Matrix Metalloproteinases and Cocaine

描述（由申请人提供）：持续吸毒行为涉及对药物和与药物相关的线索和背景的记忆巩固。当记忆被重新激活（检索）时，记忆变得不稳定，容易被重新激活时存在的遗忘因子破坏。对啮齿类动物的药物滥用研究表明，再巩固可以被破坏，当动物随后被用于重新激活记忆的相同刺激启动时，这表现为抑制药物寻求行为。然而，大多数研究都集中在药物诱导的条件位置偏好（CPP）上，其中只给予少量药物注射；因此，记忆可能更容易被破坏。很少有实验室关注大鼠自我给药模型，这种模型对人类成瘾具有更高的面孔效度。自我给药研究表明，对药物线索或环境的记忆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。这是很重要的，因为这种药物在大鼠中诱导了强大的恢复，并增加了人类的复发。我们的重点是基质金属蛋白酶（MMPs），这是新兴的关键分子在学习和记忆的神经可塑性。MMPs是一个金属肽酶家族，通过细胞外基质（ECM）的降解直接改变突触形态。我们之前在CPP研究中表明，MMPs抑制剂阻断了可卡因相关记忆的再巩固，并且内侧前额叶皮层（mPFC）的MMP-9活性在该记忆的再激活时升高。令人兴奋的初步自我给药研究表明，在可卡因启动记忆重新激活期间向mPFC注射MMP抑制剂抑制了后来的可卡因启动记忆恢复。然而，我们不知道抑制的反应是否是由于再巩固的破坏，也不知道哪些MMPs参与其中。此外，没有研究明确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，并在再巩固过程中对突触施加新的可塑性。我们将验证一个中心假设，即在可卡因启动恢复期间给予MMP抑制剂会减少与可卡因相关的记忆，并且这种记忆表达的减少是通过mPFC中兴奋电流与抑制电流的比例降低而发生的。特异性目的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可卡因相关记忆的再巩固。特异性目的2将确定MMP抑制对可卡因自我给药大鼠mPFC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。

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.