Impact of stress on heroin seeking and ventral pallidal synapse function

压力对海洛因寻求和腹侧苍白球突触功能的影响

基本信息

批准号：
10693872
负责人：
Carley N Miller
金额：
$ 3.9万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-03 至 2025-08-02
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693872
关键词：
Acute Address Adult Affect Automobile Driving Behavior Behavior Disorders Behavioral Binding Brain region Catheters Cells Cessation of life Clinical Clinical Data Cues Data Development Disease Drug usage Electrophysiology (science)Evaluation Event Exposure to Female Globus Pallidus Glutamates Goals Growth Heroin Image Implant Intervention Intravenous Investigation Knowledge Label Life Literature Mediating Mediator Membrane Modeling Monitor Motivation Mus Neurons Opioid Opioid agonist Outcome Pathology Patients Pharmaceutical Preparations Physicians Population Positioning Attribute Predisposition Property Public Health Receptor Activation Relapse Reporter Reporting Research Rewards Risk Factors Rodent Model Scientist Self Administration Slice Stress Stressful Event Substance Use Disorder Synapses Synaptic Transmission System Training Transgenic Organisms Work acute stress behavioral response biological adaptation to stress clinically relevant comparative disorder prevention drug relapse drug seeking behavior effective intervention experience experimental study heroin use in vivo induced pluripotent stem cell insight male mu opioid receptors nerve supply neuroadaptation neurobiological mechanism neuromechanism neuropathology opioid overdose opioid use opioid use disorder patch clamp postsynaptic pre-clinical preclinical study psychostimulant response restraint stress reward processing sex sexual dimorphism skills stress reactivity stress reduction synaptic function therapeutically effective therapy development

项目摘要

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.

项目摘要：近年来，与阿片类药物使用障碍（OUD）有关的死亡人数已迅速高涨，导致广泛的公众健康危机。由于缺乏有效的治疗干预策略，这种阿片类药物流行恶化了直接靶向或逆转阿片类药物诱导的神经适应性驱动药物使用和复发。先前的研究表明生活中发生重大压力事件是加剧阿片类药物的最大风险因素和成人之间的复发。与临床数据一致，临床前工作表明成年后的急性应力在静脉药自给啮齿动物模型中增加心理刺激性寻求剂，但急性的影响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敏感性尚不清楚。新兴文献表明腹侧苍白球谷氨酸神经元（VPGLU）是关键寻求行为和厌恶状态的药物调节剂，这表明这种神经元亚群可以成为介导应力对与OUD相关电路功能的影响的有力候选者，这加剧了Oud 病理。我的初步数据试图通过研究如何开始解决OUD文献中的这些差距急性应力会影响海洛因的敏感性和VPGLU活性，使用体内Miniscope Ca2+成像固定的雄性和雌性小鼠。据我所知，这项初步工作代表了体内的第一个在强烈的急性应力期间的VPGLU活性表征，我是第一个报告VPGLU反应迅速的人压力和海洛因。此外，我的敏化数据表明，压力会产生性海洛因的心理运动作用的二态变化。综上所述，这些初步数据表明成人急性压力改变了海洛因的心理运动特性，并将VPGLU作为有前途的压力和与Oud相关的行为。我的数据需要进一步调查压力对临床相关的影响阿片类药物行为，例如动机和寻求海洛因的复发，以及如何系统地表征压力，阿片类药物及其相交通过改变这些细胞上的突触输入来调节VPGLU的活性。我的初步数据在一起，告诉我我的主要假设，即急性压力会增强海洛因动机和对海洛因寻求的复发，压力和阿片类药物相互作用以改变VPGLU突触功能。该提议的目标是审问1）压力如何影响动机和对海洛因的复发寻求使用静脉自我给药模型和2）评估压力，阿片类药物及其的影响使用离体全细胞贴片夹电生理学上VPGLU的突触功能的相互作用。结果该提案将确定急性压力对临床相关行为反应的后果海洛因和系统地表征了新建立的压力反应的突触功能的改变神经元亚群。完成这项建议将对我的发展成一个成功是无价的医师科学家通过提供必要的技能来执行高影响，严格的药物使用障碍在获得基本临床能力的同时进行研究，以治疗受这些疾病影响的患者。