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: 10219214
• 负责人: Kathleen M. Kantak
• 金额: $ 50.9万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219214
• 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; Modeling; Molecular; Monitor; Monkeys; NR1 gene; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Prefrontal Cortex; Procedures; Protein Overexpression; Proteins; Rattus; Relapse; Research; Retrieval; Schedule; Self Administration; Structure; Synaptic plasticity; Techniques; Testing; Therapeutic; Training; Ubiquitination; Viral; Woman; Work; base; clinically significant; cocaine relapse; cocaine self-administration; 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; multimodality; 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.

项目摘要/摘要 这个项目的目标是研究增加物种灭绝获取和恢复的策略。 记忆作为一种手段，与药物记忆竞争，并随后抑制药物记忆在经期的重新出现 可卡因再次暴露的可能性。我们之前开发了一种新的可卡因线索暴露疗法的动物模型 将药物记忆恢复方法与消退训练相结合的成瘾治疗方法 抑制可卡因复发。我们发现添加甘氨酸转运蛋白-1(GlyT-1)抑制剂显著增强 可卡因-线索戒断训练随后减少可卡因自身再获得的有效性 成年雄性大鼠和猴给药。在这个项目中，我们建议将我们的治疗模式扩展到 包括环境丰富(EE)，这是一种记录在案行为程序，可改善学习和 老鼠和人的记忆。我们的工作将集中在引入预定的有限(4小时)的EE 结合每周一次的可卡因-线索戒断训练，这种方法可以增加 在初步研究中，消除学习和减少可卡因自我管理的重新获得。至 实施多模式方法，将性别作为生物变量进行监测，我们将研究 EE和GlyT-1抑制与可卡因-线索消退训练对成年雌雄大鼠的联合作用 (目标1)。这些联合治疗之间的协同作用，以扩大物种灭绝的获取和恢复 减少可卡因复发的记忆是假想的。为了扩大我们的调查范围，我们将审查 EE和GlyT-1抑制剂作用下的关键大脑区域的分子变化。我们将重点关注 谷氨酸受体(NMDAR；AMPAR)和脑源性神经营养因子(TrkB)以及两种受体 新的靶点Nedd4和USP46，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额前皮质。我们计划了一种双重方法，在这种方法中， 相关蛋白质靶标的贩运和泛化(目标2)以及病毒介导的击倒和 在用EE和GlyT-1处理的雄性和雌性大鼠中，将研究这些靶点(目标3)的过度表达 抑制剂结合消光训练。这两种策略(EE和GlyT-1)是如何 抑制)在大鼠体内的协同作用可能具有相当大的科学和临床意义。结果 这些研究将有助于确定通过我们的 多模式治疗干预。确定这些目标作为灭绝训练的结果的关键变化 联合EE和GlyT-1抑制可能有助于开发新的药物疗法 作用机制和发现独特的行为疗法，使治疗相关 抑制成年男性和女性对可卡因滥用复发的突触可塑性。