Matrix Metalloproteinases and Cocaine

基质金属蛋白酶和可卡因

• 批准号: 8326600
• 负责人: Barbara A Sorg
• 金额: $ 18.88万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8326600
• 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; induced pluripotent stem cell; 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.

描述（由申请人提供）：持续的吸毒行为涉及对药物和药物相关的提示和环境的记忆。当记忆重新激活（检索）时，该记忆将变得不稳定，并且容易受到重新激活时存在的动物剂的破坏。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。但是，大多数研究都集中在药物引起的条件偏好（CPP）上，其中只给了少量药物注射。因此，记忆可能更容易破坏。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效率。自我管理研究表明，某些药物可以破坏药物提示或上下文的记忆的重新整合。然而，当在重新激活和随后的恢复原状时，没有研究破坏与药物本身相关的记忆的重新整合。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。我们专注于基质金属蛋白酶（MMP），这些酶是学习和记忆的神经塑性中的关键分子。 MMP是一种金属肽酶家族，通过降解细胞外基质（ECM）来直接变化突触形态。我们先前表明，在CPP研究中，MMP的抑制剂阻断了与可卡因相关的记忆的重新溶解，并且在此记忆重新激活后，内侧前额叶皮层（MPFC）中MMP-9活性升高。令人兴奋的初步自我管理研究表明，在可卡因培养的记忆重新激活过程中，将MMP抑制剂注射到MPFC中，后来抑制可卡因抗可卡因的恢复。但是，我们不知道被抑制的响应是否是由于重新固定的破坏，也不知道涉及哪些MMP。同样，尚无研究定义MMP抑制对可卡因自我管理大鼠MPFC中膜兴奋性的影响，以评估MMP抑制剂如何改变MPFC输出。我们建议MMP抑制剂可以改变可卡因诱导的可塑性变化，并在重新溶解过程中对突触施加新的可塑性。我们将测试中心假设，即可卡因抑制剂在可卡因培养的恢复期间给出的MMP抑制剂减少了，并且这种记忆的这种减少是由于MPFC中抑制性电流的兴奋性降低而导致的。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管理大鼠中可卡因相关记忆的重新固定。具体目标2将定义MMP抑制对可卡因自我管理大鼠MPFC中兴奋性/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。