Behavioral and epigenetic mechanisms in extinction of cocaine-induced memories

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DSMIV可卡因依赖和急性过量的标准，每年造成近50万次急诊室就诊。尽管如此，对可卡因成瘾和滥用的有效治疗方法非常少。药物治疗可卡因成瘾的部分困难在于，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研究记忆的方法已经确定了消退，其中线索和药物之间的关系被切断，作为消除条件行为的一种方式。然而，基于预防的治疗面临的一个挑战是，消失的行为往往会随着时间的推移或在重新接触药物后恢复。在我们最初的支持阶段，我们研究了药理学方法，当与行为消退配对时，产生了对恢复挑战具有抵抗力的药物寻求的快速和持续的损失（复发样行为）。我们的重点一直是对长期记忆形成所必需的基因表达的调控，这涉及到与染色质（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之一，是突触可塑性和记忆储存的重要分子通路。 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，在成瘾的动物模型中，慢性药物暴露诱导稳定的染色质修饰，导致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。考虑到药物成瘾与学习和记忆途径所涉及的电路的大量重叠，该拨款提案的重点是调节学习和记忆途径，以消除药物相关的记忆。在这个更新的申请中，我们专注于通过组蛋白去乙酰化酶3（HDAC3）调节组蛋白乙酰化的特定机制。我们使用遗传，病毒和药理学的操作，以调查的作用HDAC3在灭绝可卡因诱导的条件性位置偏好和静脉内可卡因自我管理。我们假设HDAC3是觅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在灭绝中的长期调节作用。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，并阐明药物干预的新分子靶点。

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.