A novel model of oxycodone seeking that considers sex and stress susceptibility.

摘要 创伤后应激障碍（PTSD）是一种使人衰弱的疾病，在以下亚群（约20-30%）中发展： 暴露在创伤事件中的人创伤后应激障碍与物质使用障碍（SUD）、酒精、 兴奋剂和阿片类药物是最经常滥用的药物。尽管PTSD+SUD的患病率 在合并症中，缺乏这种合并症的动物模型，并且迫切需要筛选潜在的治疗方法。 在这里，我们将利用我们的新的PTSD+SUD动物模型，捕捉PTSD+SUD的几个关键特征 并发症：1）PTSD通常由单一创伤引起，2）并非所有暴露于创伤的个体都会发展PTSD， 3)创伤后焦虑症状是持久的，4）增加了对药物的渴望和对传统药物的抵抗 减少SUD复发的干预措施。该模型依赖于将啮齿动物暴露于行为学相关的 “创伤”-捕食者气味应激（PSS）。我们已经成功地将PTSD的PSS模型与 扩展可卡因自我给药的途径，以研究动物中的PTSD+可卡因使用障碍（CUD）。的 本申请提出调整该动物模型以研究阿片样物质使用障碍 (OUD)和创伤后应激障碍我们的总体假设是，正如我们对可卡因所证明的那样，压力敏感的大鼠会 表现出更大的羟考酮寻求，这可能表明可卡因和可卡因的神经生物学基础相似， 和阿片类药物的寻求。我们将使用两种模型评估阿片类药物寻求。目标1将利用 需求曲线分析（增加“成本”，以获得静脉注射羟考酮超过天），以计算 对羟考酮的基本需求，并使用回归模型评估焦虑与 羟考酮的需求。这项工作将在男性和女性中进行，因此，将是评估性别的第一项工作 对羟考酮需求的差异。我们已经发现，压力敏感性的结果增加线索启动 可卡因寻求性的恢复和为获得可卡因而作出的反应的工具性消退受损。 目标2将评估羟考酮寻求是否也是如此，这意味着一个或多个共同回路 介导增强的应激易感性和药物寻求，并可能导致药物治疗， 同时患有OUD和CUD的人。我们的基本原理是，更接近模型合并症的大鼠模型 伴随着人类物质的使用， 目前在人类中，因此应该作为更好的平台，为治疗发现。因此，我们的中心， 一个统一的假设是，对压力的敏感性以类似的方式重塑了与寻求毒品有关的回路 可卡因和阿片类药物未来的研究建议将询问神经生物学底物和电路 参与了差异化羟考酮的寻找例如，我们发现mGlu 5在杏仁核中的表达 与易感大鼠相比，再次暴露于TMT后，弹性大鼠的前额叶皮层增加 在这一背景下，两个地区也涉及到灭绝和寻求滥用毒品。

ABSTRACT Post-traumatic stress disorder (PTSD) is a debilitating disorder that develops in a subpopulation (~20-30%) of people exposed to a traumatic event. PTSD is highly comorbid with substance use disorder (SUD), with alcohol, stimulants and opioids being the most frequently abused drugs. Despite the prevalence of PTSD+SUD comorbidity, animal models of such comorbidity are lacking and are sorely needed to screen potential treatments. Here we will utilize our novel animal model of PTSD+SUD that captures several key features of PTSD+SUD comorbidity: 1) PTSD typically arises from a single trauma, 2) not all trauma-exposed individuals develop PTSD, 3) post-trauma anxiety symptoms are long-lasting, and 4) increased drug-craving and resistance to traditional interventions that reduce relapse in SUD. This model relies on exposing rodents to an ethologically-relevant “trauma” - predator scent stress (PSS). We have successfully combined the PSS model of PTSD with the extended access to cocaine self-administration to study PTSD+cocaine use disorder (CUD) in animals. The present application proposes to adapt this animal model to study the interaction between opioid use disorder (OUD) and PTSD. Our overall hypothesis is that, as we demonstrated for cocaine, stress-Susceptible rats will display greater oxycodone seeking, a possible indication of similar neurobiological underpinnings of both cocaine and opioid seeking in stress susceptible rats. We will assess opioid seeking using two models. Aim 1 will utilize demand curve analyses (increasing the “cost” to obtain intravenous oxycodone infusions over days) to calculate the essential demand for oxycodone and use regression models to assess the relationship between anxiety and oxycodone demand. This work will be done in males and females, and thus, will be the first work to assess sex differences in demand for oxycodone. We have found that stress-susceptibility results in increased cue-primed reinstatement of cocaine-seeking and impaired instrumental extinction of the response made to obtain cocaine. Aim 2 will assess if the same is true for oxycodone seeking, which would imply a common circuit or circuits mediating enhanced stress susceptibility and drug-seeking and potentially lead to pharmacotherapies for individuals with both OUD and CUD. Our rationale is that rat models that more closely model comorbidities accompanying human substance use should more accurately reproduce the underlying neuroadaptations present in humans, and should thus serve as better platforms for therapeutic discovery. As such, our central, unified hypothesis is that susceptibility to stress remodels circuits involved in drug seeking in a similar manner for cocaine and opioids. Future research proposals would interrogate neurobiological substrates and circuit(s) involved in differential oxycodone seeking. For example, we have found that mGlu5 expression in the amygdala and prefrontal cortex is increased in Resilient rats relative to Susceptible rats after re-exposure to the TMT context, two regions also implicated in extinction and seeking of drugs of abuse.