Matrix Metalloproteinases and Cocaine

基质金属蛋白酶和可卡因

• 批准号: 8190078
• 负责人: Barbara A Sorg
• 金额: $ 22.53万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190078
• 关键词: Abbreviations; Animals; Behavior; Binding; Brain; Cells; Chronic; Cocaine; Cues; Drug abuse; Drug usage; Electrophysiology (science); Extracellular Matrix; Extracellular Matrix Degradation; Face; Family; Gelatinase A; Gelatinase B; Gelatinases; Goals; Human; Inhibition of Matrix Metalloproteinases Pathway; Injection of therapeutic agent; Learning; Long-Term Potentiation; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Medial; Membrane; Memory; Metalloproteases; Modeling; Morphology; Motivation; Neprilysin; Neuronal Plasticity; Neurons; Nucleus Accumbens; Outcome Study; Output; Pattern; Pharmaceutical Preparations; Prefrontal Cortex; Process; Rattus; Relapse; Rodent; SB 3CT compound; Self Administration; Self-Administered; Slice; Stimulus; Synapses; Testing; Time; Ventral Tegmental Area; Whole-Cell Recordings; addiction; cocaine use; conditioned fear; drug addict; drug of abuse; drug seeking behavior; in vivo; inhibitor/antagonist; neurotransmission; postsynaptic; preference; response

DESCRIPTION (provided by applicant): 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 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. However, most studies have focused on drug-induced conditioned place preference (CPP), in which only a few drug injections are given; thus, the memories may be easier to disrupt. Few labs have focused on the rat self-administration model, which has higher face-validity for human addiction. Self-administration studies showed that reconsolidation of a memory for the drug cue or context can be disrupted by certain agents. However, no studies have disrupted 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 focus on matrix metalloproteinases (MMPs), which are emerging as key molecules in the neuroplasticity of learning and memory. MMPs are a family of metallopeptidases that direct changes in synaptic morphology via degradation of the extracellular matrix (ECM). We previously showed that an inhibitor of MMPs blocked reconsolidation of a cocaine-associated memory in CPP studies, and that MMP-9 activity was elevated in the medial prefrontal cortex (mPFC) upon reactivation of this memory. Exciting preliminary self-administration studies show that injection of an MMP inhibitor into the mPFC during reactivation of a cocaine-primed memory suppresses later cocaine-primed reinstatement. However, we do not know if the suppressed responding is due to disruption of reconsolidation, nor do we know which MMPs are involved. Also, no studies have defined the impact of MMP inhibition on membrane excitability in the mPFC in cocaine self-administering rats to assess how MMP inhibitors may alter mPFC output. We propose that MMP inhibitors can modify previous cocaine-induced changes in plasticity and impose new plasticity on synapses during the reconsolidation process. We will test the central hypothesis that a cocaine-associated memory is diminished with MMP inhibitors given during cocaine-primed reinstatement, and that this diminished expression of memory occurs by a decreased ratio of excitatory to inhibitory currents in the mPFC. Specific Aim 1 will determine the extent to which inhibition of MMPs disrupts reconsolidation of cocaine-associated memory in cocaine self-administering rats. Specific Aim 2 will define the impact of MMP inhibition on excitatory/inhibitory synaptic input and membrane excitability in the mPFC in cocaine self-administering rats. 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）：持续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，该记忆会变得不稳定，并且容易受到重新激活时存在的记忆删除剂的破坏。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与重新激活记忆相同的刺激时，药物寻求行为受到抑制。然而，大多数研究都集中在药物诱导的条件性位置偏好（CPP）上，其中只进行了少量药物注射；因此，记忆可能更容易被破坏。很少有实验室关注老鼠的自我给药模型，该模型对人类成瘾具有更高的表面效度。自我给药研究表明，某些药物可能会破坏对药物提示或背景的记忆重新巩固。然而，当药物在重新激活和随后的恢复过程中存在时，没有研究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。我们专注于基质金属蛋白酶（MMP），它们正在成为学习和记忆神经可塑性的关键分子。 MMP 是一类金属肽酶，可通过细胞外基质 (ECM) 的降解来指导突触形态的变化。我们之前在 CPP 研究中表明，MMP 抑制剂可阻止可卡因相关记忆的重新巩固，并且在重新激活该记忆后，内侧前额叶皮层 (mPFC) 中的 MMP-9 活性升高。令人兴奋的初步自我给药研究表明，在可卡因引发的记忆重新激活期间，将 MMP 抑制剂注射到 mPFC 中可以抑制随后可卡因引发的恢复。然而，我们不知道抑制的反应是否是由于再巩固的破坏造成的，也不知道涉及哪些 MMP。此外，尚无研究明确 MMP 抑制对可卡因自我给药大鼠 mPFC 膜兴奋性的影响，以评估 MMP 抑制剂如何改变 mPFC 输出。我们认为 MMP 抑制剂可以改变先前可卡因引起的可塑性变化，并在重新巩固过程中对突触施加新的可塑性。我们将测试以下中心假设：在可卡因启动恢复期间给予 MMP 抑制剂，可卡因相关记忆会减弱，并且这种记忆表达的减弱是由于 mPFC 中兴奋性电流与抑制性电流的比率降低而发生的。具体目标 1 将确定 MMP 的抑制在多大程度上破坏可卡因自我给药大鼠中可卡因相关记忆的再巩固。具体目标 2 将定义 MMP 抑制对可卡因自我给药大鼠中 mPFC 的兴奋性/抑制性突触输入和膜兴奋性的影响。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。 公共健康相关性：拟议的研究将确定大鼠自我给药模型中可卡因相关记忆被破坏的程度。破坏这些记忆有望抑制寻求或吸食可卡因的动机。这些研究在人类中具有很高的转化潜力，因为成功破坏习得的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。