Sex Differences in a Rat Model of Opioid Use disorder

阿片类药物使用障碍大鼠模型的性别差异

• 批准号: 10604462
• 负责人: Eleanor Towers
• 金额: $ 3.66万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604462
• 关键词: Address; Animal Model; Animals; Attenuated; Automobile Driving; Behavioral; Buprenorphine; Chronic; Cues; Data; Development; Disease; Dorsal; Drug usage; Epidemic; Estradiol; FDA approved; Female; Fentanyl; Gene Expression Profile; Genes; Genetic Transcription; Goals; Health; Hormonal; Hormones; Human; Intravenous; Medial; Medical; Modeling; Molecular; Motivation; Neurobiology; Opiate Addiction; Opioid; Oral Contraceptives; Ovarian hormone; Pharmaceutical Preparations; Phenotype; Physicians; Positioning Attribute; Prefrontal Cortex; Prevention strategy; Procedures; Progesterone; Punishment; Rattus; Relapse; Reporting; Research; Role; Schedule; Scientist; Self Administration; Severities; Sex Differences; Stimulant; Substance Use Disorder; Testing; Time; Tissues; Training; United States; Withdrawal; Woman; addiction; biological sex; cohort; craving; differential expression; drug craving; drug relapse; experience; fentanyl seeking; fentanyl self-administration; fentanyl use; human model; male; medication for opioid use disorder; men; novel; opioid use disorder; preclinical study; prevent; psychologic; sex; transcriptome; transcriptome sequencing; treatment strategy

PROJECT SUMMARY Opioid use disorder (OUD) is a major epidemic in the United States, and women appear be more vulnerable than men to certain aspects of the disease. Specifically, women develop OUD more rapidly (i.e. the telescoping effect), experience higher levels of cue-induced drug craving, and suffer more serious drug-related health consequences as compared to men. Despite the severity of this problem in women, preclinical studies have historically focused on males only, resulting in a male-centric basis of OUD; therefore, the purpose of this application is to determine sex differences in the development, expression, and molecular mechanisms of OUD. Our extended access (24-hr/day) self-administration procedure readily induces an addiction-like phenotype in rats, including an enhanced motivation for the drug, compulsive use, and vulnerability to relapse, when examined following protracted withdrawal. We have also validated this animal model by showing that treatment during withdrawal with buprenorphine, an FDA-approved medication for OUD, greatly attenuated vulnerability to relapse in both males and females. Notably, in this animal model, we have established biological sex as an important vulnerability factor with females showing an enhanced vulnerability to relapse compared to males, which mirrors the sex differences observed in humans. We also have strong preliminary data indicating that, as with findings for stimulants, estradiol drives the enhanced vulnerability to OUD in females. Thus, an additional goal of this application is to evaluate the impact of ovarian hormones on the expression and molecular mechanisms of an opioid addiction-like phenotype in females. Sex and hormone-dependent differences in the molecular mechanisms underlying an addiction-like phenotype will be characterized using RNA sequencing. This will allow us to characterize the transcriptome profiles associated with addiction-like phenotype in females for the first time and to determine how these changes differ from those observed in males and in females as a function of hormonal status. We will focus on changes in the dorsal medial prefrontal cortex (dmPFC) given its critical role in OUD. Our overall hypothesis is that an addiction-like phenotype will develop sooner in females than males and that in females, estradiol will be critical for the expression of addiction-like phenotype and the corresponding transcriptional changes. To address this hypothesis, we will first determine whether the telescoping effect reported in women with an OUD is biologically based (Aim 1) and address the impact of ovarian hormones on the expression of this phenotype in females (Aim 2). We will then use RNA-seq to identify sex- and hormone-specific molecular changes associated with the development of an enhanced vulnerability to relapse (Aim 3). The findings from these studies will provide critical information on sex differences in the development and expression of key features of OUD and foundational molecular data on the underlying mechanisms of OUD in females, which can be used to guide the development of new sex-specific prevention and treatment strategies for OUD.

项目总结 阿片类药物使用障碍(OUD)是美国的一种主要流行病，女性似乎更容易受到伤害 比男性对疾病的某些方面更敏感。具体地说，妇女发展得更快(即 延长效应)，体验到更高水平的线索诱导的药物渴求，并遭受更严重的药物相关 与男性相比对健康的影响。尽管这一问题在女性中非常严重，但临床前研究 在历史上只关注男性，导致了以男性为中心的性行为；因此， 这个应用是为了确定性别差异在发育、表达和分子上的差异 OUD的作用机制。我们的扩展访问(24小时/天)自我管理程序很容易导致 大鼠的成瘾样表型，包括对药物的增强动机，强迫使用，以及 在长期戒断后进行检查时，易复发。我们还证实了这只动物的存在 模型显示在戒断期间使用丁丙诺啡治疗，丁丙诺啡是FDA批准的一种治疗OUD的药物， 极大地降低了男性和女性复发的可能性。值得注意的是，在这个动物模型中，我们有 生物性别被确定为一个重要的脆弱因素，女性表现出更强的脆弱性 与男性相比，复发的可能性更大，这反映了在人类中观察到的性别差异。我们也有很强的 初步数据表明，与兴奋剂的研究结果一样，雌二醇会增加对 雌性的声音很大。因此，这项应用的另一个目的是评估卵巢的影响 激素对阿片类成瘾表型表达及分子机制的影响 女性。性和激素依赖的差异是成瘾的分子机制 表型将通过RNA测序来确定。这将使我们能够确定转录组的特征 首次在女性中发现与成瘾样表型相关的特征，并确定这些 这种变化不同于男性和女性的变化，这是荷尔蒙状态的一个函数。我们将重点关注 背侧内侧前额叶皮质(DmPFC)的变化，因为它在OUD中起关键作用。我们的总体假设是 女性比男性更早形成一种类似成瘾的表型，而在女性中，雌二醇会 对于成瘾样表型的表达和相应的转录变化至关重要。至 为了解决这一假设，我们将首先确定在患有OUD的女性中是否报告了伸缩效应 是基于生物学的(目标1)，并解决了卵巢激素对这一表型表达的影响 女性(目标2)。然后我们将使用rna-seq来鉴定性别和荷尔蒙特异的分子变化。 与提高旧病复发的脆弱性有关(目标3)。这些研究的结果 研究将提供关键的信息，关于性别差异的发展和关键特征的表达 OUD和关于女性OUD潜在机制的基础分子数据，可用于 指导制定新的针对不同性别的OUD防治策略。