Neural Mechanisms of Extinction-Mediated Inhibition of Relapse to Cocaine-Seeking

描述（由申请人提供）：高复发率是治疗可卡因和其他药物成瘾最具挑战性的问题。与可卡因经验相关的环境刺激已被确定为引发复发的一个主要因素。人们普遍认为，这些条件刺激（CSs）通过巴甫洛夫条件反射机制获得动机价值，即使在长时间的戒断之后，接触它们也会引起强烈的药物渴望，从而驱动药物寻求行为，最终导致复发。试图使用消隐程序来减少此类CSs的动机影响的尝试取得了有限的成功。其中一个原因可能是因为动物研究中使用的与灭绝相关的范式与临床环境中使用的范式不同。在动物研究中，消退训练通常旨在消除药物寻找和服用行为（操作性消退），而不是药物CSs的条件效应，而在临床环境中，消退训练旨在消除在没有操作性消退的情况下CS的条件动机效应（巴甫洛夫消退）。这种脱节严重阻碍了基础研究向临床治疗的转化。为了克服这一困难，本应用程序提出了一种新的动物模型，可用于专门研究巴甫洛夫灭绝。在理解灭绝过程背后的分子机制方面的最新进展重新点燃了基于灭绝的药物成瘾治疗的希望。一种很有前景的策略是将巴甫洛夫灭绝训练与药物结合起来，以增强灭绝记忆背后的分子信号。该应用程序的一个目标是确定在灭绝过程中关键参与的受体机制。增强这些受体的功能可以增强CS不再与药物相关的消失记忆，从而减少药物CS对复发的动机影响。我们将验证边缘下皮层（IL）中的NMDA受体在与可卡因CSs的条件激励效应消退相关的记忆巩固中起关键作用的假设。提出的研究的一个显著特征是，将在行为正常的大鼠中监测IL中的神经元活动。同时监测神经元活动和行为为研究行为的神经元机制提供了有力的工具。此外，通过研究NMDA受体拮抗剂和激动剂微注射到IL中对消失记忆巩固的影响，我们将确定这一过程所涉及的分子机制。该应用程序的结果将为未来的转化研究提供基础，以测试NMDA受体相关药物在提高当前基于灭绝的复发治疗有效性方面的有效性。

DESCRIPTION (provided by applicant): The high rate of relapse is the most challenging issue in the treatment of cocaine and other drug addiction. The environmental stimuli associated with cocaine experience have been identified to be one main factor in triggering relapse. It is widely accepted that these conditioned stimuli (CSs) acquire motivational values through Pavlovian conditioning mechanisms and exposure to them even after a long period of abstinence can evoke powerful drug craving which drives drug-seeking behavior and ultimately, relapse. Attempts to use extinction procedures to reduce the motivation impact of such CSs have met a limited success. One reason is probably because the extinction-related paradigms used in animal studies are different from those used in clinic settings. In animal studies, extinction training is typically aimed to extinguish drug-seeking and drug- taking behavior (operant extinction) rather than the conditioned effects of drug CSs whereas in clinical settings, extinction training is aimed to extinguish the conditioned motivational effects of the CS (Pavlovian extinction) in the absence of the operant extinction. Such a disconnection severely hinders the translation of basic research into clinical treatments. To overcome this difficulty, this application proposes a novel animal model that can be used to specifically study the Pavlovian extinction. Recent advances in understanding the molecular mechanisms underlying the extinction process reignite the hope for the extinction-based treatment of drug addiction. One promising strategy is the combination of Pavlovian extinction training with drugs that can enhance the molecular signaling underlying the extinction memory. One goal of this application is to identify the receptor mechanism critically involved in the extinction process. Enhancing the function of such receptors may enhance the extinction memory that a CS is no longer associated with the drug and consequently, reduce the motivational impact of drug CSs on relapse. We will test the hypothesis that NMDA receptors in the infralimbic cortex (IL) play a critical role in consolidation of memory related to extinction of conditioned motivational effects of cocaine CSs. One distinctive feature of the proposed studies is that neuronal activity in the IL will be monitored in behaving rats. Simultaneous monitoring of neuronal activity and behavior provides a powerful tool to study the neuronal mechanisms of the behavior. In addition, by studying the effects of NMDA receptor antagonists and agonists microinjected into the IL on consolidation of extinction memory, we will identify the molecular mechanisms involved in this process. The results derived from this application will provide a basis for future translational studies to test the efficacy of NMDA receptor-related drugs in enhancing the effectiveness of the current extinction-based treatment for relapse. PUBLIC HEALTH RELEVANCE: Cocaine addiction is a public health issue and puts a heavy economic burden on society and family. The most difficult issue in treatment of this disease is the high rate of relapse. The long-term goal of the project is to understand the neural mechanism underlying extinction-mediated inhibition of relapse and such information will pave the way for development of effective drug treatments for this disease.