Psychostimulants and Dendritic Spines

精神兴奋剂和树突棘

• 批准号: 8022937
• 负责人: PAUL GREENGARD
• 金额: $ 35.04万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8022937
• 关键词: Actins; Acute; Addictive Behavior; Address; Alanine; Amygdaloid structure; Antibodies; Aspartic Acid; Behavior; Behavioral; Binding; Binding Proteins; Biochemical; Biological; Brain; Calcineurin; Cells; Chronic; Cocaine; Corpus striatum structure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoskeleton; Dendritic Spines; Development; Dopamine; Dopamine D2 Receptor; Dorsal; Drug Addiction; Drug usage; Engineering; Epitopes; Exhibits; Exposure to; F-Actin; Future; Glutamates; Goals; Hippocampus (Brain); Knock-out; Knockout Mice; Lead; Learning; Location; Maintenance; Mediating; Memory; Microfilaments; Molecular; Molecular Target; Morphology; Mus; Neurabin; Neurons; Nucleus Accumbens; Outcome Study; Partner in relationship; Pattern; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Play; Prefrontal Cortex; Principal Investigator; Protein Dephosphorylation; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; Proteomics; Recruitment Activity; Regulation; Research; Rewards; Role; Signal Transduction; Site; Substantia nigra structure; Synapses; Synaptic Transmission; System; Transgenic Mice; Ventral Striatum; Ventral Tegmental Area; Vertebral column; Wild Type Mouse; addiction; base; calmodulin-dependent protein kinase II; cell type; density; inhibitor/antagonist; mutant; nerve supply; novel; polymerization; preference; programs; promoter; psychostimulant; putamen; receptor; response; rho; spinophilin; transmission process

Drug addiction is defined as a compulsive pattern of drug-seeking and drug-taking behavior that takes places at the expense of most other activities. To address the question why addicts find it so difficult to stop using drugs, much research has been aimed at characterization ol brain systems that mediate the rewarding effects of addictive drugs. The brain reward circuits include dopaminergic innervations from ventral tegmental area and substantia nigra to the nucleus accumbens (ventral striatum) and caudate putamen (dorsal stnatum) as well as glutamate inputs from the prefrontal cortex, amygdala and hippocampus. The dendritic spines of medium spiny neurons in striatum are the cellular location for the integration of dopamine and glutamate transmission both of which are important for development and expression of the adaptive effects of psychostimulants. Because of the long lasting aspects of drug addiction, reorganization of synaptic connections and their maintenance have been suggested as a cellular mechanism of learning and enduring memory associated with addictive behaviors. However, the function and molecular mechanism of psychostimulant-induced dendritic spine proliferation are not fully understood. We propose to investigate cocaine-induced spine proliferation and its physiological significance in two major neuronal subpopulations in striatum: striatonigral and striatopallidal neurons (Aim I). We hypothesize that reorganization of actin filaments may underlie the mechanisms involved in spine proliferation induced by psychostimulants. Regulators of the actin cytoskeleton may play an essential role in drug-induced spine formation. We therefore propose to study five regulators of actin dynamics as targets of psychostimulants in spine proliferation: Cdk5 (Aim II),WAVE1 (Aim III)as a new substrate of Cdk5, spmophilin (Aim IV), neurabin (Aim IV) and Lfc (Aim IV) as a new molecule interacting with spinpphilin/neurabin. hi order to address the role of the five key regulators in psychostimulants-induced spine proliferation, we will analyze the biochemical, cell morphological, electrophysiological and behavioral responses to administration of cocaine in neuronal type-specific or conventional knockout mice and wild type mice. Furthermore, to identify novel targets involved in the actions of psychostimulants on spine formation, we propose to perform quantitative proteomic analysis of purified post-synaptic density after chronic treatment with cocaine (Aim I). Taken together, these studies will lead to elucidation of molecular mechanism(s) leading to spine formation after repeated exposure to addictive drugs and the role of spine formation in the actions of psychostimulants.

吸毒成瘾被定义为一种强迫性毒品和吸毒行为的模式，发生在 大多数其他活动的费用。为了解决为什么瘾君子发现很难停止使用药物的问题， 大量研究的目的是表征脑系统，以调解 令人上瘾的药物。大脑奖励电路包括腹侧换段区域的多巴胺能神经和 黑质拟南芥（腹侧纹状体）和尾状壳核（背骨）以及 前额叶皮层，杏仁核和海马的谷氨酸输入。中刺的树突状刺 纹状体中的神经元是整合多巴胺和谷氨酸传播的细胞位置 这对于精神刺激物的适应性作用的发展和表达很重要。因为 吸毒成瘾的持久方面，突触连接的重组及其维护一直是 建议是学习和与成瘾行为相关的学习和持久记忆的一种细胞机制。 但是，精神刺激剂诱导的树突状脊柱增殖的功能和分子机制是 不完全理解。我们建议研究可卡因诱导的脊柱增殖及其生理 纹状体中两个主要神经元亚群的显着性：纹状体和纹状体神经元（AIM I）。 我们假设肌动蛋白丝的重组可能是脊柱涉及的机制的基础 由精神刺激物引起的增殖。肌动蛋白细胞骨架的调节剂可能在 药物诱导的脊柱形成。因此，我们建议将肌动蛋白动力学的五个调节剂作为目标 脊柱增殖中的精神刺激剂：CDK5（AIM II），Wave1（AIM III）作为CDK5的新底物， Spmophilin（AIM IV），神经IV（AIM IV）和LFC（AIM IV）作为新分子与 Spinpphilin/neurabin。嗨，下令解决五个关键调节器在心理刺激诱导的脊柱中的作用 扩散，我们将分析生化，细胞形态，电生理和行为 对神经元特异性或常规敲除小鼠和野生型中可卡因的给药的反应 老鼠。此外，为了确定精神刺激物对脊柱形成的作用涉及的新颖目标，我们 建议对慢性治疗后纯化后突触后密度进行定量蛋白质组学分析 与可卡因（AIM I）。综上所述，这些研究将导致阐明分子机制的领先 反复暴露于成瘾药物以及脊柱形成在作用中的作用后形成脊柱 精神刺激剂。