NMDA Receptor-Mediated Plasticity in Extinction of Conditioned Opiate Withdrawal

描述（由申请人提供）：药物戒断可以作为对环境线索的条件反应与药物使用或戒断本身相结合而引起。条件性戒断是戒断成瘾者寻求药物的强大动力，就像急性戒断驱动主动吸毒者寻求药物一样。由于这个原因，减少或消除康复成瘾者的条件性戒断状态具有临床意义。消退是减少条件反应的一种手段，涉及在不存在先前发出信号的非条件刺激（US）的情况下暴露于条件刺激（CS）。关于某些类型的条件反应的消退，人们已经了解了很多，例如由与厌恶事件配对的线索引起的条件恐惧，但基本上对条件阿片戒断的消退一无所知。本申请的目的是开始一个系统的研究机制的消退条件阿片戒断使用纳洛酮诱导的条件性位置厌恶（CPA）在吗啡依赖大鼠作为模型系统。初步数据表明，CPA可以通过反复暴露于先前撤回配对的环境中的情况下，纳洛酮熄灭，CPA灭绝可以促进NMDA受体部分激动剂D-环丝氨酸。这里描述的实验将从几个方面扩展这些发现。首先，他们将使用基本的药理学技术来确定NMDA受体依赖性神经可塑性在基底外侧杏仁核（BLA）和边缘下皮层（IL）中的作用，这两个区域与条件性恐惧的消退密切相关。其次，他们将使用蛋白质（Western）免疫印迹法来研究CPA消退后BLA和IL内NMDA受体亚基的表达是否受到调节。第三，他们将研究病毒载体介导的NMDA受体亚单位表达与BLA和IL的升高是否影响CPA消退。这些实验是基于这样的假设，即BLA和IL是CPA消退的主要参与者，并且BLA和IL内的NMDA受体依赖性突触可塑性是这种学习形式的关键机制。我们希望，随着对条件性戒断消失机制的更好理解，将有更好的技术来解决临床问题，并最终改善康复成瘾者的结果，这些成瘾者不太容易因条件性戒断而复发。 公共卫生相关性：药物戒断可以作为对与药物使用或戒断本身配对的线索的条件反应而引起，即使在戒断期后也会导致复发。由于这个原因，减少或消除康复成瘾者的条件性戒断状态具有临床意义。在本申请中描述的实验将开始对一种减少条件性退缩的方法（称为消退）的神经机制的系统研究，其中退缩诱发线索被反复呈现，直到条件性退缩反应消失。

DESCRIPTION (provided by applicant): Drug withdrawal can be elicited as a conditioned response to environmental cues paired with drug use or withdrawal itself. Conditioned withdrawal is a powerful motivator of drug seeking in abstinent addicts just as acute withdrawal drives drug seeking in active drug users. For this reason it is of clinical interest to reduce or eliminate conditioned withdrawal states in recovering addicts. Extinction is a means of decreasing conditioned responses and involves exposure to a conditioned stimulus (CS) in the absence of the unconditioned stimulus (US) it signaled previously. Much has been learned about extinction of certain types of conditioned responses, such as conditioned fear elicited by a cue paired with an aversive event, but essentially nothing is known about extinction of conditioned opiate withdrawal. This application aims to begin a systematic examination of the mechanisms of extinction of conditioned opiate withdrawal using naloxone-induced conditioned place aversion (CPA) in morphine-dependent rats as a model system. Preliminary data indicate that CPA can be extinguished through repeated exposure to a previously withdrawal-paired environment in the absence of naloxone, and that CPA extinction can be facilitated by the NMDA receptor partial agonist D-cycloserine. The experiments described here will extend these findings in several ways. First, they will use basic pharmacological techniques to determine the role of NMDA receptor-dependent neuroplasticity within the basolateral amygdala (BLA) and infralimbic cortex (IL), two regions implicated heavily in extinction of conditioned fear, in CPA extinction. Second, they will use protein (Western) immunoblotting to investigate whether expression of NMDA receptor subunits within BLA and IL is modulated following CPA extinction. Third, they will examine whether viral vector-mediated elevations in NMDA receptor subunit expression with BLA and IL affect CPA extinction. The experiments are based on the hypothesis that BLA and IL are major players in CPA extinction and that NMDA receptor- dependent synaptic plasticity within BLA and IL is a critical mechanism underlying this form of learning. The hope is that with better understanding of the mechanisms of extinction of conditioned withdrawal will come better techniques for addressing the problem clinically, and ultimately improved outcomes for recovering addicts who are less vulnerable to relapse triggered by conditioned withdrawal. PUBLIC HEALTH RELEVANCE: Drug withdrawal can be elicited as a conditioned response to cues paired with drug use or withdrawal itself, contributing to relapse even after periods of abstinence. For this reason it is of clinical interest to reduce or eliminate conditioned withdrawal states in recovering addicts. The experiments described in this application will begin a systematic investigation of the neural mechanisms underlying one method of reducing conditioned withdrawal, called extinction, in which withdrawal-eliciting cues are presented repeatedly until the conditioned withdrawal response disappears.