Impact of stress on heroin seeking and ventral pallidal synapse function

项目概要： 近年来，与阿片类药物使用障碍（OUD）有关的死亡人数激增，导致公众广泛关注 健康危机。由于缺乏有效的治疗干预策略， 直接靶向或逆转阿片类药物诱导的神经适应，从而驱动药物使用和复发。先前的研究 表明生活中经历重大压力事件是阿片类药物使用加剧的最大风险因素 和复发的几率。与临床数据一致，临床前工作表明，成年期的急性应激 在静脉内药物自我给药啮齿动物模型中增加精神兴奋剂的寻求，但急性 对阿片类药物寻求的压力仍然未知。此外，压力赋予的神经生物学机制 OUD易感性尚不清楚。新兴的文献表明腹侧苍白球谷氨酸神经元（VPGlu）是关键 药物寻求行为和厌恶状态的调节器，这表明这种神经元亚群可能 是介导压力对OUD相关电路功能影响的强有力候选者，该电路功能加剧了OUD 病理我的初步数据试图开始解决这些差距，在OUD文献研究如何 急性应激影响海洛因敏感性和VPGlu活性，使用体内微型钙离子成像在非头部 固定的雄性和雌性小鼠。据我所知，这项初步工作代表了第一次在体内 我是第一个报道VPGlu在强烈的急性应激过程中的反应性的人， 压力和海洛因的混合物此外，我的敏感数据表明，压力产生性行为， 海洛因对精神影响的二态性变化综合来看，这些初步数据显示， 急性应激改变了海洛因的精神特性，并突出显示VPGlu是有希望的应激介质， OUD相关行为。我的数据保证了进一步调查压力对临床相关疾病的影响。 阿片类行为，如动机和复发海洛因寻求，以及如何系统的表征 应激、阿片类物质及其交叉通过改变这些细胞上的突触输入来调节VPGlu的活性。 总之，我的初步数据证实了我的主要假设，即急性压力会增强海洛因的作用。 海洛因寻求的动机和复发以及压力和阿片类药物相互作用改变VPGlu突触 功能这个建议的目的是询问1）压力如何影响海洛因的动机和复吸 寻求使用静脉内自我管理模型和2）评估压力，阿片类药物的影响， 使用离体全细胞膜片钳电生理学研究VPGlu对突触功能相互作用。成果 这一建议将确定急性应激对临床相关行为反应的后果， 海洛因和新建立应激反应神经元突触功能的系统特征性改变 神经元亚群完成这份建议书将是非常宝贵的，我的发展成为一个成功的 通过提供必要的技能来执行高影响力，严格的物质使用障碍， 研究，同时获得必要的临床专业知识，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.