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

摘要 创伤后应激障碍(PTSD)是一种衰弱障碍，发展于以下人群(约20%-30%) 暴露在创伤性事件中的人。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常被滥用的药物。尽管创伤后应激障碍+SUD盛行 然而，目前尚缺乏此类共病的动物模型，迫切需要筛选可能的治疗方法。 在这里，我们将使用我们的新的PTSD+SUD动物模型，该模型捕获了PTSD+SUD的几个关键特征 共病：1)创伤后应激障碍通常源于单一创伤，2)并不是所有接触创伤的人都会患上创伤后应激障碍， 3)创伤后焦虑症状是持久的，4)对药物的渴求和对传统药物的抵抗力增加 减少SUD复发的干预措施。这一模式依赖于让啮齿动物接触与行为学相关的 “创伤”--捕食者气味应激(PSS)。我们成功地将创伤后应激障碍的PSS模型与 扩大可卡因自我给药途径以研究动物的创伤后应激障碍+可卡因使用障碍(CUD)。这个 目前的应用建议采用这种动物模型来研究阿片类药物使用障碍之间的相互作用 (OUD)和创伤后应激障碍。我们的总体假设是，正如我们在可卡因中演示的那样，易受压力影响的大鼠将 表现出更强烈的羟考酮寻求，这可能是两种可卡因神经生物学基础相似的迹象 以及应激敏感大鼠的阿片类药物寻找。我们将使用两个模型来评估阿片类药物的寻找。目标1将利用 需求曲线分析(在几天内增加获得静脉注射羟考酮的“成本”)来计算 对羟考酮的基本需求，并使用回归模型评估焦虑与 羟考酮需求。这项工作将在男性和女性中进行，因此，将是第一个评估性别的工作。 羟考酮需求的差异。我们已经发现，压力敏感性会导致提示启动的增加 恢复对可卡因的追寻和对获得可卡因的反应的损害的工具消亡。 目标2将评估羟考酮寻找是否也是如此，这将意味着一个或多个共同的电路 介导增强的应激敏感性和药物寻找，并可能导致药物治疗 既有声音又有声音的个体。我们的理论基础是，更接近于模拟并存的大鼠模型 伴随人类物质的使用应该更准确地再现潜在的神经适应 存在于人类体内，因此应该成为治疗发现的更好平台。因此，我们的中央， 统一的假设是，对压力的敏感性以类似的方式改变了与药物寻找有关的回路 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(S) 参与了差别羟考酮的寻找。例如，我们已经发现杏仁核中mGlu5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质增加 在此背景下，两个地区还牵涉到毒品的灭绝和寻求滥用。

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.