Molecular mechanisms of neural plasticity in drug addiction

药物成瘾神经可塑性的分子机制

• 批准号: 7752965
• 负责人: Laura Nicole Smith
• 金额: $ 4.52万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/7752965
• 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

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，9%的12岁及以上的人被认为滥用一种或多种物质，尽管有严重的负面后果（物质滥用和精神卫生服务管理局，2008年）。人类药物滥用通常遵循戒断和复吸的循环，其持久性可能是对临床治疗的最大挑战。由于啮齿动物中药物诱导的致敏作用被用来模拟成瘾的寿命，因此理解影响这种行为的机制以及相关的大脑适应性，应该为治疗干预或可能的预防提供目标。最近，研究表明，慢性可卡因暴露通过环磷酸腺苷（cAMP）依赖性抑制一种称为肌细胞增强因子2（MEF 2）的转录因子来调节大脑奖赏中心中脑核的棘密度。此外，MEF 2下调和脊柱上调与针对可卡因诱导的行为敏化的保护有关（Pulipparacharuvil等人，2008年）。目前建议的目标是确定负责MEF 2调节的特定信号传导机制，以及确定可卡因诱导的MEF 2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MEF 2的cAMP依赖性抑制的信号传导机制。最初的重点将是是否调节钙调素信号（RCS），一个小的神经元磷蛋白，是需要这个过程中使用的RCS敲除小鼠培养的神经元。基于RNAi的蛋白质替代测定和针对MEF 2 Ser 408/444的特异性磷酸化抗体将用于测试磷酸化在cAMP对MEF 2的作用中的功能作用，并且钙非依赖性形式的CaMK将用于测试该蛋白质家族的参与。具体目标#2是确定RCS在体内MEF 2的可卡因依赖性调节、脊柱上调和行为致敏中的作用。这一目标将在RCS敲除可卡因使用小鼠模型中进行，以确定RCS对可卡因诱导的这些区域中的每一个变化的必要性。这些研究的结果将有助于阐明cAMP和可卡因如何调节MEF 2，以及最终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的变化，这可能与成瘾的持久性有关。该项目的目标是了解这些变化是如何发生的，这可能会导致潜在的治疗或预防成瘾的目标。