NMDA Receptor-Mediated Plasticity in Extinction of Conditioned Opiate Withdrawal

NMDA 受体介导的条件性阿片戒断消退的可塑性

基本信息

批准号：
7771993
负责人：
KARYN M MYERS
金额：
$ 6.91万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-15 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7771993
关键词：
Abstinence Acute Address Affect Agonist Amygdaloid structure Animals Basal Ganglia Biological Models Cerebellum Clinical Complex Conditioned Stimulus Cues Cycloserine Data Dependence Drug Addiction Drug usage Drug user Environment Event Exposure to Extinction (Psychology)Fright Glutamate Receptor HSV vector Infusion procedures Injection of therapeutic agent Investigation Lateral Learning Mediating Memory Methods Morphine N-Methyl-D-Aspartate Receptors NMDA receptor antagonist NR1 gene Naloxone Neurobiology Neuronal Plasticity Opiates Outcome Pharmaceutical Preparations Prefrontal Cortex Proteins Rattus Relapse Role Series Signal Transduction Site Sodium Channel Blockers Stimulus Structure Synaptic plasticity Techniques Testing Tetrodotoxin Tissues Training Up-Regulation Viral Vector Western Blotting Withdrawal Withdrawal Symptom Work base conditioned fear drug seeking behavior drug withdrawal ifenprodil improved interest neuromechanism public health relevance receptor receptor expression research study response voltage

项目摘要

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.

描述（由申请人提供）：药物戒断可以作为对与药物使用或戒断本身配对的环境线索的条件反应而引发。条件性戒断是戒断成瘾者寻求毒品的强大动力，就像急性戒断会促使活跃吸毒者寻求毒品一样。因此，减少或消除成瘾者康复过程中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方法，涉及在没有先前发出的无条件刺激（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失，例如由与厌恶事件配对的线索引起的条件性恐惧，人们已经了解了很多，但基本上对条件性阿片戒断的消失一无所知。本申请旨在使用吗啡依赖大鼠中纳洛酮诱导的条件性位置厌恶（CPA）作为模型系统，开始系统检查条件性阿片戒断的消失机制。初步数据表明，在没有纳洛酮的情况下，反复暴露于先前戒断配对的环境中可以消除CPA，并且NMDA受体部分激动剂D-环丝氨酸可以促进CPA消除。这里描述的实验将以多种方式扩展这些发现。首先，他们将使用基本药理学技术来确定基底外侧杏仁核 (BLA) 和边缘皮层 (IL) 内 NMDA 受体依赖性神经可塑性的作用，这两个区域与条件性恐惧的消退和 CPA 消退密切相关。其次，他们将使用蛋白质（Western）免疫印迹来研究 BLA 和 IL 内 NMDA 受体亚基的表达是否在 CPA 灭绝后受到调节。第三，他们将检查病毒载体介导的 BLA 和 IL 的 NMDA 受体亚基表达升高是否会影响 CPA 消退。这些实验基于以下假设：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。希望通过更好地了解条件性戒断的消除机制，能够找到更好的技术来解决临床问题，并最终改善戒断中的成瘾者的治疗结果，使他们不易因条件性戒断而复发。公共卫生相关性：药物戒断可能是对与药物使用或戒断本身相结合的线索的条件反应，即使在戒断一段时间后也会导致复发。因此，减少或消除成瘾者康复过程中的条件性戒断状态具有临床意义。本申请中描述的实验将开始对减少条件性戒断的一种方法（称为消退）的神经机制进行系统研究，其中反复出现戒断诱发线索，直到条件性戒断反应消失。