Matrix Metalloproteinases and Cocaine

描述（由申请人提供）：持续性吸毒行为涉及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，并且容易被重新激活时存在的遗忘剂破坏。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。然而，大多数研究都集中在药物诱导的条件性位置偏爱（CPP），其中只有少数药物注射;因此，记忆可能更容易被破坏。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。自我给药研究表明，药物提示或背景的记忆的重新巩固可以被某些药剂破坏。然而，当药物在重新激活和随后的恢复过程中存在时，没有研究会破坏与药物本身相关的记忆的重新巩固。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。我们专注于基质金属蛋白酶（MMPs），这是新兴的学习和记忆的神经可塑性的关键分子。MMPs是通过降解细胞外基质（ECM）来指导突触形态变化的金属肽酶家族。我们以前的研究表明，MMPs的抑制剂阻断了CPP研究中可卡因相关记忆的再巩固，并且在这种记忆的再激活后，内侧前额叶皮层（mPFC）中MMP-9的活性升高。令人兴奋的初步自我管理的研究表明，注射MMP抑制剂到mPFC在重新激活可卡因引发的记忆抑制后来可卡因引发的恢复。然而，我们不知道这种抑制反应是否是由于再巩固的中断，也不知道涉及哪些MMPs。此外，没有研究确定MMP抑制对可卡因自我给药大鼠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抑制剂可以修改以前可卡因诱导的可塑性变化，并施加新的可塑性突触在再巩固过程中。我们将测试的中心假设，可卡因相关的记忆减少与MMP抑制剂在可卡因引发的恢复过程中，这减少了记忆的表达发生的mPFC的兴奋性抑制电流的比例降低。具体目标1将确定MMPs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): 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.