Extracellular Matrix, Cocaine, and Memory

描述（由申请人提供）：减弱药物成瘾者的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。持续的吸毒行为涉及对药物和药物相关线索和背景的记忆巩固。当记忆被重新激活（检索）时，该记忆变得不稳定并且容易被遗忘剂破坏（例如，蛋白质合成抑制剂）。啮齿动物的药物滥用研究表明，再巩固可以被破坏，这表现为当动物随后被用于重新激活记忆的相同刺激引发时，药物寻求行为受到抑制。大多数研究都集中在药物诱导的条件性位置偏爱（CPP）;由于只有少数药物注射与CPP一起使用，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。到目前为止，没有自我给药研究试图破坏与药物本身相关的记忆的再巩固，当药物在再激活和随后的恢复过程中存在时。这一点很重要，因为该药物在大鼠中诱导了强有力的复发，并增加了人类的复发。我们提出的第一次数据表明，管理健忘剂到内侧前额叶皮层（mPFC）在重新激活可卡因相关的记忆抑制随后可卡因引发的恢复时，健忘剂不再存在。该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，其可以通过其对细胞外基质（ECM）的作用来指导突触形态的变化。ECM的一些成分密集地组织成神经元周网（perineuronalnets，PNNs），其主要包裹皮层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MMPs参与维持和减少可卡因相关的记忆。我们推测，PNN内的ECM成分必须在突触重塑过程中被MMP短暂降解，以允许记忆的重新巩固。我们将在三个特定目标中检验我们的假设：特定目标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将确定在何种程度上MMP抑制mPFC破坏可卡因相关的记忆在自我管理的大鼠的再巩固。具体目标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对可卡因相关记忆的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抑制剂破坏可卡因记忆再巩固的潜力，这可能是慢性复发的基础。 公共卫生相关性：拟议的研究将确定可卡因相关记忆在大鼠自我给药模型中被破坏的程度。这些记忆的中断有望抑制寻求或服用可卡因的动机。这些研究在人类中具有很高的转化潜力，因为成功地破坏与药物相关的记忆将有助于打破人类可卡因成瘾者复发的循环。

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. PUBLIC HEALTH RELEVANCE: The proposed studies will determine the extent to which cocaine-associated memories are able to be disrupted in a rat self-administration model. Disruption of these memories is expected to suppress the motivation to seek or take cocaine. These studies have high translational potential in humans because successful disruption of learned drug-associated memories would help break the cycle of relapse in human cocaine addicts.