Reduced complexity mapping of oxycodone self-administration and stress responsiveness in rats

大鼠羟考酮自我给药和应激反应的复杂性降低图

基本信息

批准号：
10359156
负责人：
Hao Chen
金额：
$ 34.56万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10359156
关键词：
Affect Analgesics Animal Model Animals Automobile Driving Backcrossings Behavioral Brain region Candidate Disease Gene Cessation of life Chromosome Mapping Clinical Consumption Corticosterone Data Development Dose Drug Addiction Drug usage Female Future Gene Expression Genes Genetic Genetic Polymorphism Genetic study Genome Genotype Glucocorticoid Receptor Goals Heritability Hippocampus (Brain)Hormones Human Human Genetics Inbred Strains Rats Inbred WKY Rats Inbreeding Individual Intake Knock-in Location Maps Modeling Mutation Nucleus Accumbens Opiate Addiction Opioid Opioid Analgesics Opioid abuser Oral Overdose Oxycodone Pattern Persons Pharmaceutical Preparations Phenotype Plasma Population Population Genetics Predisposing Factor Prefrontal Cortex Prescription opioid overdose Prevalence Quantitative Trait Loci Rattus Regulation Research Risk Factors Rodent Self Administration Sex Differences Site Stress System Tablets Time Transgenes Transgenic Organisms Translating Variant Ventral Tegmental Area Viral Vector Withdrawal abuse liability addiction base biological adaptation to stress causal variant combat comorbidity controlled release depression model design drug action drug seeking behavior genetic approach genetic variant genome editing genome sequencing genome wide association study in vivo male motivated behavior multiple data types novel strategies offspring opioid abuse opioid epidemic opioid misuse opioid use disorder opioid withdrawal power analysis prescription opioid public health emergency receptor response spatiotemporal study population success trait transcriptome sequencing whole genome

Affect Analgesics Animal Model Animals Automobile Driving Backcrossings Behavioral Brain region Candidate Disease Gene Cessation of life Chromosome Mapping Clinical Consumption Corticosterone Data Development Dose Drug Addiction Drug usage Female Future Gene Expression Genes Genetic Genetic Polymorphism Genetic study Genome Genotype Glucocorticoid Receptor Goals Heritability Hippocampus (Brain)Hormones Human Human Genetics Inbred Strains Rats Inbred WKY Rats Inbreeding Individual Intake Knock-in Location Maps Modeling Mutation Nucleus Accumbens Opiate Addiction Opioid Opioid Analgesics Opioid abuser Oral Overdose Oxycodone Pattern Persons Pharmaceutical Preparations Phenotype Plasma Population Population Genetics Predisposing Factor Prefrontal Cortex Prescription opioid overdose Prevalence Quantitative Trait Loci Rattus Regulation Research Risk Factors Rodent Self Administration Sex Differences Site Stress System Tablets Time Transgenes Transgenic Organisms Translating Variant Ventral Tegmental Area Viral Vector Withdrawal abuse liability addiction base biological adaptation to stress causal variant combat comorbidity controlled release depression model design drug action drug seeking behavior genetic approach genetic variant genome editing genome sequencing genome wide association study in vivo male motivated behavior multiple data types novel strategies offspring opioid abuse opioid epidemic opioid misuse opioid use disorder opioid withdrawal power analysis prescription opioid public health emergency receptor response spatiotemporal study population success trait transcriptome sequencing whole genome

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项目摘要

Abstract The current opioid epidemic is fueled by the steady rise of prescription painkillers, such as OxyContin, which is a controlled-release tablet of oxycodone. Although both clinical and animal studies have found that the rate of onset of drug action influences the development of addiction, the exceptionally strong abuse liability of oxycodone was manifested even when it was consumed in the controlled-release from. The heritability of opioid addiction has been estimated to be approximately 0.5 in humans. However, few human genetics studies have been conducted due to the difficulty in assembling the necessary large study population. In this proposal, we aim to conduct a genetic mapping study to identify genetic factors influencing oxycodone-motivated behaviors and vulnerability to stress, a major risk factor of opioid use disorder. To follow the clinical use pattern, we developed an operant oral oxycodone self-administration model, where rats voluntarily consume oral oxycodone to obtain doses that are well above clinical prescriptions. The WMI and WLI inbred strains of rats we propose to use in this study were selectively bred from the stress-vulnerable Wistar Kyoto rat. The WMI is an established animal model of depression and vulnerability to stress, while the WLI serves as its isogenic control. Our preliminary data showed higher levels of oxycodone intake and oxycodone seeking in the WMI compared to the WLI strains. We also found that females have higher oxycodone intake than males. There were also strain and sex differences in basal plasma corticosterone (CORT) and steady-state hippocampal glucocorticoid receptor (Nr3c1) expression. We therefore hypothesized that genetically-determined stress response to oxycodone withdrawal drives the strain differences in oxycodone self-administration and reinstatement of oxycodone seeking. In Aim 1, we will use a reduced complexity mapping strategy to identify the causal genetic factors for oxycodone and stress response phenotypes. This mapping strategy is supported by the high heritability, large effect size of strain on phenotypes, and existing whole genome sequencing data for the WMI and WLI strains ( ~100x coverage per strain, with ~4,400 high confidence polymorphisms between strains). In Aim 2, we will identify candidate genes using a systems genetics approach. The low number of segregating variants between WLI and WMI greatly facilitates this goal. In Aim 3, we will confirm causal genes using an established knockin CAG-LSL-Cas9 rat model on the WMI/WLI genetic background.

抽象的当前的阿片类药物流行是由处方止痛药的稳定上升所激发的，例如oxycontin 羟考酮的受控释放片。尽管临床和动物研究都发现毒品行动的发作影响成瘾的发展，这是极大的虐待责任羟考酮即使在受控释放中被消耗掉也表现出来。遗传力人类的阿片类药物成瘾估计约为0.5。但是，人类遗传学研究很少由于难以组装必要的大型研究人群而进行的。在此提案中，我们旨在进行一项遗传学图研究，以确定影响羟考酮动机的遗传因素行为和压力脆弱性，这是阿片类药物使用障碍的主要危险因素。遵循临床用途模式，我们开发了一种操作的口服羟考酮自我管理模型，其中大鼠自愿消耗口服羟考酮获得远高于临床处方的剂量。 WMI和WLI近交菌株我们建议在这项研究中使用的大鼠是从可应激的Wistar京都大鼠中选择性地育出来的。这 WMI是抑郁和压力脆弱性的既定动物模型，而WLI则是等源性控制。我们的初步数据显示，在与WLI菌株相比，WMI。我们还发现，女性的羟考酮摄入量高于男性。基础等离子体皮质酮（CORT）和稳态也存在应变和性别差异海马糖皮质激素受体（NR3C1）表达。因此，我们假设对羟考酮戒断的遗传确定应力反应驱动羟考酮的应变差异寻求羟考酮的自我管理和恢复原状。在AIM 1中，我们将使用降低的复杂性绘制策略以识别羟考酮和应力反应表型的因果遗传因素。这映射策略受到高遗传力，对表型的应变效果的巨大影响以及现有的支持 WMI和WLI菌株的整个基因组测序数据（每应变约100倍，〜4,400高菌株之间的置信度多态性）。在AIM 2中，我们将使用系统确定候选基因遗传学方法。 WLI和WMI之间的隔离变体数量少，极大地促进了这一目标。在AIM 3中，我们将使用已建立的敲蛋白CAG-LSL-CAS9大鼠模型在WMI/WLI上确认因果基因遗传背景。