Role of Matrix Metalloproteinases in Drug Relapse

描述（由申请人提供）：本申请关注新型分子基质金属蛋白酶（MMPs）在可卡因和甲基苯丙胺（Meth）复发中的作用。MMPs是调节细胞外基质（ECM）和细胞粘附蛋白的酶家族，最近已被证明参与空间记忆的形成。潜在的药物成瘾是对药物的持久记忆，这种记忆被认为会产生渴望和复发。吸毒行为本身涉及药物记忆的巩固。随着每次药物使用，记忆可能被重新激活（检索），随后重新巩固以保持原始记忆。在重新激活的过程中，记忆被认为是不稳定的，容易受到破坏。因此，参与塑性的分子应该影响再固结。基于我们的初步数据和药物滥用领域以外的几项研究，我们提出，原始记忆（巩固）的形成以及再巩固过程需要MMP介导的事件的转变。最近的工作表明，在海马中的酶MMP-3和MMP-9的活性与学习空间水迷宫任务相关。此外，脑室内（i. c. v.）注射MMP抑制剂（FN-439）抑制这种空间学习。我们实验室的研究已经将这些发现扩展到可卡因诱导的条件性位置偏爱（CPP）行为。MMPs的抑制显著减弱CPP的获得并阻断可卡因记忆的再巩固。在本申请中，我们希望阐述这些发现。我们将测试的中心假设，基质金属蛋白酶是至关重要的药物记忆的再巩固，这种记忆可以被破坏或减少与基质金属蛋白酶抑制剂在可卡因和甲基引发的恢复。具体而言，我们希望测试1）MMP抑制剂是否可以以再激活依赖性方式减少可卡因引发的自我给药的恢复，以及2）MMP抑制剂是否也可以以再激活依赖性方式减少Meth-primed的恢复。这些研究的最终意义是确定MMP抑制剂是否可以以再激活依赖性方式破坏对可卡因或甲氧苯丙氨酸的记忆，从而提供治疗药物成瘾的新疗法。

DESCRIPTION (provided by applicant): This application focuses on the role of novel molecules, the matrix metalloproteinases (MMPs), in relapse to cocaine and methamphetamine (Meth). MMPs are a family of enzymes that regulate the extracellular matrix (ECM) and cell-adhesion proteins, and very recently have been shown to be involved in spatial memory formation. Underlying drug addiction are persistent memories of the drug that are believed to produce craving and relapse. Drug taking behavior itself involves the consolidation of a drug memory. With each drug use, the memory may be reactivated (retrieved) and subsequently reconsolidated to maintain the original memory. During reactivation, the memory is thought to be labile and susceptible to disruption. Therefore, molecules involved in plasticity should influence reconsolidation. Based on our preliminary data and several studies outside the field of drug abuse, we propose that formation of the original memory (consolidation) as well as reconsolidation processes require shifts in MMP-mediated events. Recent work has demonstrated that activity of the enzymes MMP-3 and MMP-9 in the hippocampus is correlated with learning a spatial water maze task. Further, intracerebral ventricular (i.c.v.) injection of an MMP inhibitor (FN-439) suppresses this spatial learning. Studies in our laboratory have extended these findings to cocaine-induced conditioned place preference (CPP) behavior. Inhibition of MMPs significantly attenuates the acquisition of CPP and blocks reconsolidation of the cocaine memory. In this application we wish to expound on these findings. We will test the central hypothesis that MMPs are critical for reconsolidation of the drug memory such that this memory can be disrupted or diminished with MMP inhibitors during cocaine- and Meth-primed reinstatement. Specifically, we wish to test 1) whether MMP inhibitors can diminish cocaine-primed reinstatement of self-administration in a reactivation-dependent manner, and 2) whether MMP inhibitors can also diminish Meth-primed reinstatement in a reactivation-dependent. The ultimate significance of these studies is to determine whether an MMP inhibitor can disrupt the memory for cocaine or Meth in a reactivation-dependent manner thus providing a novel treatment for treating drug addiction.