Role of Matrix Metalloproteinases in Drug Relapse

描述(由申请人提供)：本申请侧重于新分子，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是一个调节细胞外基质(ECM)和细胞黏附蛋白的酶家族，最近被证明参与了空间记忆的形成。毒品成瘾的基础是对毒品的持久记忆，人们认为这些记忆会产生渴望和复发。吸毒行为本身就涉及到毒品记忆的巩固。每次用药时，记忆都可能被重新激活(取回)，然后重新巩固，以保持原来的记忆。在重新激活期间，记忆被认为是不稳定的，容易受到干扰。因此，参与塑性的分子应该会影响再固结。基于我们的初步数据和药物滥用领域外的几项研究，我们认为原始记忆的形成(巩固)以及再巩固过程需要改变基质金属蛋白酶介导的事件。最近的研究表明，海马区的酶MMP3和MMP9的活性与学习空间水迷宫任务有关。此外，脑室(i.c.v.)注射基质金属蛋白酶抑制剂(FN-439)可抑制这种空间学习。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。抑制MMPs可显著减弱CPP的获得并阻断可卡因记忆的再巩固。在本申请中，我们希望对这些发现进行阐述。我们将检验一个中心假设，即MMPs对于药物记忆的重新巩固至关重要，因此在可卡因和冰毒诱导的恢复过程中，这种记忆可以被MMPI抑制剂破坏或减弱。具体地说，我们希望测试1)基质金属蛋白酶抑制剂是否能以重新激活依赖的方式减少可卡因诱导的自我给药的恢复，以及2)基质金属蛋白酶抑制剂是否也能以重新激活依赖的方式减少甲基启动的自我给药恢复。这些研究的最终意义在于确定基质金属蛋白酶抑制剂是否能以重新激活依赖的方式扰乱对可卡因或甲基苯丙胺的记忆，从而为治疗药物成瘾提供一种新的治疗方法。

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.