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：
10576397
负责人：
Hao Chen
金额：
$ 34.33万
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/10576397
关键词：
Affect Analgesics Animal Model Animals Automobile Driving Backcrossings Behavioral Brain region Breeding 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 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 Prefrontal Cortex Prescription opioid overdose Prevalence Quantitative Trait Loci Rat Transgene 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 biological adaptation to stress candidate identification causal variant combat comorbidity controlled release depression model design drug action drug seeking behavior genetic approach genetic risk factor 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 segregation spatiotemporal study population success trait transcriptome sequencing whole genome

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.

抽象的当前阿片类药物的流行是由奥施康定等处方止痛药的稳步增长推动的。羟考酮控释片。尽管临床和动物研究均发现药物作用的发生会影响成瘾的发展，特别强烈的滥用倾向即使在控释中消耗羟考酮时，羟考酮也表现出来。遗传力为据估计，人类的阿片类药物成瘾率约为 0.5。然而，人类遗传学研究却很少由于难以聚集必要的大量研究人群，因此进行了这项研究。在这个提案中，我们的目标是进行遗传图谱研究，以确定影响羟考酮驱动的遗传因素行为和对压力的脆弱性是阿片类药物使用障碍的主要风险因素。遵循临床使用模式，我们开发了一种操作性口服羟考酮自我给药模型，其中大鼠自愿消耗口服羟考酮以获得远高于临床处方的剂量。 WMI 和 WLI 近交系我们建议在这项研究中使用的大鼠是从压力脆弱的 Wistar 京都大鼠中选择性培育出来的。这 WMI 是一种已建立的抑郁症和易受压力的动物模型，而 WLI 则作为其模型同基因控制。我们的初步数据显示，羟考酮摄入量和羟考酮寻求水平较高 WMI 与 WLI 菌株的比较。我们还发现女性的羟考酮摄入量高于男性。基础血浆皮质酮 (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。因此我们假设基因决定的对羟考酮戒断的应激反应驱动了羟考酮的菌株差异自我管理和恢复羟考酮寻求。在目标 1 中，我们将使用降低的复杂性绘制策略以确定羟考酮和应激反应表型的致病遗传因素。这作图策略得到高遗传力、菌株对表型影响大以及现有的支持 WMI 和 WLI 菌株的全基因组测序数据（每个菌株约 100 倍覆盖率，约 4,400 个高菌株之间的置信度多态性）。在目标 2 中，我们将使用系统识别候选基因遗传学方法。 WLI 和 WMI 之间的隔离变体数量较少，极大地促进了这一目标的实现。在目标 3 中，我们将使用 WMI/WLI 上已建立的敲入 CAG-LSL-Cas9 大鼠模型来确认因果基因遗传背景。