DAT-Regulation of Nucleus Accumbens Microcircuitry by Oxycodone Exposure and Withdrawal

羟考酮暴露和撤回对伏核微电路的 DAT 调节

• 批准号: 10453673
• 负责人: Patrick Rothwell
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453673
• 关键词: Acute; Analgesics; Behavior; Brain; Brain region; Cells; Chronic; Clinical; Consumption; Data; Dopamine Receptor; Exhibits; Goals; Helping to End Addiction Long-term; Hour; Human; Individual; Infusion procedures; Interneurons; Knowledge; Measures; Mediating; Methods; Modeling; Monitor; Naloxone; National Institute of Drug Abuse; Nature; Negative Reinforcements; Neuronal Plasticity; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Antagonist; Output; Oxycodone; Patients; Pattern; Periodicity; Pharmaceutical Preparations; Procedures; Property; Publishing; Pump; Regulation; Relapse; Reporting; Research; Research Project Grants; Rewards; Role; Side; Slice; Source; Stimulant; Synapses; Synaptic Transmission; United States National Institutes of Health; Withdrawal; addiction; base; clinically relevant; controlled release; drug action; experience; experimental study; gamma-Aminobutyric Acid; in vivo; interest; mu opioid receptors; neural circuit; new therapeutic target; novel; opioid abuse; opioid epidemic; opioid exposure; opioid injection; opioid withdrawal; osmotic minipump; patch clamp; prescription drug abuse; prescription opioid; prevent; programs; synaptic inhibition

DAT18-07: The aversive nature of withdrawal represents a powerful source of negative reinforcement, perpetuating the use and abuse of oxycodone and other prescription opioids. More effective strategies to relieve and prevent withdrawal may decrease consumption of prescription opioids, and facilitate efforts to discontinue use and prevent relapse. These strategies must be informed by a deeper understanding of the neural circuits mediating aversion and other facets of prescription opioid withdrawal. The long-term goal of our research is to determine how opioid exposure and withdrawal modify nucleus accumbens inhibitory microcircuits, and ultimately use this knowledge to reverse or prevent maladaptive changes that contribute to addiction. The nucleus accumbens is commonly associated with reward but also has a “dark side”, contributing to the aversive aspects of opioid withdrawal and other states of aversion. The specific goals of this proposal are to evaluate the contribution of nucleus accumbens fast-spiking interneurons (FSIs) and medium spiny neurons (MSNs) to aversive behavior during oxycodone withdrawal, and determine how oxycodone withdrawal modifies cellular properties of FSIs and MSNs. The scientific premise for this proposal is based on published and preliminary data that nucleus accumbens FSIs and D2-MSNs are activated during opioid withdrawal and regulate aversive states. Our central hypothesis is that FSIs are inhibited by opioid exposure and exhibit rebound activation during opioid withdrawal, modulating aversion through their GABAergic synapses onto MSNs. We predict that chronic oxycodone exposure reorganizes synaptic output of FSIs onto MSNs, changing how FSIs regulate aversion. In AIM 1, we will determine how FSIs, D2-MSNs, and D1-MSNs regulate aversion during oxycodone withdrawal. Using a clinically relevant model of spontaneous oxycodone withdrawal, we will use chemogenetic methods to manipulate the activity of FSIs and MSNs, and measure conditioned place aversion as well as classic somatic signs of withdrawal. We will also determine how FSI manipulations regulate the activation of MSNs. We predict that FSI activation constrains the expression of oxycodone withdrawal through an inhibitory influence on D2-MSNs. In AIM 2, we will determine how the cellular properties of FSIs and MSNs are altered by oxycodone withdrawal. After continuous oxycodone exposure for one week, we will prepare acute brain slices in the presence of oxycodone, and precipitate withdrawal ex vivo by exposing the brain slice to naloxone. We expect to find an increase of GABA release from FSIs onto D2-MSNs during withdrawal, a neuroplastic change that would explain why FSIs constrain aversion during withdrawal. We will also measure the trajectory of cellular changes after repeated withdrawals in vivo, and predict the cyclical engagement of FSIs and MSNs during each withdrawal episode will generate enduring and maladaptive neuroplasticity in the nucleus accumbens. Successful completion of these experiments will uncover a novel role for nucleus accumbens FSIs in opioid effects, and indicate these cells represent a new therapeutic target for alleviating states of opioid withdrawal.

DAT18-07：退缩的厌恶本质是负强化的强大来源， 持续使用和滥用羟考酮和其他处方阿片类药物 更有效的缓解策略。 预防和戒断可能会减少处方阿片类药物的消费，并促进停药的努力 这些策略必须基于对神经回路的更深入的了解。 调解处方阿片类药物戒断的厌恶和其他方面我们研究的长期目标是 确定阿片类药物暴露和戒断如何改变伏隔核抑制微电路，以及 最终利用这些知识来扭转或防止导致成瘾的适应不良变化。 伏隔核通常与奖励相关，但也有“阴暗面”，会导致厌恶 该提案的具体目标是评估阿片类药物戒断和其他厌恶状态。 伏隔核快速尖峰中间神经元（FSIs）和中等棘神经元（MSN）的贡献 羟考酮戒断期间的厌恶行为，并确定羟考酮戒断如何改变细胞 FSI 和 MSN 的特性 该提案的科学前提基于已发布的初步数据。 伏核 FSI 和 D2-MSN 在阿片类药物戒断期间被激活并调节厌恶状态。 我们的中心假设是，FSI 受到阿片类药物暴露的抑制，并在阿片类药物期间表现出反弹激活 戒断，通过 GABA 能突触调节 MSN 的厌恶感，我们预测这种情况会长期存在。 羟考酮暴露将 FSI 的突触输出重组到 MSN 上，改变 FSI 调节厌恶的方式。 AIM 1，我们将确定 FSI、D2-MSN 和 D1-MSN 如何调节羟考酮期间的厌恶感 使用自发羟考酮戒断的临床相关模型，我们将使用化学遗传学。 操纵 FSI 和 MSN 活动的方法，并测量条件性地方厌恶以及经典方法 我们还将确定 FSI 操作如何调节 MSN 的激活。 预测 FSI 激活通过抑制影响来限制羟考酮戒断的表达 在 AIM 2 中，我们将确定 FSI 和 MSN 的细胞特性如何通过以下方式改变： 羟考酮戒断后，连续接触羟考酮一周，我们将准备急性脑切片。 在羟考酮存在的情况下，通过将脑切片暴露于纳洛酮来加速离体戒断。 预计在戒断期间发现 GABA 从 FSI 释放到 D2-MSN 上增加，这是一种神经塑性变化 这可以解释为什么 FSI 会限制戒断期间的厌恶情绪。我们还将测量细胞的轨迹。 体内反复撤药后的变化，并预测每次期间 FSI 和 MSN 的周期性参与 戒断事件会在伏隔核中产生持久的、适应不良的神经可塑性。 这些实验的成功完成将揭示伏隔核 FSI 在阿片类药物中的新作用 效应，并表明这些细胞代表了缓解阿片类药物戒断状态的新治疗靶点。