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

• 批准号: 8212323
• 负责人: KARYN M MYERS
• 金额: $ 12.09万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 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/8212323
• 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; Health; 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; receptor; receptor expression; research study; response; voltage

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）：可以作为对环境提示与吸毒或戒断本身的条件反应引起的药物提取。有条件的戒断是在戒烟成瘾者中寻求毒品的有力动力，就像急性戒断驱动在活跃的吸毒者中寻求药物一样。因此，在恢复吸毒者中减少或消除条件戒断状态具有临床意义。灭绝是减少条件反应的一种手段，并在没有以前发出的无条件刺激（US）的情况下涉及暴露于条件刺激（CS）。关于某些类型的条件反应的灭绝已经了解了很多，例如由提示与厌恶事件相结合引起的条件恐惧，但基本上对条件鸦片戒断的灭绝一无所知。该应用程序旨在开始系统地检查条件鸦片戒断的机制，使用纳洛酮诱导的条件位置厌恶（CPA）作为吗啡依赖性大鼠作为模型系统。初步数据表明，在没有纳洛酮的情况下，可以反复暴露于先前戒断的环境中CPA，并且可以通过NMDA受体部分激动剂D-Cycloserine促进CPA灭绝。此处描述的实验将以几种方式扩展这些发现。首先，他们将使用基本的药理学技术来确定基底外侧杏仁核（BLA）（BLA）和输缘性皮层（IL）内NMDA受体依赖性神经塑性的作用，这两个区域在CPA灭绝中严重涉及条件恐惧的灭绝。其次，他们将使用蛋白质（西方）免疫印迹来研究CPA灭绝后BLA和IL中NMDA受体亚基的表达是否受到调节。第三，他们将检查病毒载体介导的NMDA受体亚基表达中的升高是否会影响CPA灭绝。该实验基于以下假设：BLA和IL是CPA灭绝的主要参与者，并且NMDA受体依赖于BLA和IL内的依赖性突触可塑性是这种学习形式的关键机制。希望是，有了更好地了解条件戒断的灭绝机制，将获得更好的技术来临床解决该问题，并最终改善了恢复成瘾者的结果，这些成瘾者不太容易受到条件戒断触发的复发。 公共卫生相关性：可以将戒毒作为对提示与吸毒或戒断本身配对的有条件反应，即使在禁欲后也有助于复发。因此，在恢复吸毒者中减少或消除条件戒断状态具有临床意义。本应用中描述的实验将开始系统地研究一种减少条件戒断方法的神经机制，称为灭绝，在该方法中，反复提出了撤回提示提示，直到条件戒断反应消失为止。