Impact of stress on heroin seeking and ventral pallidal synapse function

项目总结： 近年来，与阿片类药物使用障碍(OUD)有关的死亡人数激增，导致广泛的公众 健康危机。这种阿片类药物流行因缺乏有效的治疗干预策略而恶化 直接靶向或逆转阿片类药物诱导的神经适应，推动药物使用和复发。前期研究 表明经历生活中的重大压力事件是加剧阿片类药物使用的最大风险因素 并在成年人中复发。与临床数据一致，临床前研究表明，成年后的急性应激 在静脉给药的啮齿动物模型中增加精神刺激剂的寻求，但急性 对阿片类药物寻求的压力仍不清楚。此外，压力带来的神经生物学机制 OUD的易感性尚不清楚。新兴文献表明，腹侧苍白球谷氨酸神经元(VPGlu)是 药物寻求行为和厌恶状态的调节者，这表明这个神经元亚群可能 作为一个强有力的候选者，调解应激对OUD相关电路功能的影响，从而加剧OUD 病理学。我的初步数据试图通过检查如何开始解决这些不足之处 急性应激对非头部海洛因敏化和VPGlu活性的影响 修复了雄性和雌性小鼠。据我所知，这项初步工作是体内第一次 剧烈急性应激时VPGlu活性的特征，我是第一个报告VPGlu有反应的人 对压力和海洛因都有影响。此外，我的敏感化数据表明，压力会产生性行为 海洛因精神运动效应的二相性变化。综合来看，这些初步数据显示，成年人 急性应激改变海洛因的精神运动特性，并强调VPGlu是应激和 OUD相关的行为。我的数据为进一步研究压力对临床相关性的影响提供了依据 阿片类行为，如寻找海洛因的动机和复发，以及如何系统地描述 应激、阿片类药物和它们的交集通过改变这些细胞的突触输入来调节VPGlu的活动。 总而言之，我的初步数据告诉我的主要假设是，急性压力会增加海洛因 海洛因寻找的动机和复发以及应激和阿片类药物相互作用改变VPGlu突触 功能。这项建议的目的是询问压力如何影响海洛因的动机和复吸性 寻求使用静脉自我给药模型和2)评估应激、阿片类药物和他们的影响 体外全细胞膜片钳电生理学对VPGlu突触功能的影响。结果是 将决定急性应激对临床相关行为反应的影响 海洛因和系统表征新建立的应激反应突触功能的变化 神经元亚群。完成这项建议对我成为一名成功的 医生-科学家，通过提供必要的技能来执行高影响，严格的物质使用障碍 研究同时获得基本的临床熟练程度，以治疗受这些疾病影响的患者。

PROJECT SUMMARY: Deaths related to opioid use disorders (OUD) have sky-rocketed in recent years, leading to a widespread public health crisis. This opioid endemic is worsened by a lack of effective therapeutic intervention strategies that directly target or reverse the opioid induced neuroadaptations driving drug use and relapse. Prior research indicates that experiencing a major stressful event in life is the greatest risk factor for exacerbated opioid use and relapse among adults. Congruent with clinical data, preclinical work indicates that acute stress in adulthood increases psychostimulant seeking in intravenous drug self-administration rodent models, but the effects of acute stress on opioid seeking remain unknown. Further, the neurobiological mechanisms by which stress confers OUD susceptibility are unclear. Emerging literature shows that ventral pallidal glutamate neurons (VPGlu) are key regulators of drug seeking behavior and aversive states, which suggests that this neuronal subpopulation may be a strong candidate for mediating the effects of stress on OUD-relevant circuit function that exacerbates OUD pathology. My preliminary data sought to begin addressing these gaps in the OUD literature by examining how acute stress impacts heroin sensitization and VPGlu activity using in vivo miniscope Ca2+ imaging in non-head fixed male and female mice. To the best of my knowledge, this preliminary work represents the first in vivo characterization of VPGlu activity during intense acute stress, and I am the first to report that VPGlu are responsive to both stress and heroin. Furthermore, my sensitization data demonstrate that stress produces sexually dimorphic changes in the psychomotor effects of heroin. Taken together, these preliminary data show that adult acute stress alters the psychomotor properties of heroin and highlight VPGlu as promising mediators of stress and OUD-relevant behaviors. My data warrant further investigation into the impact of stress on clinically relevant opioid behaviors such as motivation and relapse to heroin seeking, and the systematic characterization of how stress, opioids, and their intersection regulate the activity of VPGlu by altering synaptic inputs onto these cells. Together, my preliminary data informed my main hypothesis that acute stress will enhance heroin motivation and relapse to heroin seeking and that stress and opioids interact to alter VPGlu synaptic function. The goals of this proposal are to interrogate 1) how stress impacts the motivation and relapse to heroin seeking using an intravenous self-administration model and 2) assess the effect of stress, opioids, and their interaction on synaptic function of VPGlu using ex vivo whole cell patch clamp electrophysiology. The outcomes of this proposal will determine the consequences of acute stress on clinically relevant behavioral responses to heroin and systematically characterize alterations in synaptic function of a newly established stress-reactive neuronal subpopulation. Completing this proposal will be invaluable to my development into a successful physician-scientist by providing the necessary skills to perform high-impact, rigorous substance use disorder research while gaining essential clinical proficiencies to treat patients affected by these disorders.