Behavioral and epigenetic mechanisms in extinction of cocaine-induced memories

可卡因诱发记忆消退的行为和表观遗传机制

• 批准号: 8636891
• 负责人: K Matthew Lattal
• 金额: $ 53.42万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636891
• 关键词: Abstinence; Accident and Emergency department; Acute; Affect; American; Animal Model; Applications Grants; Behavior; Behavior Therapy; Behavioral; Behavioral Mechanisms; Brain region; Cell physiology; Cells; Chromatin; Chronic; Clinical; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Cognitive Therapy; Cues; DNA Packaging; Deacetylase; Dopamine; Drug Addiction; Drug Exposure; Early Gene Transcriptions; Epigenetic Process; Exposure to; Extinction (Psychology); FDA approved; Funding; Future; Gene Expression; Gene Expression Regulation; Gene Family; Gene Targeting; Genes; Grant; Histone Acetylation; Histones; Immediate-Early Genes; Intervention; Intravenous; Lead; Learning; Letters; Medical; Memory; Modeling; Molecular; Molecular Target; Mus; Neurobiology; Neuronal Plasticity; Neurotransmitters; Nuclear Orphan Receptor; Overdose; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Procedures; Public Health; Rattus; Regulation; Relapse; Research; Resistance; Rodent Model; Role; Self Administration; Signal Transduction; Site; Synaptic plasticity; System; Testing; Therapeutic Intervention; Time; Transcriptional Regulation; Translating; United States; Visit; Wood material; addiction; attenuation; base; chromatin modification; cofactor; craving; drug relapse; drug seeking behavior; effective therapy; histone acetyltransferase; histone deacetylase 3; histone modification; inhibitor/antagonist; insight; learning extinction; long term memory; meetings; mutant; novel; novel therapeutics; overexpression; preference; protein complex; public health relevance; research study; therapeutic development; transcription factor; virus genetics

DESCRIPTION (provided by applicant): Cocaine abuse is a significant public health problem, with approximately 1.4 million Americans meeting the DSMIV criteria for cocaine dependence and acute overdoses causing nearly 500,000 emergency room visits each year. In spite of this, there are remarkably few effective treatments for cocaine addiction and abuse. Part of the difficulty in the medical treatment of cocaine addiction is that even after successful short-term treatment, environmental cues can evoke craving and drug relapse. Behavioral and neurobiological approaches to memory have identified extinction, in which the relation between the cue and the drug is severed, as a way to eliminate conditioned behavior. A challenge for extinction-based therapies, however, is that extinguished behavior often returns with time or after re-exposure to the drug. In our initial period of support, we examined pharmacological approaches that, when paired with behavioral extinction, generated a rapid and persistent loss of drug-seeking that was resistant to reinstatement challenges (relapse-like behavior). Our focus has been on the regulation of gene expression necessary for long-term memory formation, which involves the concerted action of multiple transcription factors and cofactors that interact with chromatin, a protein complex that packages DNA. Chromatin modification is a main mechanism of epigenetic gene regulation, which is emerging as a major molecular pathway involved in synaptic plasticity and memory storage. Epigenetic gene regulation has been shown to underlie persistent long-term changes at the cellular level as well as the behavioral level. Importantly, in animal models of addiction, chronic drug exposure induces stable chromatin modification resulting in stable synaptic plasticity changes, which is thought to drive persistnt changes in behavior. Considering the substantial overlap in the circuitry involved in drug addiction and learning and memory pathways, the focus of this grant proposal is to modulate learning and memory pathways in order to extinguish drug associated memories. In this renewal application, we focus on a specific mechanism of regulating histone acetylation via histone deacetylase 3 (HDAC3). We use genetic, viral, and pharmacological manipulations to investigate the role of HDAC3 in extinction of cocaine-induced conditioned place preferences and intravenous cocaine self-administration. We hypothesize that HDAC3 is a key negative regulator of extinction of drug-seeking behavior and that HDAC3 modulates extinction via regulation of Nr4a (nuclear orphan receptor) gene family. In Specific Aim 1, we will use a novel pharmacological approach to determine the role of HDAC3 specifically in memory consolidation during extinction. In Specific Aim 2, we will use a genetic and viral approach to determine the role of long-term modulation of HDAC3 in extinction. In Specific Aim 3, we will use a molecular approach to determine the role of the Nr4a gene family (HDAC3 target genes) in extinction. Our approach promises to elucidate behavioral, systems, and epigenetic mechanisms of extinction and elucidate novel molecular targets for pharmacological interventions.

描述(申请人提供)：可卡因滥用是一个严重的公共卫生问题，大约有140万美国人符合DSMIV的可卡因依赖和急性过量的标准，每年导致近50万急诊室就诊。尽管如此，针对可卡因成瘾和滥用的有效治疗方法却非常少。可卡因成瘾的医疗治疗的部分困难在于，即使在成功的短期治疗之后，环境线索也会引起渴望和药物复发。行为学和神经生物学的记忆方法已经确定了消亡，即切断线索和药物之间的关系，作为消除条件性行为的一种方式。然而，基于灭绝的疗法的一个挑战是，消失的行为通常会随着时间的推移或在再次接触药物后恢复。在我们最初的支持阶段，我们检查了一些药理学方法，当与行为灭绝结合在一起时，会导致快速和持续的药物寻找损失，这种损失对恢复能力的挑战(复发行为)具有抵抗性。我们的重点一直是长期记忆形成所需的基因表达调控，这涉及到多个转录因子和辅助因子的协同作用，这些转录因子和辅因子与染色质相互作用，染色质是包装DNA的蛋白质复合体。染色质修饰是表观遗传基因调控的主要机制，是参与突触可塑性和记忆存储的主要分子途径。表观遗传基因调控已被证明是细胞水平和行为水平持久长期变化的基础。重要的是，在成瘾动物模型中，慢性药物暴露诱导了稳定的染色质修饰，导致了稳定的突触可塑性变化，这被认为是驱动行为持续变化的原因。考虑到参与药物成瘾和学习记忆通路的回路有很大的重叠，这项拨款提案的重点是调节学习和记忆通路，以消除与药物相关的记忆。在这一新的应用中，我们将重点放在通过组蛋白脱乙酰酶3(HDAC3)调节组蛋白乙酰化的特定机制上。我们使用遗传、病毒和药物操作来研究HDAC3在可卡因诱导的条件性位置偏爱和静脉注射可卡因自我给药的消退中的作用。我们假设HDAC3是药物寻找行为消失的关键负性调节因子，并且HDAC3通过调节Nr4a(核孤儿受体)基因家族来调节药物寻找行为的消失。在具体目标1中，我们将使用一种新的药理学方法来确定HDAC3在灭绝期间记忆巩固中的具体作用。在具体目标2中，我们将使用遗传和病毒方法来确定HDAC3的长期调节在物种灭绝中的作用。在具体目标3中，我们将使用分子方法来确定Nr4a基因家族(HDAC3靶基因)在物种灭绝中的作用。我们的方法有望阐明灭绝的行为、系统和表观遗传学机制，并阐明药物干预的新分子靶点。