insight into genes and molecular pathways in reward-related brain regions that are affected by prolonged exposure to oxycodone and subsequent withdrawal in the presence or absence of chronic neuropathic pain. RNA-Sequencing (RNA-Seq) and bioinformatic analyses revealed that oxycodone withdrawal alone triggers robust gene expression adaptations in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and ventral tegmental area (VTA), with numerous genes and pathways selectively affected by oxycodone withdrawal under peripheral nerve injury states. Our pathway analysis predicted that histone deacetylase 1 (HDAC1), an epigenetic modifier with a prominent role in striatal plasticity, is a top upstream regulator in opioid withdrawal in both the NAc and mPFC. Indeed, treatment with the novel HDAC1/2 inhibitor RBC1HI (Regenacy Brain Class 1 HDAC Inhibitor) attenuated behavioral manifestations of oxycodone withdrawal, with the drug being more efficacious under states of neuropathic pain. Since RBC1HI displays antiallodynic actions in models of neuropathic pain, inhibition of HDAC1/2 may provide an avenue for chronic pain patients dependent on opioids to transition to non-opioid analgesics. Overall, our study highlights transcriptomic events in components of the reward circuitry associated with oxycodone withdrawal under pain-free and prolonged neuropathic pain states, thereby providing information on possible new targets for the treatment of physical dependence to opioids and transitioning individuals to non-opioid medications for chronic pain management.
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