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Cocaine and Brain Extracellular Matrix

可卡因和脑细胞外基质

基本信息

批准号：
6523549
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
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2004-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6523549
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

项目摘要

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）重复的可卡因暴露诱导神经可塑性，如实验所示。依赖性和敏感性的发展。一个探索不足但至关重要的可卡因依赖性可塑性的一个方面是可卡因对蛋白质的影响参与药物寻求行为中的突触重塑。这项建议重点是调节细胞外基质（ECM）的蛋白质。这些蛋白质是参与突触重组的动态过程的关键在学习期间。我们设想ECM作为一个支架，突触前和突触后元件，在突触形成过程中必须短暂降解。突触重塑因为药物滥用被认为是一种学习在这一过程中，参与重塑的分子应该在大脑区域发生改变，涉嫌吸毒这一观点得到了最近研究报告的支持，对吸毒行为至关重要的大脑区域的形态学变化。我们假设这些形态学变化需要表达的变化， ECM蛋白质，这是依赖于监管机构，基质金属蛋白酶（MMP）和MMP的组织抑制剂（TIMP）。最近的工作我们的实验室已经证明，MMP-9酶的活性，海马与水迷宫空间学习的主动学习相关任务此外，急性可卡因治疗增加了MMP-9的活性，前额叶皮层和内侧前额叶皮层，伴随着减少，腹侧被盖区相比之下，只有小的变化，发现在黑质和纹状体，这表明可卡因的作用的特异性，中皮质边缘通路的可塑性。拟议研究将评估MMPs和TIMPs的表达水平，重塑过程被认为发生在学习和灭绝的过程中，可卡因条件性位置偏爱（CPP）。这些研究将决定哪些大脑区域表现出与配对相关的可塑性变化，背景信息与可卡因，无论是否相同的大脑部位，参与可卡因CPP行为的消失，如果这些分子可以一旦CPP任务的初始学习已经发生，就可以进一步改变。我们假设重复的可卡因最初会引起突触重排，与药物渴望和成瘾有关的特定大脑区域， MMPs/TIMPs的表达是这种重排的指标。此外，继重复可卡因治疗，可能会出现神经功能的减弱或丧失，这些大脑部位的可塑性，有助于持久的性质，成瘾