Hippocampus and Relapse Associated with Drug Addiction

海马体和与毒瘾相关的复发

• 批准号: 8239734
• 负责人: KRISTEN A KEEFE
• 金额: $ 22.43万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239734
• 关键词: Abstinence; Alcohols; Applications Grants; Attenuated; Behavior; Behavioral; Cellular Compartment Analysis; Cocaine; Complement; Complex; Cues; Data; Detection; Development; Drug Addiction; Drug abuse; Exposure to; Future; Goals; Gold; Hippocampus (Brain); Immediate-Early Genes; In Situ Hybridization; Information Retrieval; Infusion procedures; Lateral; Lead; Learning; Lesion; Location; Maps; Mediating; Memory; Methamphetamine; Molecular; Naloxone; Narcotic Antagonists; Neurons; Opiates; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Play; Process; Rattus; Recurrence; Relapse; Research; Retrieval; Role; Signal Transduction; Societies; Stimulus; Testing; Variant; Visual; Work; base; cocaine exposure; drug craving; drug development; drug of abuse; drug relapse; drug seeking behavior; entorhinal cortex; hippocampal subregions; innovation; mRNA Expression; new therapeutic target; novel; operation; preference; prevent; relating to nervous system; response; theories; therapeutic target

DESCRIPTION (provided by applicant): Relapse associated with return to drug-seeking and drug-taking behavior after a prolonged period of abstinence represents a serious problem for society. This problem provides a challenge in terms of understanding processes that support relapse and the development of drugs that can attenuate or prevent relapse. Pattern completion functions of the CA3 subregion of the hippocampus have been demonstrated in the context of object based-cue memory tasks, but to date have not been examined in the context of object-based cue-induced relapse to drug-seeking behavior. Furthermore, prior work on visual cue memory functions of the hippocampus have demonstrated disruption of pattern completion following infusion of an opioid antagonist into CA3, providing a potential novel therapeutic target for managing relapse and drug-seeking behavior. This proposal therefore will test the hypothesis that a pattern completion process involving hippocampal CA3 encoding and opiate signaling therein underlies the ability of subsets of object-based cues to evoke relapse to drug seeking/preference. The first aim of this proposal is to use a variant of the conditioned place preference task in which the number of available object-based cues is parametrically adjusted to assess the role of pattern completion in cue-induced relapse to drug-seeking behavior. Furthermore, this aim will provide additional evidence for a pattern completion process and a potential therapeutic target for managing relapse in that it will determine whether systemic administration or local infusion of naloxone into the CA3 region disrupts cue-induced relapse for cocaine. The second aim of this proposal will provide additional evidence for pattern completion in the CA3 during cue- induced relapse to drug seeking. In situ hybridization analysis of Arc mRNA expression will be used to map neural activation in CA3 and the extent to which the same neuronal ensembles are activated by exposure of rats to a subset of drug-associated cues vs. exposure to all cues. Successful completion of these aims should lead to the identification of novel, specific, neural substrates that may be targeted for future behavioral and pharmacological manipulation to better manage drug abuse. PUBLIC HEALTH RELEVANCE: The first goal of this research is to provide evidence for a cue-based pattern completion process mediated by the CA3 subregion of the hippocampus during cue relapse following cocaine exposure. In addition, the results may provide for a potential therapeutic target for managing relapse in drug seeking for cocaine in that it will determine whether systemic administration or local infusion of naloxone into the CA3 region disrupts cue-induced relapse for cocaine. The second goal of this research is to provide additional evidence for pattern completion in the CA3 during cue-induced relapse of drug seeking based on arc mRNA expression in the CA3 region. Successful completion of these goals should lead to the identification of novel, specific, neural substrates that may be targeted for future behavioral and pharmacological manipulation to better manage drug abuse.

描述（由申请人提供）： 长期戒毒后，与重新寻求毒品和吸毒行为相关的复发是一个严重的社会问题。这个问题对理解支持复发的过程以及开发可以减轻或预防复发的药物提出了挑战。海马 CA3 亚区的模式完成功能已在基于对象的线索记忆任务的背景下得到证实，但迄今为止尚未在基于对象的线索诱导的药物寻求行为复发的背景下进行检查。此外，先前对海马视觉提示记忆功能的研究表明，将阿片拮抗剂注入 CA3 后，模式完成会受到破坏，为控制复发和药物寻求行为提供了潜在的新治疗靶点。因此，该提案将检验以下假设：涉及海马 CA3 编码和阿片信号传导的模式完成过程是基于对象的线索子集诱发药物寻求/偏好复发的能力的基础。该提案的第一个目标是使用条件性位置偏好任务的变体，其中可用的基于对象的线索的数量进行参数调整，以评估模式完成在线索诱导的药物寻求行为复发中的作用。此外，这一目标将为模式完成过程和管理复发的潜在治疗目标提供额外的证据，因为它将确定纳洛酮全身给药或局部输注到 CA3 区域是否会破坏提示诱导的可卡因复发。该提案的第二个目标将为线索诱导的药物寻求复发期间 CA3 中的模式完成提供额外的证据。 Arc mRNA 表达的原位杂交分析将用于绘制 CA3 中的神经激活图谱，以及大鼠暴露于一部分药物相关线索与暴露于所有线索时相同神经元群被激活的程度。成功完成这些目标应该能够识别出新颖的、特异性的神经底物，这些底物可以作为未来行为和药理学操作的目标，以更好地管理药物滥用。 公共健康相关性：本研究的首要目标是为可卡因暴露后提示复发期间海马 CA3 亚区介导的基于提示的模式完成过程提供证据。此外，该结果可能为管理可卡因药物寻找复发提供潜在的治疗靶点，因为它将确定纳洛酮全身给药或局部输注到CA3区域是否会破坏提示诱导的可卡因复发。本研究的第二个目标是根据 CA3 区域中的 arc mRNA 表达，为线索诱导的寻药复发期间 CA3 中的模式完成提供额外的证据。成功完成这些目标应该能够识别出新颖的、特异的神经底物，这些底物可以作为未来行为和药理学操作的目标，以更好地管理药物滥用。