COCAINE-INDUCED SYNAPTIC PLASTICITY IN LIMBIC BRAIN REGIONS

可卡因诱导边缘脑区域的突触可塑性

• 批准号: 7318812
• 负责人: VIRGINIA M PICKEL
• 金额: $ 22.96万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318812
• 关键词: Acute; Address; Adult; Affect; Amygdaloid structure; Behavior; Behavioral; Brain region; CRF receptor type 1; Cell Nucleus; Cells; Chromosome Pairing; Chronic; Cocaine; Condition; Core Facility; Corticotropin; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; DNA; Dendrites; Dopamine; Dopamine D1 Receptor; Drug Addiction; Dynorphins; Electrons; Emotional; Extinction (Psychology); Gene Deletion; Gene Expression; Glutamate Receptor; Glutamates; Goals; Green Fluorescent Proteins; Health; Human; Individual; Knock-out; Learning; Localized; Location; Mediating; Microinjections; Microscopic; Molecular; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 NMDA receptor; NR1 gene; National Institute of Drug Abuse; Neurons; Nucleus Accumbens; Pattern; Peptides; Pharmaceutical Preparations; Phenotype; Physiological; Range; Recombinants; Reporter; Research; Research Personnel; Resources; Rewards; Route; Site; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Surface; Synapses; Synaptic plasticity; System; Testing; Universities; Ventral Tegmental Area; Viral; Viral Vector; Withdrawal; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; cocaine receptor; day; dopamine system; dopaminergic neuron; drug reward; drug seeking behavior; human NR1 protein; multidisciplinary; opioid abuse; postsynaptic; preference; receptor; recombinase; reward circuitry; trafficking; transmission process

Drug addiction is a major health issue worldwide, and the central focus of the NIDA Center at Rockefeller University. All addictive substances enhance dopamine in the mesolimbic reward circuit from the ventral tegmental area (VTA) to the nucleus accumbens shell (Acb-SH), a limbic brain region included with the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) as components of the extended amygdala. These regions are also targeted by many excitatory inputs, whose physiological actions are largely ascribed to activation of glutamate (NMDA and AMP A) receptors. Glutamatergic transmission is potently modulated by dopamine acting at Dl receptors and corticotrophin releasing factor (CRF) peptides active at CRF type-1 (CRF1) receptors that are prevalent in both the central extended and basolateral (BLA) amygdala. The more cortical-like BLA has bidirectional connections with the VTA-and other limbic structures implicated in emotional behavior and learning of drug/reward associations. Glutamate receptor plasticity and associations with the dopamine and/or CRF systems contribute to persistent drugseeking behaviors that are powerfully influenced by stress. The subcellular changes in receptor distributions occurring in neurons with these identified transmitter phenotypes in individual brain regions are largely unknown. To begin addressing these key questions, Project 3 in the renewal application will combine research strategies using electron microscopic immunolabeling and spatial-temporal deletion (knock-out) of the NR1 NMDA receptor subunit in limbic brain regions critical for drug seeking behaviors. The long-range goal is to test the hypotheses that (1) limbic NMDA receptors have subcellular distributions conducive to regionally selective associations with dopamine and CRF systems, and (2) NR1 gene expression in the VTA and/or BLA is essential for the synaptic targeting and cocaine-induced trafficking of both AMP A and dopamine Dl receptors, and for cocaine conditioned place preference (CPP) influenced by stress. The studies will be conducted in wild-type and NR1 "floxed" (flanked by loxP) mice, some of which will receive acute or chronic (14 day) cocaine given in an escalating "binge" pattern mimicking that seen in human addicts. Project 3 reflects a collaborative effort by investigators in existing projects within the NIDA Center and is totally dependent on the core resources and facilities. The results obtained from Project 3, together with those in other projects in the renewal application, will provide important new information that is essential for understanding and treating drug addiction.

药物成瘾是一个全球性的重大健康问题，也是洛克菲勒NIDA中心的中心焦点。 大学所有成瘾物质都能增强中脑边缘奖赏回路中的多巴胺， 被盖区（VTA）到脑桥核壳（Acb-SH），这是一个边缘脑区域，包括在大脑皮层中。 杏仁核中央核（CeA）和终纹床核（BNST）作为 延伸的杏仁核这些区域也是许多兴奋性输入的靶点，其生理学上的兴奋性输入可以刺激这些区域。 这些作用主要归因于谷氨酸（NMDA和AMPA）受体的激活。谷氨酸能 通过作用于D1受体的多巴胺和促肾上腺皮质激素释放因子， (CRF)在CRF-1型（CRF 1）受体上有活性的肽，所述受体在中枢扩展和中枢神经系统中普遍存在， 基底外侧（BLA）杏仁核。更像皮质的BLA与VTA有双向连接-并且 其他边缘系统结构与情绪行为和药物/奖励关联的学习有关。谷氨酸 受体可塑性和与多巴胺和/或CRF系统的关联有助于持续的药物寻求 这些行为受到压力的强烈影响。受体分布的亚细胞变化 发生在神经元中的这些识别出的递质表型在个体脑区域中主要是 未知为了开始解决这些关键问题，更新申请中的项目3将结合联合收割机 使用电子显微镜免疫标记和时空缺失（敲除）的研究策略 边缘脑区的NR 1 NMDA受体亚单位对药物寻求行为至关重要。远程 目的是检验以下假设：（1）边缘系统NMDA受体具有亚细胞分布，有助于 与多巴胺和CRF系统的区域选择性关联，以及（2）VTA中NR 1基因表达 和/或BLA对于突触靶向和可卡因诱导的AMP A和BLA的运输是必需的。 多巴胺D1受体，和可卡因条件性位置偏爱（CPP）的压力的影响。研究 将在野生型和NR 1“floxed”（侧翼为loxP）小鼠中进行，其中一些小鼠将接受急性或 慢性（14天）可卡因给药，以逐步升级的“狂欢”模式，模仿人类成瘾者。 项目3反映了NIDA中心内现有项目的调查人员的合作努力， 完全依赖核心资源和设施。项目3的结果，以及 在其他项目的续期申请中，将提供重要的新信息， 了解和治疗药物成瘾。