COCAINE, OPIOIDS AND DRUG ABUSE

可卡因、阿片类药物和药物滥用

• 批准号: 7271283
• 负责人: Peter W Kalivas
• 金额: $ 34.26万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271283
• 关键词: AMPA Receptors; Abbreviations; Acetylcysteine; Actins; Active Biological Transport; Acute; Affect; Animals; Antisense Oligonucleotides; Association Learning; Astrocytes; Autoreceptors; Behavior; Behavioral; Binding; Binding Sites; Brain region; Carrier Proteins; Catalytic Domain; Chimeric Proteins; Chromosome Pairing; Cocaine; Cocaine Dependence; Cystine; Dendritic Spines; Dependovirus; Development; Dopamine; Down-Regulation; Drug Sensitization; Drug abuse; Evaluation; Excitatory Synapse; Exposure to; F-Actin; G Actin; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; Genes; Glutamate Receptor; Glutamates; Goals; Grant; Homer protein; In Vitro; Infusion procedures; Injection of therapeutic agent; Investigation; Knowledge; Learning; Literature; Long-Term Depression; Long-Term Potentiation; Maintenance; Measures; Mediating; Membrane; Memory; Mental Depression; Metabotropic Glutamate Receptors; Methods; Microdialysis; Molecular; Monitor; Motor; Mus; Neuronal Plasticity; Neurons; Nucleus Accumbens; Numbers; Opioid; Paranoia; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Prefrontal Cortex; Principal Investigator; Progress Reports; Propionic Acids; Propionic acid; Proteins; Publications; Reagent; Receptor Signaling; Regulation; Relapse; Relative (related person); Reporting; Research; Research Design; Role; Site; Source; Stimulus; Surface; Synapses; System; Withdrawal; Work; addiction; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; behavioral sensitization; density; design; dopamine transporter; extracellular; human RASD1 protein; in vivo; interest; intracellular protein transport; kinase inhibitor; metabotropic glutamate receptor 2; monoamine; neuroadaptation; neurochemistry; novel; numb protein; polymerization; postsynaptic; presynaptic; presynaptic density protein 95; prevent; programs; protein transport; receptor; research study; response; trafficking; transmission process; treatment effect; uptake

Repeated exposure to cocaine produces enduring behavioral changes, such as the sensitization of the motor stimulation. This proposal seeks to identify the cellular basis for the enduring behavioral plasticity produced by withdrawalfrom repeated cocaine administration. The focus of this work is on neuroadaptations in the glutamatergic projection from the prefrontal cortex to the nucleus accumbens. Accordingly, the project is comprised to two specific aims, one describing experiments to evaluate presynaptic changes in glutamate release in the nucleus accumbens, and another aim is designed to characterize postsynaptic changes. The projects involve in vivo estimates of extracellular glutamate and subcellular localization of specific proteins shown during the present grant period to be involved in cocaine addiction, including Homer, Lim kinase, F- actin, cystine-glutamate exchanger, as well as certain surface receptors whose trafficking is altered by cocaine, including ionotropic glutamate and adenosinel receptors. The importance of alterations in these proteins will be evaluated not only by examining for influences of these proteins on enduring changes produced by repeated cocaine in extracellular glutamate, but also on the capacity of withdrawalfrom repeated cocaine to induce locomotor sensitization. In order to accomplish this, it will often be necessary to design novel reagents to affect intracellular protein levels and/or function. For example, adeno-associated virus to transfect neurons with various Homer cDNA's or Tat-HIV fusion proteins to inhibit Lim-kinase have been constructed. The primary significance of this research is two-fold. First, novel neuroadaptations associated with withdrawal from repeated cocaine administration will be demonstrated, and second, novel reagents to normalize these adaptations and alter the development or expression of cocaine-induced behavioral plasticity will be characterized.

重复接触可卡因会产生持久的行为改变，例如电动机的敏化 刺激。该建议旨在确定产生的持久行为可塑性的细胞基础 通过撤回可卡因给药。这项工作的重点是 从前额叶皮层到伏隔核的谷氨酸能投射。因此，该项目是 包含两个特定目标，一个描述实验以评估谷氨酸的突触前变化 在伏隔核中释放，另一个目的旨在表征突触后变化。这 项目涉及细胞外谷氨酸的体内估计和特定蛋白的亚细胞定位 在目前的赠款期间显示可卡因成瘾，包括荷马，林激酶，f- 肌动蛋白，胱氨酸 - 谷氨酸交换剂以及某些经过贩运的表面受体。 可卡因，包括离子谷氨酸和腺苷受体。这些改变的重要性 不仅可以通过检查这些蛋白质对持久变化的影响来评估蛋白质 由重复可卡因在细胞外谷氨酸中产生，但也以戒断的能力产生 重复可卡因诱导运动敏化。为了实现这一目标，通常有必要 设计新型试剂以影响细胞内蛋白水平和/或功能。例如，腺相关 用各种荷马cDNA或TAT-HIV融合蛋白转染神经元的病毒抑制LIM-激酶 已构造。这项研究的主要意义是两倍。首先，新颖的神经照射 将证明与重复可卡因给药的退出有关，其次是新颖的 试剂使这些适应并改变可卡因诱导的发展或表达 行为可塑性将被表征。