Mechanisms of Extinction Memory Enhancement for Cocaine Addiction Treatment

可卡因成瘾治疗的消退记忆增强机制

• 批准号: 9440014
• 负责人: Kathleen M. Kantak
• 金额: $ 56.47万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9440014
• 关键词: Adult; Amygdaloid structure; Animal Model; Behavior; Behavior Therapy; Behavioral; Biological; Brain region; Brain-Derived Neurotrophic Factor; Cocaine; Cocaine Abuse; Cocaine Dependence; Combined Modality Therapy; Complement; Cues; Development; Effectiveness; Environmental Impact; Enzymes; Extinction (Psychology); Female; GLYT1; Glutamate Receptor; Goals; Individual; Intervention; Investigation; Learning; Link; Measurement; Mediating; Memory; Methods; Modality; Modeling; Molecular; Monitor; Monkeys; NR1 gene; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Prefrontal Cortex; Procedures; Protein Overexpression; Proteins; Rattus; Relapse; Research; Retrieval; Schedule; Self Administration; Self-Administered; Structure; Synaptic plasticity; Techniques; Testing; Therapeutic; Training; Ubiquitination; Viral; Woman; Work; base; clinically significant; cocaine relapse; disorder later incidence prevention; drug addiction therapy; environmental enrichment for laboratory animals; improved; inhibitor/antagonist; interest; knock-down; learning extinction; male; man; memory retrieval; men; novel; overexpression; response; sex; synergism; trafficking; treatment strategy

PROJECT SUMMARY/ABSTRACT The goal of this project is to investigate strategies that augment the acquisition and retrieval of extinction memory as a means to compete with and subsequently inhibit the reemergence of drug memory during periods of cocaine reexposure. We previously developed a novel animal model of cue exposure therapy for cocaine addiction treatment that incorporates drug memory retrieval methods with extinction training as a means to inhibit cocaine relapse. We found that adding a glycine transporter-1 (GlyT-1) inhibitor significantly enhanced the effectiveness with which cocaine-cue extinction training subsequently reduces reacquisition of cocaine self- administration in adult male rats and monkeys. In this project, we propose to extend our treatment model to include environmental enrichment (EE), a documented behavioral procedure that improves learning and memory in rat and man. Our work will focus on the introduction of limited (4hr) periods of EE scheduled in conjunction with weekly sessions of cocaine-cue extinction training, an approach that augmented the rate of extinction learning and reduced reacquisition of cocaine self-administration in preliminary studies. To implement a multi-modal approach for which sex as a biological variable will be monitored, we will examine the combined effects of EE and GlyT-1 inhibition with cocaine-cue extinction training in adult male and female rats (Aim 1). Synergy between these combined treatments for augmenting acquisition and retrieval of extinction memory to reduce cocaine relapse is hypothesized. To broaden the scope of our investigation, we will examine molecular changes in key brain regions that underlie the effects of EE and a GlyT-1 inhibitor. We will focus on receptors for glutamate (NMDAR; AMPAR) and brain derived neurotrophic factor (TrkB) as well as on two novel targets Nedd4 and USP46, as these influence the primary cellular means by which learning, memory and synaptic plasticity unfold. Our preliminary studies support an investigation of these targets, particularly in basolateral amygdala and ventromedial prefrontal cortex. We plan a dual approach in which expression, trafficking and ubiquination of relevant protein targets (Aim 2) as well as viral-mediated knockdown and overexpression of those targets (Aim 3) will be studied in male and female rats treated with EE and a GlyT-1 inhibitor combined with extinction training. An investigation into how these two strategies (EE and GlyT-1 inhibition) synergize in combination in rats could have considerable scientific and clinical significance. Results from these studies will help identify mechanisms that mediate behavioral improvements attained through our multi-modal treatment intervention. Identifying critical changes in these targets as a result of extinction training combined with EE and GlyT-1 inhibition may aid in the development of pharmacotherapies with novel mechanisms of action and in the discovery of unique behavioral therapies that enable therapeutically relevant synaptic plasticity that inhibits relapse to cocaine abuse in adult men and women.

项目总结/摘要 这个项目的目标是调查策略，增加收购和检索的灭绝 记忆作为一种手段，以竞争和随后抑制药物记忆的重现期间， 可卡因再暴露我们以前开发了一种新的可卡因线索暴露治疗的动物模型 成瘾治疗，将药物记忆恢复方法与消退训练相结合， 抑制可卡因复发。我们发现，加入甘氨酸转运蛋白-1（GlyT-1）抑制剂显著增强了 可卡因线索消退训练随后减少可卡因自我再摄取的有效性， 在成年雄性大鼠和猴中给药。在这个项目中，我们建议将我们的治疗模式扩展到 包括环境富集（EE），这是一种记录在案行为程序，可以改善学习， 我们的工作将集中在引入有限的（4小时）EE时间安排在大鼠和人的记忆。 与每周一次的可卡因线索消退训练相结合，这种方法增加了 在初步研究中，消退学习和减少可卡因自我给药的重新获得。到 实施多模式方法，将性别作为一个生物变量进行监测，我们将审查 成年雄性和雌性大鼠中EE和GlyT-1抑制与可卡因-线索消退训练的联合作用 (Aim 1）。这些联合治疗之间的协同作用，以增强获取和检索灭绝 记忆减少可卡因复吸是假设。为了扩大我们的调查范围，我们将研究 EE和GlyT-1抑制剂作用下关键脑区的分子变化。我们将专注于 谷氨酸受体（NMDAR; AMPAR）和脑源性神经营养因子（TrkB）以及两种 新的靶点Nedd 4和USP 46，因为它们影响学习、记忆和 突触可塑性展开。我们的初步研究支持对这些目标的调查，特别是在 基底外侧杏仁核和腹内侧前额叶皮质。我们计划一个双重的方法， 相关蛋白靶点的运输和泛素化（Aim 2）以及病毒介导的敲除， 将在用EE和GlyT-1处理的雄性和雌性大鼠中研究这些靶点的过表达（Aim 3）。 抑制剂结合消退训练。研究了这两种策略（EE和GlyT-1） 抑制）协同作用可能具有相当的科学和临床意义。结果 从这些研究中将有助于确定介导通过我们的研究获得的行为改善的机制， 多模式治疗干预。识别这些目标由于灭绝训练而发生的关键变化 与EE和GlyT-1抑制相结合，可以帮助开发具有新的 作用机制和发现独特的行为疗法，使治疗相关的 突触可塑性，抑制成年男性和女性可卡因滥用复发。