Mechanisms Regulating Cocaine Memory Strength

调节可卡因记忆强度的机制

基本信息

批准号：
10399792
负责人：
Mary M Torregrossa
金额：
$ 1.44万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10399792
关键词：
Administrative Supplement Affect Agonist Amygdaloid structure Animal Model Behavior Behavioral Behavioral Mechanisms Calcineurin Calmodulin Caring Chemosensitization Clinical Cocaine Cues Data Disease Drug Addiction Drug usage Electrophysiology (science)Equilibrium Event Exposure to Extinction (Psychology)Female Geniculate body structure Goals Homosynaptic Depression Individual Internships Lateral Learning Long-Term Depression Maintenance Measures Medial Mediating Memory Methods Molecular National Institute of Drug Abuse Neuronal Plasticity Operative Surgical Procedures Pattern Pharmaceutical Preparations Pharmacology Phosphopeptides Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Process Protein Dephosphorylation Proteomics Rattus Regulation Relapse Research Rodent Role Self Administration Serine Sex Differences Signal Pathway Signal Transduction Societies Substance Use Disorder Synapses Testing Thalamic structure Time Tissues Training Viral addiction base calcineurin phosphatase calmodulin-dependent protein kinase II cocaine self-administration cohort conditioned fear craving cue reactivity design disorder later incidence prevention drug of abuse experience experimental study improved interest learning extinction male memory process mimetics mutant neural circuit neurobiological mechanism non-drug novel phosphoproteomics prevent receptor relating to nervous system response student training substance use substance user summer research treatment research treatment strategy undergraduate student

项目摘要

Abstract Drug addiction is a serious disorder that affects millions of people and produces a large burden on society. Many individuals try to abstain from use, but at least 60% of people relapse within one year. Thus, relapse prevention remains an important goal for addiction treatment research. One of the primary causes of relapse is exposure to the environmental cues (people, places, and things) that remind individuals of drug use and initiate craving. One potential treatment strategy is to reduce the strength of these drug-cue memories so that they are less able to cause renewed drug use. Clinically, this can be accomplished using exposure therapy, which is based on extinction learning and involves multiple presentations of drug-associated cues until the craving response is reduced. Unfortunately, this approach is only mildly effective. Thus, we have investigated the neurobiological mechanisms underlying the maintenance and extinction of cocaine memories, in order to identify potential strategies for improving the ability of cue exposure therapy to reduce relapse. We identified both neural circuit and molecular mechanisms that underlie cocaine memory formation and extinction. Specifically, we found that plasticity at synapses in the lateral amygdala (LA) that receive inputs from the medial geniculate nucleus of the thalamus (MGN) are strengthened after cocaine self-administration and that this plasticity is reversed by cue extinction training. We further found that we could induce long-term depression (LTD) at MGN-LA synapses to reduce relapse-like behavior in a manner that mimicked cue extinction training. Additionally, we found that modulating the activity of kinases and phosphatases in this region could either promote extinction learning or disrupt memory reconsolidation to reduce relapse and the strength of MGN-LA synapses. Thus, in this administrative supplement to support a NIDA Summer Research Intern, we aim to train the student in how to perform experiments investigating the regulation of cocaine- associated memories. The intern will be trained to perform IV drug self-administration experiments, including being given the opportunity to perform surgical procedures. The intern will be trained in proper care and handling of rodents and in the common behavioral methods used in the substance use disorder field. The intern will be assigned a specific experiment to investigate the role of GABAB receptors as a potential target for cocaine memory manipulation. The intern will test whether GABAB receptor agonists could be useful adjuncts to exposure therapy. We will determine if GABAB agonists enhance extinction, prevent reconsolidation, and if pharmacologically assisted exposure therapy is associated with changes in cue-associated neural activity across contexts. We will test if GABAB agonists are effective when infused directly into the LA, and if they are effective when given systemically. Overall, the proposed studies are designed to provide a rich training experience for an undergraduate fellow interested in substance use research.

抽象的吸毒成瘾是一种严重的疾病，会影响数百万人，并给社会带来巨大负担。许多人试图禁止使用，但至少有60％的人在一年内复发。因此，复发预防仍然是成瘾治疗研究的重要目标。复发的主要原因之一是接触环境提示（人，地方和事物），使人想起吸毒和启动渴望。一种潜在的治疗策略是降低这些药物记忆的强度，以便它们是不太有能力引起新的吸毒。临床上，这可以使用曝光疗法来完成基于灭绝学习，并涉及与药物相关线索的多次演示直到渴望响应减少。不幸的是，这种方法只有轻度有效。因此，我们调查了可卡因记忆的维持和灭绝的神经生物学机制，以便确定提高提示暴露疗法减少复发能力的潜在策略。我们确定了神经回路和分子机制，这些机制是可卡因记忆形成和灭绝的基础。具体而言，我们发现在侧向杏仁核（LA）中的突触中的可塑性接收了从可卡因自我给药后，丘脑（MGN）的内侧基因核得到加强，提示灭绝训练可以逆转这种可塑性。我们进一步发现我们可以诱导长期 MGN-LA突触的抑郁（LTD）以模仿提示的方式减少复发样行为灭绝训练。此外，我们发现在此调节激酶和磷酸酶的活性区域可以促进灭绝学习或破坏记忆重新整合以减少复发和 MGN-LA突触的强度。因此，在这种管理补充剂中，以支持NIDA夏季研究实习生，我们旨在培训学生如何进行研究可卡因调节的实验相关的记忆。实习生将接受培训以执行IV毒品自我管理实验，包括有机会执行手术程序。实习生将接受适当护理的培训，处理啮齿动物以及在物质使用障碍领域中使用的常见行为方法中的处理。这实习生将被分配一个特定的实验，以研究GABAB受体作为潜在目标的作用可卡因记忆操纵。实习生将测试GABAB受体激动剂是否可以有用暴露疗法。我们将确定Gabab激动剂是否增强灭绝，防止重新溶解，以及是否是否药理辅助暴露疗法与提示相关神经活动的变化有关跨环境。我们将测试Gabab激动剂在直接注入洛杉矶时是否有效，是否是有系统地给予有效。总体而言，拟议的研究旨在提供丰富的培训对有兴趣药物使用研究感兴趣的本科生的经验。