Extracellular Matrix, Cocaine, and Memory

描述（由申请人提供）：药物成瘾者减弱药物相关记忆的能力很重要，因为这种减弱有望抑制药物复发的循环。持续吸毒行为涉及对药物和与药物有关的线索和背景的记忆巩固。当记忆被重新激活（检索）时，该记忆变得不稳定，容易被重新激活时存在的遗忘剂（如蛋白质合成抑制剂）破坏。对啮齿类动物的药物滥用研究表明，再巩固可以被破坏，当动物随后被用于重新激活记忆的相同刺激启动时，这表现为抑制药物寻求行为。大多数研究集中在药物诱导的条件位置偏好（CPP）上；由于只有少量药物注射给CPP，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，没有自我给药研究试图破坏与药物本身相关的记忆再巩固，当药物在重新激活和随后的恢复期间存在时。这是很重要的，因为这种药物在大鼠中诱导了强大的恢复，并增加了人类的复发。我们首次提出的数据表明，在可卡因相关记忆的重新激活期间，将遗忘药物注入内侧前额叶皮层（mPFC），当遗忘药物不再存在时，会抑制随后的可卡因启动恢复。本提案的重点是这些药物之一，基质金属蛋白酶（MMPs）的抑制剂。MMPs属于金属内肽酶家族，可以通过其对细胞外基质（ECM）的影响来指导突触形态的变化。ECM的一些成分被密集地组织成神经元周围网（PNNs），这些网络包住皮层中主要的抑制性中间神经元。根据我们和其他人的工作，我们认为MMPs参与维持和减少与可卡因有关的记忆。我们假设pnn内的ECM成分必须在突触重塑过程中被MMPs短暂地降解，以允许记忆的再巩固。我们将在三个特定目标中验证我们的假设：特定目标1将确定mPFC中MMPs抑制MMP活性并增加PNN密度和PNN糖蛋白水平的程度。特异性目标2将确定在自我给药大鼠中，mPFC中的MMP抑制在多大程度上破坏了可卡因相关记忆的再巩固。特异性Aim 3将确定MMP抑制对mPFC中含有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影响可卡因相关记忆的关键机制步骤。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。

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.