Cocaine and Brain Extracellular Matrix

可卡因和脑细胞外基质

• 批准号: 6447735
• 负责人: Barbara A Sorg
• 金额: $ 14.5万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6447735
• 关键词: behavior test; behavioral /social science research tag; behavioral habituation /sensitization; brain mapping; cocaine; drug abuse; extracellular matrix; hippocampus; immunocytochemistry; laboratory rat; metalloendopeptidases; neural plasticity; preference; prefrontal lobe /cortex; substance abuse related behavior; synaptic vesicles; tissue inhibitor of metalloproteinases; western blottings

DESCRIPTION: (provided by the applicant) Repeated cocaine exposure induces neural plasticity as implied by the development of dependence and sensitization. An under explored but critical aspect of cocaine-dependent plasticity is the impact of cocaine on proteins involved in synaptic remodeling during drug-seeking behaviors. This proposal focuses on the proteins that regulate the extracellular matrix (ECM). These proteins are critical for dynamic processes involved in synaptic reorganization during learning. We envision that the ECM acts as a scaffold to optimally align pre- and postsynaptic elements, which must be transiently degraded during synaptic remodeling. Since drug abuse is believed to involve a learning process, molecules involved in remodeling should be altered in brain areas implicated in drug abuse. This notion is supported by recent studies reporting morphological changes in brain regions critical for drug-taking behavior. We hypothesize that these morphological changes require shifts in the expression of ECM proteins, which are dependent on the regulators, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). Recent work in our laboratories has demonstrated that activity of the enzyme MMP-9 in the hippocampus is correlated with active learning of a water maze spatial learning task. In addition, acute cocaine treatment increases MMP-9 activity in the nucleus accumbens and medial prefrontal cortex, with a concomitant decrease in the ventral tegmental area. In contrast, only small changes were found in the substantia nigra and striatum, suggesting a specificity of cocaine's effects on plasticity of mesocorticolimbic pathways. The proposed studies will assess the level of expression of MMPs and TIMPs critical for remodeling processes believed to occur during learning and extinction of a cocaine conditioned place preference (CPP) task. These studies will determine which brain regions exhibit plastic changes associated with the pairing of contextual information with cocaine, whether or not the same brain sites are involved in the extinction of cocaine CPP behavior, and if these molecules can be further altered once initial learning of the CPP task has taken place. We postulate that repeated cocaine initially produces synaptic rearrangement in specific brain regions linked to drug craving and addiction, and that changes in MMPs/TIMPs are indicators of this rearrangement. Moreover, subsequent to repeated cocaine treatment, there may be an attenuation or loss of neural plasticity in these brain sites that contributes to the long-lasting nature of addiction.

描述：（申请人提供） 重复可卡因暴露会诱导神经可塑性，如 依赖和敏感性的发展。探索但关键的 可卡因依赖性可塑性的方面是可卡因对蛋白质的影响 参与寻求毒品行为的突触重塑。这个建议 专注于调节细胞外基质（ECM）的蛋白质。这些 蛋白质对于参与突触重组的动态过程至关重要 在学习过程中。我们设想ECM充当最佳对齐的脚手架 前后突触后元素，必须在 突触重塑。由于据信药物滥用涉及学习 过程，重塑的分子应在大脑区域改变 与药物滥用有关。最近的研究报告支持了这个概念 大脑区域的形态变化对于吸毒行为至关重要。我们 假设这些形态学的变化需要表达式变化 依赖调节剂的ECM蛋白质的矩阵 金属蛋白酶（MMP）和MMP的组织抑制剂（TIMP）。最近的工作 我们的实验室表明，酶MMP-9的活性 海马与积极学习水迷宫空间学习相关 任务。此外，急性可卡因治疗增加了MMP-9的活性 伏隔核和内侧前额叶皮层，随之而来的降低 腹侧对段区域。相反，在 黑质和纹状体，表明可卡因对 中皮质胶途径的可塑性。提议 研究将评估MMP和TIMP的表达水平 重塑过程被认为是在学习和灭绝期间发生的 可卡因条件的位置偏好（CPP）任务。这些研究将确定 哪些大脑区域表现出与配对相关的塑料变化 可卡因的上下文信息，是否相同的大脑站点是 涉及可卡因CPP行为的灭绝，如果这些分子可以 一旦完成了CPP任务的初步学习，就会进一步更改。我们 假设重复可卡因最初会在 与渴望和成瘾有关的特定大脑区域，并改变 在MMP/TIMP中，是此重排的指标。此外，之后 重复可卡因治疗，可能会衰减或神经丧失 这些大脑部位的可塑性有助于持久的性质 瘾。