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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) 反复接触可卡因可诱导神经可塑性，这是由依赖和敏感化的发展。一个未被充分挖掘但具有批判性的可卡因依赖可塑性的一个方面是可卡因对蛋白质的影响参与了寻毒行为中的突触重构。这项建议重点介绍调节细胞外基质(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过程中。我们设想ECM将作为一个脚手架，以最佳方式调整突触前和突触后的元素，必须在突触重塑。因为吸毒被认为涉及到一种学习过程中，参与重塑的分子应该在大脑区域改变与药物滥用有关。这一观点得到了最近的研究报告的支持大脑中对吸毒行为至关重要的区域的形态变化。我们假设这些形态变化需要改变表达方式依赖于调节剂、基质的ECM蛋白金属蛋白酶(MMPs)及其组织抑制因子(TIMPs)最近的工作在我们的实验室已经证明了金属蛋白酶-9在体内的活性海马区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脑组织中基质金属蛋白酶-9的活性。伏隔核和内侧前额叶皮质，并伴随着腹侧被盖区。相比之下，只有微小的变化在黑质和纹状体，提示可卡因对皮质边缘系膜通路的可塑性。建议数研究将评估MMPs和TIMP的表达水平重塑过程被认为发生在学习和灭绝可卡因条件性位置偏爱(CPP)任务。这些研究将确定大脑的哪些区域表现出与配对相关的可塑性变化与可卡因有关的背景信息，无论相同的大脑部位是否参与了可卡因CPP行为的灭绝，如果这些分子可以一旦对CPP任务进行了初步学习，就会进一步改变。我们假设重复的可卡因最初会在大脑中产生突触重排与药物渴望和成瘾相关的特定大脑区域，这种情况发生了变化在MMPs/TIMP中，是这种重新安排的指标。此外，在反复吸食可卡因，可能会出现神经衰弱或丧失在这些大脑部位的可塑性有助于长期的性质上瘾。