Role of TrkB and TrkC in Cocaine-Induced Sensitization

TrkB 和 TrkC 在可卡因诱导致敏中的作用

• 批准号: 6515898
• 负责人: AUSAF BARI
• 金额: $ 3.93万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6515898
• 关键词: behavior test; behavioral /social science research tag; behavioral habituation /sensitization; brain derived neurotrophic factor; cocaine; craving; dopamine; enzyme activity; growth factor receptors; immunocytochemistry; laboratory rat; microinjections; mitogen activated protein kinase; neural plasticity; receptor expression; statistics /biometry; tegmentum; transfection /expression vector; tyrosine 3 monooxygenase; western blottings

There are several important reasons for studying the cellular and molecular mechanisms underlying the behavioral effects of repeated psychostimulant administration. First, abuse of psychostimulants such as cocaine is a major medical and social problem. Studies suggest that the neurophysiological adaptations associated with repeated psychostimulant administration contribute to drug craving. Second, the cellular changes underlying repeated psychostimulant administration are a form of neuronal plasticity. Studying the psychostimulant-induced neuronal adaptations will shed more light on the mechanisms of neuronal plasticity in general. Third, studying the molecular adaptations associated with psychostimulant exposure will help us to understand the neural mechanisms that lead to subjective experiences such as pleasure and pain, one of the most fascinating problems in the field of neuroscience. Growing evidence indicates that the neurotrophin family of growth factors plays an important role in the effects of psychostimulants. BDNF and NT-3 microinjections into the VTA have been shown to enhance the behavioral activating effects of cocaine. The goal of the research outlined in this proposal is to expand on these findings by studying the role of BDNF and NT-3 receptors, trkB and trkC respectively, in cocaine-induced behavioral sensitization. Specifically, this will be accomplished in the following two stages. First, rats will be injected with acute and repeated systemic injections of cocaine and levels of trkB and trkC protein in the ventral tegmental area (VTA) will be measured. Second, trkB and trkC receptors will be up-regulated and down-regulated in the VTA using sense and antisense recombinant adenovirus vectors. Following virus treatment, rats will be given acute and repeated systemic cocaine injections. Subsequent behavioral activity will be measured and the VTA will be excised to test for changes in tyrosine hydroxylase activity as a measure of cocaine-induced neuronal plasticity.

研究细胞和分子有几个重要的原因 反复使用精神刺激剂行为效应的机制 行政管理。首先，滥用可卡因等精神刺激剂是一个主要原因 医疗和社会问题。研究表明，神经生理学 与反复服用精神刺激剂相关的适应 对毒品的渴望。第二，反复发生的细胞变化 精神刺激剂的使用是神经元可塑性的一种形式。正在研究的 心理刺激剂诱导的神经元适应将更多地揭示 神经元可塑性的一般机制。第三，研究分子 与心理刺激剂暴露相关的适应将有助于我们理解 导致主观体验的神经机制，如愉悦和 疼痛，神经科学领域最令人着迷的问题之一。 越来越多的证据表明，神经营养因子家族的生长因子发挥作用 在精神刺激剂的作用中起着重要作用。脑源性神经营养因子与NT-3 向VTA内微量注射已被证明能增强行为。 可卡因的兴奋作用。这篇文章中概述的研究目标 建议通过研究BDNF和NT-3的作用来扩展这些发现 可卡因诱导行为中的受体TrkB和trkC 敏化。具体地说，这将在以下两个步骤中完成 各阶段。首先，大鼠将急性和反复全身注射 可卡因注射对腹侧TrkB和trkC蛋白水平的影响 将测量被盖面积(VTA)。其次，TrkB和trkC受体将是 正义和反义在VTA中的上调和下调 重组腺病毒载体。在病毒治疗之后，老鼠将被给予 急性和反复全身注射可卡因。后续行为活动 将被测量，并切除VTA以测试酪氨酸的变化 羟基酶活性作为可卡因诱导的神经元可塑性的衡量标准。