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Alterations of expression of inflammation/immune-related genes in the dorsal and ventral striatum of adult C57BL/6J mice following chronic oxycodone self-administration: a RNA sequencing study.

ABSTRACT: Non-medical use of prescription opioids such as the mu opioid receptor (MOP-r) agonist oxycodone is a growing problem in the USA and elsewhere. There is limited information about oxycodone's impact on diverse gene systems in the brain.The current study was designed to examine how chronic oxycodone self-administration (SA) affects gene expression in the terminal areas of the nigrostriatal and mesolimbic dopaminergic pathways in mice.Adult male C57BL/6J mice underwent a 14-day oxycodone self-administration procedure (4 h/day, 0.25 mg/kg/infusion, FR1) and were euthanized 1 h after the last session. The dorsal and ventral striata were dissected, and total RNAs were extracted. Gene expressions were examined using RNA sequencing.We found that oxycodone self-administration exposure led to alterations of expression in numerous genes related to inflammation/immune functions in the dorsal striatum (54 upregulated genes and 1 downregulated gene) and ventral striatum (126 upregulated genes and 15 downregulated genes), with 38 upregulated genes identified in both brain regions.This study reveals novel neurobiological mechanisms underlying some of the effects of a commonly abused prescription opioid. We propose that inflammation/immune gene systems may undergo a major change during chronic self-administration of oxycodone.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5826641 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Alterations of expression of inflammation/immune-related genes in the dorsal and ventral striatum of adult C57BL/6J mice following chronic oxycodone self-administration: a RNA sequencing study.

Zhang Yong Y Liang Yupu Y Levran Orna O Randesi Matthew M Yuferov Vadim V Zhao Connie C Kreek Mary Jeanne MJ

Psychopharmacology 20170626 15

<h4>Introduction</h4>Non-medical use of prescription opioids such as the mu opioid receptor (MOP-r) agonist oxycodone is a growing problem in the USA and elsewhere. There is limited information about oxycodone's impact on diverse gene systems in the brain.<h4>Objectives</h4>The current study was designed to examine how chronic oxycodone self-administration (SA) affects gene expression in the terminal areas of the nigrostriatal and mesolimbic dopaminergic pathways in mice.<h4>Method</h4>Adult mal ...[more]

PMID: 28653080

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Project description:Oxycodone is one a commonly used medication for pain, and is also a widely abused prescription opioid, like other short-acting MOPr agonists. Neurochemical and structural adaptations in brain following chronic MOPr-agonist administration are thought to underlie pathogenesis and persistence of opiate addiction. Many axon guidance molecules, such as integrins, semaphorins, and ephrins may contribute to oxycodone-induced neuroadaptations through alterations in axon-target connections and synaptogenesis, that may be implicated in the behaviors associated with opiate addiction. However, little is known about this important area. The aim of this study is to investigate alterations in expression of selected integrin, semaphorin, ephrins, netrin, and slit genes in the nucleus accumbens (NAc) and caudate putamen (CPu) of mice following extended 14-day oxycodone self-administration (SA), using RNAseq. Methods: Total RNA from the NAc and CPu were isolated from adult male C57BL/6J mice within 1 h after the last session of oxycodone in a 14-day self-administration paradigm (4h/day, 0.25 mg/kg/infusion, FR1) or from yoked saline controls. Gene expressions were examined using RNA sequencing (RNA-Seq) technology. RNA-Seq libraries were prepared using Illumina's TruSeq® Stranded Total RNA LT kit. The reads were aligned to the mouse reference genome (version mm10) using STAR. DESeq2 was applied to the counts of protein coding genes to estimate the fold change between the treatment groups. False Discovery Rate (FDR) q < 0.1 were used to select genes that have a significant expression change. For selection of a subset of genes related to axon guidance pathway, REACTOME was used. Results: Among 38 known genes of the integrin, semaphorin, and ephrin gene families, RNA-seq data revealed up-regulation of six genes in the NAc: heterodimer receptor, integrins Itgal, Itgb2, and Itgam, and its ligand semaphorin Sema7a, two semaphorin receptors, plexins Plxnd1 and Plxdc1. There was down-regulation of eight genes in this region: two integrin genes Itga3 and Itgb8, semaphorins Sema3c, Sema4g, Sema6a, Sema6d, semaphorin receptor neuropilin Nrp2, and ephrin receptor Epha3. In the CPu, there were five differentially expressed axon guidance genes: up-regulation of three integrin genes, Itgal, Itgb2, Itga1, and down-regulation of Itga9 and ephrin Efna3 were thus observed. No significant alterations in expression of Netrin-1 or Slit were observed. Conclusion: We provide evidence for alterations in the expression of selective axon guidance genes in adult mouse brain following chronic self-administration of oxycodone. Further examination of oxycodone-induced changes in the expression of these specific axon guidance molecules and integrin genes in relation to behavior may provide new insights into development of addiction to oxycodone.

Project description:BackgroundHuman laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self-administration, is warranted. The current study is a secondary analysis examining whether alcohol cue-induced activation in the ventral striatum is predictive of subsequent alcohol self-administration in the laboratory.MethodsNon-treatment-seeking heavy drinkers of East Asian descent (n = 41) completed a randomized, placebo-controlled, double-blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue-reactivity task. On the following day (day 5), participants completed a 60-minute alcohol self-administration paradigm.ResultsMultilevel Cox regressions indicated a significant effect of taste cue-elicited ventral striatum activation on latency to first drink, Wald χ2 = 2.88, p = 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self-administration outcomes.ConclusionsNeuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self-administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development.

Dataset Information

Alterations of expression of inflammation/immune-related genes in the dorsal and ventral striatum of adult C57BL/6J mice following chronic oxycodone self-administration: a RNA sequencing study.

Publications

Alterations of expression of inflammation/immune-related genes in the dorsal and ventral striatum of adult C57BL/6J mice following chronic oxycodone self-administration: a RNA sequencing study.

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