Extracellular Matrix, Cocaine, and Memory

细胞外基质、可卡因和记忆

• 批准号: 8661732
• 负责人: Barbara A Sorg
• 金额: $ 30.2万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661732
• 关键词: Animals; Anisomycin; Attenuated; Behavior; Chronic; Cocaine; Cues; Data; Drug abuse; Drug usage; Excision; Extracellular Matrix; FOS gene; Face; Family; Gelatinase A; Gelatinase B; Glycoproteins; Goals; Human; Inhibition of Matrix Metalloproteinases Pathway; Injection of therapeutic agent; Interneurons; Learning; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Medial; Mediating; Memory; Metalloendopeptidases; Modeling; Morphology; Motivation; Neurons; Outcome Study; Pharmaceutical Preparations; Prefrontal Cortex; Protein Synthesis Inhibitors; Proteins; Rattus; Relapse; Rodent; SB 3CT compound; Self Administration; Self-Administered; Staining method; Stains; Stimulus; Synapses; Testing; Time; Work; addiction; aggrecan; attenuation; base; cocaine use; density; drug addict; drug of abuse; drug seeking behavior; in vivo; inhibitor/antagonist; janusin; link protein; preference; prevent; response

DESCRIPTION (provided by applicant): The ability to attenuate drug-associated memories in drug addicts is important because this attenuation is expected to suppress the cycle of relapse to drugs. Persistent drug-taking behavior involves consolidation of memory for the drug and drug-associated cues and contexts. When a memory is reactivated (retrieved), that memory becomes labile and susceptible to disruption by amnestic agents (e.g., protein synthesis inhibitors) present at the time of reactivation. Drug abuse studies in rodents indicate that reconsolidation can be disrupted, and this is manifest as suppressed drug-seeking behavior when animals are subsequently primed with the same stimulus used to reactivate the memory. Most studies have focused on drug-induced conditioned place preference (CPP); since only a few drug injections are given with CPP, the memories may be relatively easy to disrupt. However, few labs have focused on the rat self-administration model, which has higher face validity for human addiction. To date, no self-administration studies have attempted to disrupt reconsolidation of the memory associated with the drug itself, when the drug is present during reactivation and subsequent reinstatement. This is significant because the drug induces powerful reinstatement in rats and augments relapse in humans. We present for the first time data showing that administration of amnestic agents into the medial prefrontal cortex (mPFC) during reactivation of a cocaine- associated memory suppresses subsequent cocaine-primed reinstatement when amnestic agents are no longer present. The focus of this proposal is on one of these agents, an inhibitor of matrix metalloproteinases (MMPs). MMPs belong to a family of metalloendopeptidases that can direct changes in synaptic morphology via their effects on the extracellular matrix (ECM). Some components of the ECM are densely organized into perineuronal nets (PNNs) that ensheath primarily inhibitory interneurons in the cortex. Based on our work and that of others, we believe that MMPs are involved in maintaining as well as diminishing cocaine-related memories. We hypothesize that components of the ECM within PNNs must be transiently degraded by MMPs during synaptic remodeling to permit the reconsolidation of memory. We will test our hypothesis in three Specific Aims: Specific Aim 1 will determine the extent to which inhibition of MMPs in the mPFC suppresses MMP activity and increases PNN density and PNN glycoprotein levels. Specific Aim 2 will determine the extent to which MMP inhibition in the mPFC disrupts reconsolidation of cocaine-associated memories in self-administering rats. Specific Aim 3 will determine the impact of MMP inhibition on c-Fos activation in PNN-containing interneurons in the mPFC and whether dynamic changes in PNNs are a key mechanistic step for MMP effects on cocaine-associated memories. These studies will have a positive impact on the drug abuse field because they will determine the potential for using MMP inhibitors to disrupt reconsolidation of cocaine memories that may underlie chronic relapse.

描述（由申请人提供）：减弱吸毒者与药物相关的记忆的能力很重要，因为这种减弱预计会抑制药物复发的周期。持续的吸毒行为涉及巩固对药物以及与药物相关的线索和背景的记忆。当记忆被重新激活（检索）时，该记忆变得不稳定，并且容易受到重新激活时存在的记忆消除剂（例如蛋白质合成抑制剂）的破坏。对啮齿类动物的药物滥用研究表明，重新巩固可能会被破坏，这表现为当动物随后接受用于重新激活记忆的相同刺激时，药物寻求行为受到抑制。大多数研究都集中在药物引起的条件性位置偏好（CPP）上；由于 CPP 只进行了几次药物注射，因此记忆可能相对容易被破坏。然而，很少有实验室关注大鼠自我给药模型，该模型对人类成瘾具有更高的表面效度。迄今为止，当药物在重新激活和随后的恢复过程中存在时，还没有自我给药研究试图破坏与药物本身相关的记忆的重新巩固。这很重要，因为该药物可以在大鼠中诱导强大的恢复，并在人类中增加复发。我们首次提供的数据显示，在可卡因相关记忆重新激活期间，将遗忘剂注射到内侧前额叶皮层（mPFC）会抑制随后的可卡因引发的恢复（当遗忘剂不再存在时）。该提案的重点是其中一种药物，即基质金属蛋白酶 (MMP) 抑制剂。 MMP 属于金属内肽酶家族，可通过对细胞外基质 (ECM) 的影响来指导突触形态的变化。 ECM 的一些组件密集地组织成神经周围网 (PNN)，主要包裹皮质中的抑制性中间神经元。根据我们和其他人的工作，我们相信 MMP 参与维持和减少可卡因相关记忆。我们假设 PNN 内 ECM 的成分必须在突触重塑过程中被 MMP 暂时降解，以允许记忆重新巩固。我们将在三个具体目标中检验我们的假设：具体目标 1 将确定 mPFC 中 MMP 的抑制抑制 MMP 活性并增加 PNN 密度和 PNN 糖蛋白水平的程度。具体目标 2 将确定 mPFC 中的 MMP 抑制在多大程度上破坏自我给药大鼠中可卡因相关记忆的重新巩固。具体目标 3 将确定 MMP 抑制对 mPFC 中包含 PNN 的中间神经元中 c-Fos 激活的影响，以及 PNN 的动态变化是否是 MMP 对可卡因相关记忆影响的关键机制步骤。这些研究将对药物滥用领域产生积极影响，因为它们将确定使用 MMP 抑制剂破坏可能导致慢性复发的可卡因记忆重新巩固的潜力。