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配对。条件戒断是戒断成瘾者寻求药物的强大动力，正如急性戒断驱使活跃吸毒者寻求药物一样。由于这个原因，减少或消除条件戒断状态在恢复成瘾者是临床的兴趣。消退是一种减少条件反应的手段，涉及在没有条件刺激（US）的情况下暴露于条件刺激（CS）。人们对某些类型的条件反射的消失已经了解了很多，比如由提示与厌恶事件配对引起的条件恐惧，但基本上对条件鸦片戒断的消失一无所知。本研究旨在以吗啡依赖大鼠为模型系统，对纳洛酮诱导的条件性场所厌恶（CPA）消除条件阿片戒断的机制进行系统研究。初步数据表明，在没有纳洛酮的情况下，CPA可以通过反复暴露于先前的戒断配对环境中而消失，并且NMDA受体部分激动剂d -环丝氨酸可以促进CPA的消失。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受体依赖的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，这两个区域在条件恐惧的消退中有很大的关联，在CPA消退中。其次，他们将使用蛋白质（Western）免疫印迹法来研究在CPA消失后，BLA和IL中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受体亚基表达与BLA和IL的升高是否影响CPA的消失。这些实验是基于这样的假设，即BLA和IL是CPA灭绝的主要参与者，而BLA和IL中NMDA受体依赖的突触可塑性是这种学习形式的关键机制。我们希望，随着对条件戒断的消退机制的更好理解，将会有更好的技术在临床上解决这个问题，并最终改善成瘾者康复的结果，使他们不那么容易因条件戒断而复发。公共卫生相关性：药物戒断可以作为一种条件反应引起，与药物使用或戒断本身相匹配，即使在戒断期后也会导致复发。由于这个原因，减少或消除条件戒断状态在恢复成瘾者是临床的兴趣。本应用程序中描述的实验将开始系统地研究一种减少条件戒断的方法的神经机制，这种方法被称为消退，在这种方法中，引发戒断的线索被反复呈现，直到条件戒断反应消失。

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.