Determining if Activity in Specific Lateral Habenula Output Pathways Motivates Avoidance of Synthetic Opioid Withdrawal or Cue Induced Reinstatement

确定特定外侧缰核输出通路的活动是否会促使避免合成阿片类药物戒断或提示诱导的恢复

• 批准号: 10425427
• 负责人: Kevin R. Coffey
• 金额: $ 17.45万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425427
• 关键词: Abstinence; Acute; Animals; Award; Behavior; Behavioral; Behavioral Model; Brain region; CAV2 gene; Calcium; Cell Nucleus; Complex; Coupled; Cues; Disease; Distress; Dose; Drug Delivery Systems; Emotional; Emotions; Environment; Epidemic; Euphoria; Exposure to; Extinction (Psychology); Fentanyl; Fiber; Future; Grant; Habenula; Head; Image; Individual; Injections; Jaw; Lateral; Learning; Light; Malaise; Mentors; Mentorship; Midbrain structure; Modeling; Motivation; Naloxone; Negative Reinforcer; Neural Pathways; Neurobiology; Neurons; Opiate Addiction; Opioid; Opsin; Oral; Output; Pain; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase; Positive Reinforcer; Process; Production; Public Health; Rattus; Relapse; Research; Rewards; Role; Scientist; Self Administration; Stress; Substance abuse problem; Tegmentum Mesencephali; Testing; Time; Training; Ultrasonics; United States; Ventral Tegmental Area; Withdrawal; Writing; addiction; base; behavior test; behavioral response; career; combat; design; dorsal raphe nucleus; dysphoria; experience; experimental group; experimental study; gene therapy; improved; in vivo calcium imaging; model development; negative affect; next generation; novel; novel therapeutics; opioid abuse; opioid mortality; opioid withdrawal; optogenetics; overdose death; programs; response; reward processing; skills; synthetic opioid; tool; vocalization

Project Summary Opioid abuse has reached epidemic proportions in the United States and is responsible for more than 40,000 overdose deaths each year 1. In particular, synthetic opioid addiction has proven to be extremely difficult to combat, in part because it generates powerful opponent processes in the user. Each dose of synthetic opioid produces rapid and potent euphoria that is strongly associated to drug cues, while withdrawal and abstinence from synthetic opioids induce severe distress. Avoidance of withdrawal and subsequent exposure to drug cues are key deterrents to long-term abstinence. The Lateral Habenula (LHb) is an exciting target for studying neuronal facilitation of relapse, as LHb activity is correlated with both stress evasion and the encoding of motivational value 6. LHb activity during acute withdrawal may motivate relapse via stress avoidance mechanisms, while during abstinence cues that are normally paired with drugs go unrewarded, inducing activity in the LHb. This activity may motivate drug seeking via a process akin to reward prediction error. Under the primary mentorship of Drs. John Neumaier, Michael Bruchas, Paul Phillips, and Charles Chavkin, this K99/R00 Pathway to Independence award will allow me to obtain training in cutting edge in-vivo calcium imaging and optogenetics, and oral self-administration model development. This training will allow me to elucidate the roles of the major LHb output pathways in motivating avoidance of fentanyl withdrawal and cued reinstatement. During the mentored phase of this grant I will be trained to use GCaMP6-based in-vivo calcium imaging to record LHb neurons that project specifically to the ventral tegmental area (VTA), the rostromedial tegmentum (RMTg), or the dorsal raphe nucleus (DRN) during naloxone-precipitated withdrawal, conditioned place aversion testing, and fentanyl reinstatement. I will also be trained to combine in-vivo calcium imaging with red-shifted optogenetic inhibition in order to leverage simultaneous circuit imaging and recording, and test causal relationships between neural pathway activity and behavior. Finally, I will be trained in novel oral fentanyl self-administration (SA) model development, which will be invaluable to my independent research career as a behavioral neuroscientist. During the independent phase of the award, I will combine this training with my prior expertise to determine if activity in each LHb pathway is necessary for expression of withdrawal related negative affect, withdrawal induced CPA, or cued reinstatement to fentanyl seeking. I will do so by simultaneously inhibiting LHb projections and recording from each LHb target region (VTA, RMTg, or DRN) to determine the effect of inhibition on behavior and monoaminergic nucleus activity. In summary, the research proposed in this Pathway to Independence Award will elucidate the role of individual LHb pathways in motivating avoidance of withdrawal and cued reinstatement, as well as their role in the expression of negative affect. This award will provide training in new technical tools, grant writing, lab management, mentorship, and other skills necessary to establish an independent research program capable of producing high impact studies and training the next generation of scientists.

项目概要 阿片类药物滥用在美国已达到流行病的程度，导致超过 40,000 人死亡 每年因药物过量死亡 1. 特别是，合成阿片类药物成瘾已被证明极其困难 战斗，部分原因是它在用户中产生强大的对手过程。每剂合成阿片类药物 产生与药物暗示密切相关的快速而有效的欣快感，同时戒断和禁欲 合成阿片类药物会引起严重的痛苦。避免戒断和随后接触药物线索 是长期禁欲的主要障碍。外侧缰核 (LHb) 是一个令人兴奋的研究目标 神经元促进复发，因为 LHb 活性与应激逃避和编码相关 动机价值 6. 急性戒断期间 LHb 活性可能通过避免压力而促使复发 机制，而在戒断期间，通常与药物配对的提示没有得到奖励，从而诱发活动 在左手。这种活动可能会通过类似于奖励预测错误的过程来激发药物寻找。下 博士的主要指导。 John Neumaier、Michael Bruchas、Paul Phillips 和 Charles Chavkin，这款 K99/R00 独立之路奖将使我能够获得尖端体内钙成像和 光遗传学和口服自我给药模型开发。这次培训将使我阐明角色 主要 LHb 输出途径在激励避免芬太尼戒断和提示恢复方面的作用。期间 在这笔资助的指导阶段，我将接受培训，使用基于 GCaMP6 的体内钙成像来记录 LHb 专门投射到腹侧被盖区 (VTA)、喙内侧被盖区 (RMTg) 或 纳洛酮诱发戒断期间的中缝背核（DRN），条件性位置厌恶测试，以及 芬太尼恢复。我还将接受培训，将体内钙成像与红移光遗传学相结合 抑制，以利用同时电路成像和记录，并测试之间的因果关系 神经通路活动和行为。最后，我将接受新型口服芬太尼自我给药（SA）模型的培训 的发展，这对于我作为行为神经科学家的独立研究生涯来说是无价的。期间 在奖项的独立阶段，我将把这次培训与我之前的专业知识结合起来，以确定活动是否 每个 LHb 途径对于表达戒断相关的负面情绪、戒断诱导的 CPA、 或提示恢复芬太尼寻求。我将通过同时抑制 LHb 投射和记录来做到这一点 从每个 LHb 目标区域（VTA、RMTg 或 DRN）确定抑制对行为和行为的影响 单胺能核活性。总之，独立之路奖中提出的研究 将阐明个体 LHb 通路在激励避免戒断和提示恢复中的作用， 以及它们在负面情绪表达中的作用。该奖项将提供新技术工具的培训， 资助写作、实验室管理、指导以及建立独立研究所需的其他技能 该计划能够进行高影响力的研究并培训下一代科学家。