Extracellular Matrix, Cocaine, and Memory

描述(由申请人提供)：减弱吸毒者与药物相关的记忆的能力是重要的，因为这种减弱预计会抑制药物复发的循环。持续的吸毒行为包括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(取回)时，该记忆变得不稳定，并且容易被重新激活时存在的健忘剂(例如，蛋白质合成抑制剂)破坏。对啮齿动物的药物滥用研究表明，再巩固可以被破坏，当动物随后被用来重新激活记忆的相同刺激启动时，这表现为被抑制的寻药行为。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是与CPP一起进行的，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较高的表面有效性。到目前为止，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，当药物在重新激活和随后恢复期间存在时。这一点意义重大，因为这种药物能在大鼠身上诱导强大的复苏力，并增加人类的复发。我们首次提供的数据显示，在与可卡因相关的记忆重新激活期间，向内侧前额叶皮质(MPFC)注入健忘剂可抑制随后在健忘剂不再存在时由可卡因引发的恢复。这项提案的重点是其中一种制剂，一种基质金属蛋白酶(MMPs)的抑制剂。MMPs属于金属内肽酶家族，可通过作用于细胞外基质(ECM)来引导突触形态的改变。细胞外基质的一些成分被密集地组织成神经周围神经网络(PNNS)，主要覆盖皮质中的抑制性中间神经元。根据我们和其他人的工作，我们认为基质金属蛋白参与维持和减少与可卡因有关的记忆。我们假设，在突触重塑过程中，PNNS内ECM的成分必须被MMPs瞬时降解，以允许记忆的重新巩固。我们将在三个特定目标中验证我们的假设：特定目标1将确定在多大程度上抑制mPFC中的MMPs抑制MMP活性，并增加PNN密度和PNN糖蛋白水平。具体目标2将确定在多大程度上抑制mPFC中的基质金属蛋白酶干扰自我给药大鼠与可卡因相关的记忆的重新巩固。具体目的3将确定抑制MMPs对mPFC内含PNN的中间神经元c-Fos激活的影响，以及PNN的动态变化是否是MMPs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基质金属蛋白酶抑制剂来破坏可能导致慢性复发的可卡因记忆重新巩固的可能性。 公共卫生相关性：拟议的研究将确定在大鼠自我给药模型中与可卡因相关的记忆能够被扰乱的程度。这些记忆的中断预计会抑制寻找或服用可卡因的动机。这些研究在人类身上具有很高的翻译潜力，因为成功地破坏获得性药物相关记忆将有助于打破人类可卡因成瘾者的复发循环。

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.