Extracellular Matrix, Cocaine, and Memory

细胞外基质、可卡因和记忆

• 批准号: 8273234
• 负责人: Barbara A Sorg
• 金额: $ 28.93万
• 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/8273234
• 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. 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.

描述（由申请人提供）：减弱吸毒者中与药物相关的记忆的能力很重要，因为这种衰减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环境的记忆巩固。当记忆重新激活（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膜片破坏（例如蛋白质合成抑制剂）。啮齿动物中的药物滥用研究表明可以破坏重新溶解，这表明是当动物随后用相同的刺激刺激以重新激活记忆的刺激时被抑制的寻求毒品的行为。大多数研究都集中在药物引起的条件偏好（CPP）上。由于只给了少量药物注射CPP，因此记忆可能相对容易破坏。但是，很少有实验室专注于大鼠自我管理模型，该模型对人类成瘾具有更高的面部有效性。迄今为止，尚无自我管理研究试图破坏与药物本身相关的记忆的重新固定，而在重新激活和随后的恢复期间存在药物时。这很重要，因为该药物会诱导大鼠的强大恢复和增强人类复发。我们首次提供数据，显示可卡因相关记忆重新激活过程中内侧前额叶皮层（MPFC）的给药会抑制随后可卡因抗可卡因剂时，如果不再存在炎症药。该提案的重点是这些药物之一，一种基质金属蛋白酶（MMP）的抑制剂。 MMP属于一个金属肽酶家族，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的某些成分密集地组织成神经元网（PNN），这些网络主要抑制皮质中的抑制性中间神经元。根据我们的工作和他人的工作，我们认为MMP参与了维持和可卡因相关的记忆。我们假设PNN中ECM的组件必须在突触重塑期间通过MMP瞬时降解，以允许重新整合内存。我们将在三个特定目标中检验我们的假设：具体目标1将决定MPFC中MMP抑制MMP活性的程度，并增加了PNN密度和PNN糖蛋白水平。具体目标2将确定MMP在MPFC中的抑制程度破坏了自我管理大鼠中可卡因相关的记忆的重新整合。具体目标3将确定MMP抑制对MPFC中含PNN的中间神经元中C-FOS激活的影响，以及PNN中的动态变化是否是MMP对可卡因相关记忆的影响的关键机械步骤。这些研究将对药物滥用领域产生积极的影响，因为它们将确定使用MMP抑制剂破坏可能是慢性复发的可卡因记忆的重新稳定的潜力。 公共卫生相关性：拟议的研究将确定可卡因相关的记忆能够在大鼠自我管理模型中破坏的程度。这些记忆的破坏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，因为成功破坏了与药物相关的记忆会有助于破坏人类可卡因成瘾者复发的循环。