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

灭绝介导抑制可卡因复发的神经机制

• 批准号: 7577287
• 负责人: WENLIN SUN
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7577287
• 关键词: Abstinence; Agonist; Animal Model; Animals; Applications Grants; Basic Science; Behavior; Behavioral; Brain; Clinic; Clinical; Clinical Treatment; Cocaine; Cocaine Dependence; Condition; Data; Development; Disease; Dose; Drug Addiction; Economic Burden; Effectiveness; Exposure to; Extinction (Psychology); Family; Future; Goals; Knowledge; Mediating; Memory; Molecular; Monitor; Motivation; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Neurons; Pharmaceutical Preparations; Pharmacotherapy; Play; Procedures; Process; Public Health; Rate; Rattus; Relapse; Rewards; Role; Signal Transduction; Societies; Stimulus; Testing; Time; Training; Translations; base; behavior observation; classical conditioning; drug craving; drug seeking behavior; experience; insight; learning extinction; neurobiological mechanism; neuromechanism; novel; preclinical study; receptor; response; success; tool; translational study

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.

描述(由申请人提供)：高复发率是可卡因和其他药物成瘾治疗中最具挑战性的问题。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，即使在长期戒毒后，接触它们也会引发强烈的药物渴望，从而驱动药物寻找行为，并最终导致复发。试图使用灭绝程序来减少这类CS的动机影响，但收效甚微。一个原因可能是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不同。在动物研究中，消退训练的目的通常是消除寻找毒品和吸毒行为(操纵物消退)，而不是药物CS的条件性作用；而在临床环境中，消退训练的目的是在没有操作者消退的情况下消除巴甫洛夫消退(CS)的条件性动机效应。这种脱节严重阻碍了基础研究转化为临床治疗。为了克服这一困难，本申请提出了一种新的动物模型，可以用来专门研究巴甫洛夫灭绝。最近在了解药物消退过程的分子机制方面取得的进展，重新点燃了基于消退的药物成瘾治疗的希望。一种有希望的策略是将巴甫洛夫灭绝训练与药物相结合，这种药物可以增强灭绝记忆背后的分子信号。这项应用的一个目标是确定在灭绝过程中至关重要的受体机制。增强这种受体的功能可能会增强CS不再与药物相关的消退记忆，从而降低药物CS对复发的动机影响。我们将验证这一假设，即下缘皮质(IL)中的NMDA受体在与可卡因CS的条件性动机效应消退相关的记忆巩固中发挥关键作用。这项拟议研究的一个显著特点是，将对行为正常的大鼠的IL中的神经元活动进行监测。同时监测神经元的活动和行为为研究行为的神经机制提供了有力的工具。此外，通过研究IL内微量注射NMDA受体拮抗剂和激动剂对消退记忆巩固的影响，我们将确定这一过程中涉及的分子机制。这一应用的结果将为未来的转译研究提供基础，以测试NMDA受体相关药物在提高目前基于消退的复发治疗的有效性方面的有效性。 公共卫生相关性：可卡因成瘾是一个公共卫生问题，给社会和家庭带来了沉重的经济负担。该病治疗中最困难的问题是复发率高。该项目的长期目标是了解灭绝介导的抑制复发的神经机制，这些信息将为开发有效的药物治疗这种疾病铺平道路。