Functional and Genomic Signatures of Escalated Fentanyl Use

项目摘要/摘要 滥用阿片类药物在美国和全世界都是一个巨大的公共和经济负担。现有的 治疗阿片类药物使用障碍(OUD)的药理学方法与 针对个别触发因素的行为疗法，以减少或消除过度药物消耗。而当 在动物行为模型中，阿片类药物使用的个体差异性已经被反复承认 与这种变异性背后的神经生物学适应相关的基因组标记还没有被很好地理解。我们 认为了解个体行为易感性差异的分子背景 阿片类药物的使用对于开发针对OUD的个性化药物基因组学方法至关重要，该方法可能 复制个性化癌症治疗的临床成功。根据这一论点，我们假设 芬太尼使用升级的个体行为变异与系统水平的变异有关 伏隔核和前额叶皮质内的基因组和功能网络。升级 药物摄取是OUD诊断的中心组成部分，可以在经过自我管理训练的动物身上进行模拟 延长使用条件下的阿片类药物。基于已发表的文献和初步数据，我们建议 三个相辅相成的目标是在行为、功能上监测摄入量增加的发展 细胞/网络和基因组水平的分析。我们的目标1假设芬太尼摄入量的增加 出现在个体对非药物(蔗糖)奖励敏感性不同的背景下。查找 支持这一目标的证据有可能在开始使用阿片类药物之前确定易受伤害的个人。 目的2检查与芬太尼摄入量增加相关的神经元结局。具体地说，我们将评估 摄入量增加的个体特征是否反映了四种钾对细胞兴奋性调节的改变 单细胞和网络水平上的通道家族及其对神经元输出的影响。作为部分内容收集的数据 这一目标的实现将建立功能性、神经元驱动因素，使其容易受到摄入量增加的影响。最后，目标3 比较实验动物(大鼠)和人类的变异性芬太尼升高背后的基因组图谱 阿片类药物使用数据库。在这个目标中，我们利用细胞类型特定的RNA测序来评估这两个 伏隔核和前额叶皮质摄取增加的神经元和非神经元机制。 这一目标有望识别与芬太尼升级有关的新分子途径，并测试 我们的临床前研究结果与人类样本的翻译相关性。要描述在 行为、功能和基因组水平的分析，一个统一的统计框架是基于 线性混合模型检验行为升级之间双向关系的强度 摄入量和分子结果。

Project Summary/Abstract Misuse of opioids represents a substantial public and economic burden in the US and worldwide. The existing pharmacological approaches to treatment of opioid use disorder (OUD) are most efficacious when coupled with behavioral therapies that target individual triggers to reduce or eliminate excessive drug consumption. While individual variability in opioid use have been acknowledged repeatedly in animal behavioral models, the genomic markers linked to neurobiological adaptations underlying such variability are not well understood. We argue that understanding the molecular background of individual differences in behavioral vulnerability to opioid use is critical for development of personalized pharmacogenomic approaches for OUD that may replicate clinical success of personalized cancer treatments. In line with this argument, we hypothesize that individual behavioral variability in escalation of fentanyl use is linked to systems level variability of genomic and functional networks within in the nucleus accumbens and prefrontal cortex. Escalation of drug intake is a central component of OUD diagnosis that can be modeled in animals trained to self-administer opioids under extended access conditions. Based on the published literature and preliminary data, we propose three complementary Aims to monitor development of escalated intake at behavioral, functional cellular/network, and genomic levels of analysis. Our Aim 1 hypothesizes that escalation of fentanyl intake emerges on the background of individual differences in sensitivity to non-drug (sucrose) reward. Finding evidence to support this aim has the potential to identify vulnerable individuals prior to initiation of opioid use. Aim 2 examines neuronal outcomes associated with escalated fentanyl intake. Specifically, we will evaluate whether individual profiles of escalated intake reflect altered regulation of cell excitability by four potassium channel families and the impact on neuronal output at single cell and network levels. The data collected as part of this aim will establish functional, neuronal drivers of vulnerability to escalated intake. Finally, Aim 3 compares the genomic landscape underlying variable fentanyl escalation in laboratory animals (rats) to human opioid use databases. In this aim, we take advantage of cell-type specific RNA sequencing to evaluate both neuronal and non-neuronal mechanisms of escalated intake in the nucleus accumbens and prefrontal cortex. This aim is expected to identify novel molecular pathways linked to fentanyl escalation and test the translational relevance of our preclinical findings to a human sample. To characterize interactions at the behavioral, functional, and genomic levels of analysis, a unifying statistical framework is developed based on linear mixed models to examine the strength of bi-directional relationships between behavioral escalation of intake and molecular outcomes.