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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：可卡因滥用是一个重大的公共卫生问题，大约有 140 万美国人符合可卡因依赖和急性过量用药的 DSMIV 标准，每年导致近 50 万人次到急诊室就诊。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后，环境因素也会引起渴望和药物复发。研究记忆的行为和神经生物学方法已经确定了消退，即切断线索和药物之间的关系，作为消除条件行为的一种方法。然而，基于消除的疗法面临的挑战是，消除的行为通常会随着时间的推移或重新接触药物后重新出现。在我们最初的支持期间，我们研究了药理学方法，当与行为消退相结合时，会产生快速而持续的药物寻求丧失，这种丧失对恢复挑战（类似复发的行为）具有抵抗力。我们的重点是长期记忆形成所需的基因表达调控，这涉及与染色质（一种包装 DNA 的蛋白质复合物）相互作用的多种转录因子和辅因子的协同作用。染色质修饰是表观遗传基因调控的主要机制，它正在成为涉及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续长期变化的基础。重要的是，在成瘾动物模型中，慢性药物暴露会诱导稳定的染色质修饰，从而导致稳定的突触可塑性变化，这被认为会驱动行为的持续变化。考虑到药物成瘾以及学习和记忆通路所涉及的电路存在大量重叠，该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。在此更新应用中，我们重点关注通过组蛋白脱乙酰酶 3 (HDAC3) 调节组蛋白乙酰化的特定机制。我们利用遗传、病毒和药理学操作来研究 HDAC3 在消除可卡因诱导的条件性位置偏好和静脉注射可卡因自我给药中的作用。我们假设 HDAC3 是寻药行为消退的关键负调节因子，并且 HDAC3 通过调节 Nr4a（核孤儿受体）基因家族来调节消退。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 在消退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 目标基因）在灭绝中的作用。我们的方法有望阐明灭绝的行为、系统和表观遗传机制，并阐明药理学干预的新分子靶标。