Matrix Metalloproteinases and Cocaine

描述(申请人提供)：持续的吸毒行为包括巩固对药物和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，并容易受到重新激活时存在的健忘剂的干扰。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。然而，大多数研究都集中在药物诱导的条件性位置偏爱(CPP)，即只给几次药物注射，因此记忆可能更容易被破坏。很少有实验室将重点放在大鼠自我给药模型上，这种模型对人类成瘾具有较高的表面有效性。自我给药研究表明，药物线索或背景记忆的重新巩固可能会被某些药物破坏。然而，当药物在重新激活和随后的恢复过程中存在时，没有研究破坏与药物本身相关的记忆的重新巩固。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。我们专注于基质金属蛋白酶(MMPs)，它是学习和记忆神经可塑性中的关键分子。MMPs是一类金属多肽酶家族，通过降解细胞外基质(ECM)直接改变突触形态。我们之前在CPP研究中发现，MMPs的抑制剂阻止了可卡因相关记忆的重新巩固，并且当这种记忆重新激活时，内侧前额叶皮质(MPFC)的基质金属蛋白酶-9活性升高。令人兴奋的初步自我给药研究表明，在可卡因启动的记忆重新激活期间，在mPFC中注射一种基质金属蛋白酶抑制剂，可以抑制后来可卡因启动的恢复。然而，我们不知道被抑制的反应是否由于再整合的中断，也不知道涉及哪些MMP。此外，还没有研究确定基质金属蛋白酶抑制对可卡因自身给药大鼠mPFC膜兴奋性的影响，以评估基质金属蛋白酶抑制剂如何改变mPFC的输出。我们认为，基质金属蛋白酶抑制剂可以改变先前可卡因诱导的可塑性变化，并在再巩固过程中对突触施加新的可塑性。我们将检验这一中心假设，即在可卡因诱导的恢复过程中给予基质金属蛋白酶抑制剂，与可卡因相关的记忆减少，并且这种记忆的减少是通过mPFC中兴奋电流与抑制电流的比率降低而发生的。具体目标1将确定抑制MMPs在多大程度上破坏了可卡因自我给药大鼠与可卡因相关的记忆的重新巩固。具体目标2将确定抑制基质金属蛋白酶对兴奋性/抑制性突触输入和可卡因自身给药大鼠mPFC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。

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.