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Molecular mechanisms of neural plasticity in drug addiction

药物成瘾神经可塑性的分子机制

基本信息

批准号：
7885466
负责人：
Laura Nicole Smith
金额：
$ 4.76万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7885466
关键词：
Abstinence Address Adenylate Cyclase Adult Age Agonist Antibodies Applications Grants Area Behavior Behavioral Biological Assay Biological Process Brain Calcineurin Calcium Calcium/calmodulin-dependent protein kinase Calmodulin Camping Chronic Clinical Treatment Cocaine Corpus striatum structure Cyclic AMP Cyclin-Dependent Kinase 5 Data Dendritic Spines Dependence Dopamine Dopamine Receptor Down-Regulation Drug Addiction Drug Exposure Drug abuse Exposure to Forskolin Goals Green Fluorescent Proteins Hour Human Individual Injection of therapeutic agent Investigation Knock-out Knockout Mice Lead Learning Link Longevity Mediating Modeling Molecular Nature Neuronal Plasticity Neurons Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Phospho-Specific Antibodies Phosphoproteins Phosphorylation Play Prevention Process Protein Family Protein phosphatase Proteins RNA Interference Receptor Activation Regulation Relapse Rewards Rodent Role Serine Signal Transduction Site Slice Societies Structure Substance abuse problem Synapses Synaptic plasticity Testing Therapeutic Intervention United States Substance Abuse and Mental Health Services Administration Up-Regulation Vertebral column Viral Antibodies Wild Type Mouse Work addiction base behavior change behavior influence behavioral sensitization cocaine exposure cocaine use density drug of abuse in vivo interest mouse model muscle enhancer factor-2A myocyte-specific enhancer-binding factor 2 overexpression receptor response therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): In the U.S., 9% of individuals age 12 and over are considered abusers of one or more substances despite serious negative consequences (Substance Abuse & Mental Health Services Administration, 2008). Human drug abuse typically follows a cycle of abstinence and relapse, the lasting nature of which poses perhaps the greatest challenge to clinical treatment. Since drug-induced sensitization in rodents is used to model the longevity of addiction, understanding mechanisms influencing this behavior, as well as associated brain adaptations, should suggest targets for therapeutic intervention, or possibly, prevention. Recently, it has been shown that chronic cocaine exposure regulates spine density in the nucleus accumbens, the brain's reward center, via cyclic-adenosine monophosphate (cAMP)-dependent inhibition of a transcription factor known as myocyte enhancer factor 2 (MEF2). Furthermore, MEF2 downregulation and spine upregulation are associated with protection against cocaine-induced behavioral sensitization (Pulipparacharuvil et al., 2008). The goal of the current proposal is to determine specific signaling mechanisms responsible for MEF2 regulation, as well as to determine signaling mechanisms involved in cocaine-induced MEF2 regulation, dendritic spine density and behavioral sensitization. Specific aim #1 is to elucidate signaling mechanisms underlying cAMP-dependent inhibition of MEF2. Initial focus will be on whether regulator of calmodulin signaling (RCS), a small neuronal phosphoprotein, is required for this process using neurons cultured from RCS-knockout mice. RNAi-based protein-replacement assays and specific phospho-antibodies to MEF2 Ser408/444 will be used to test the functional role of phosphorylation in cAMP's effect on MEF2, and a calcium-independent form of CaMK will be used to test the involvement of this protein family. Specific aim #2 is to determine the role of RCS in cocaine-dependent regulation of MEF2, spine upregulaton and behavioral sensitization in vivo. This aim will be carried out in a RCS-knockout mouse model of cocaine use in order to determine the necessity of RCS for cocaine-induced changes in each of these areas. Findings from these studies, taken together, will help elucidate how cAMP and cocaine regulate MEF2, and ultimately, how signaling mechanisms in these pathways may contribute to drug-induced spine plasticity and behavioral responses. Relevance: Repeated exposure to drugs of abuse, such as cocaine, is known to cause changes in brain structure and function that may relate to the longevity of addiction. The goal of this project is to understand how these changes occur, which may lead to targets for potential treatment or prevention of addiction.

描述（由申请人提供）：在美国，12 岁及以上的人中有 9% 被认为是一种或多种物质的滥用者，尽管会产生严重的负面后果（物质滥用和心理健康服务管理局，2008 年）。人类药物滥用通常遵循戒断和复发的循环，其持久性可能对临床治疗构成最大的挑战。由于啮齿类动物药物诱导的致敏作用被用来模拟成瘾的寿命，因此了解影响这种行为的机制以及相关的大脑适应，应该可以提出治疗干预或可能预防的目标。最近，研究表明，长期接触可卡因可通过环磷酸腺苷 (cAMP) 依赖性抑制心肌细胞增强因子 2 (MEF2) 转录因子来调节伏隔核（大脑奖励中心）的脊柱密度。此外，MEF2 下调和脊柱上调与防止可卡因诱导的行为过敏有关（Pulipparacharuvil 等，2008）。当前提案的目标是确定负责 MEF2 调节的特定信号传导机制，以及确定可卡因诱导的 MEF2 调节、树突棘密度和行为敏化中涉及的信号传导机制。具体目标#1 是阐明 MEF2 的 cAMP 依赖性抑制背后的信号传导机制。最初的重点是使用从 RCS 敲除小鼠中培养的神经元，这一过程是否需要钙调蛋白信号传导 (RCS)（一种小神经元磷蛋白）的调节剂。基于 RNAi 的蛋白质替代测定和针对 MEF2 Ser408/444 的特异性磷酸化抗体将用于测试磷酸化在 cAMP 对 MEF2 的影响中的功能作用，并且钙独立形式的 CaMK 将用于测试该蛋白质家族的参与。具体目标#2是确定RCS在MEF2的可卡因依赖性调节、脊柱上调和体内行为敏化中的作用。这一目标将在可卡因使用的 RCS 敲除小鼠模型中进行，以确定 RCS 对于可卡因诱导的每个区域变化的必要性。这些研究的结果综合起来将有助于阐明 cAMP 和可卡因如何调节 MEF2，并最终阐明这些途径中的信号传导机制如何有助于药物诱导的脊柱可塑性和行为反应。相关性：众所周知，反复接触可卡因等滥用药物会导致大脑结构和功能发生变化，这可能与成瘾的持续时间有关。该项目的目标是了解这些变化是如何发生的，这可能会导致潜在治疗或预防成瘾的目标。