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

一种考虑性别和压力敏感性的羟考酮寻求新模型。

• 批准号: 10057442
• 负责人: Marek Schwendt
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057442
• 关键词: Alcohol or Other Drugs use; Alcohols; Amygdaloid structure; Anhedonia; Animal Model; Animals; Anxiety; Behavior; Biological; Cocaine; Cues; Diagnosis; Disease; Exposure to; Extinction (Psychology); Female; Funding; Future; GRM5 gene; General Population; Goals; Human; Impairment; Individual; Individual Differences; Infusion procedures; Intervention; Intravenous; Lead; Mediating; Methodology; Modeling; Neurobiology; Opioid; Oxycodone; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Prevalence; Price; Rattus; Relapse; Research; Research Proposals; Resistance; Rewards; Rodent; Self Administration; Sex Differences; Stress; Substance Use Disorder; Symptoms; Therapeutic; Time; Trauma; Work; acute stress; animal model development; anxiety symptoms; anxious; cocaine use; comorbidity; cost; design; drug craving; drug of abuse; male; neuroadaptation; novel; opioid abuse; opioid use disorder; post-trauma; response; sex; stressor; therapy development; trauma exposure; traumatic event

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.

抽象的 创伤后应激障碍 (PTSD) 是一种使人衰弱的疾病，在以下亚群 (~20-30%) 中发生 遭受创伤事件的人与物质使用障碍（SUD）、酒精、 尽管 PTSD+SUD 很普遍，但兴奋剂和阿片类药物仍然是最常滥用的药物。 由于缺乏此类合并症的动物模型，因此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型 PTSD+SUD 动物模型，该模型捕捉了 PTSD+SUD 的几个关键特征 合并症：1) PTSD 通常由单一创伤引起，2) 并非所有遭受创伤的个体都会出现 PTSD， 3) 创伤后焦虑症状是持久的，4) 药物渴望和对传统药物的抵抗力增加 减少 SUD 复发的干预措施该模型依赖于将啮齿动物暴露于与伦理相关的环境中。 “创伤”——捕食者气味应激（PSS） 我们成功地将 PTSD 的 PSS 模型与创伤后应激障碍（PTSD）相结合。 扩大可卡因自我给药的范围，以研究动物的 PTSD+可卡因使用障碍 (CUD)。 本申请建议采用该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（PTSD）我们的总体假设是，正如我们对可卡因所证明的那样，压力敏感的老​​鼠会。 显示出更大的羟考酮寻求，这可能表明两种可卡因具有相似的神经生物学基础 我们将使用目标 1 的两个模型来评估阿片类药物的寻求。 需求曲线分析（增加几天内静脉注射羟考酮输注的“成本”）来计算 对羟考酮的基本需求，并使用回归模型来评估焦虑与焦虑之间的关系 这项工作将在男性和女性中进行，因此将是第一项评估性别的工作。 我们发现压力敏感性会导致提示引发的增加。 恢复可卡因寻求和受损的工具性灭绝以获得可卡因的反应。 目标 2 将评估羟考酮寻找是否也是如此，这意味着有一个或多个共同电路 介导增强的应激敏感性和药物寻求，并可能导致药物治疗 我们的理由是，大鼠模型能够更接近地模拟合并症。 伴随人类物质使用应该更准确地再现潜在的神经适应 存在于人类中，因此应该成为更好的治疗发现平台。 统一假设是，对压力的敏感性以类似的方式重塑涉及药物寻求的回路 对于可卡因和阿片类药物，未来的研究提案将探讨神经生物学底物和回路。 例如，我们发现mGlu5在杏仁核中表达。 重新暴露于 TMT 后，恢复性大鼠的前额叶皮层相对于易感性大鼠有所增加 在此背景下，两个地区也涉及毒品的灭绝和滥用。