Extinction of cue-elicited cocaine seeking

线索引发的可卡因寻求消失

• 批准号: 7803636
• 负责人: Ming Xu
• 金额: $ 34.75万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803636
• 关键词: Amygdaloid structure; Area; Behavior; Behavioral; Biological; Brain; Brain Diseases; Cocaine; Cues; Development; Disease; Dopamine D1 Receptor; Drug Addiction; Drug abuse; Extinction (Psychology); Extracellular Signal Regulated Kinases; FOS gene; Gene Expression; Gene Expression Regulation; Genetic; Genetically Engineered Mouse; Glutamate Receptor; Goals; Immediate-Early Genes; Intervention; Mediating; Mediator of activation protein; Mental Depression; Mitogen-Activated Protein Kinases; Molecular; Mus; Mutant Strains Mice; Mutation; Neurons; Nucleus Accumbens; Pharmaceutical Preparations; Play; Process; Proteins; Relapse; Relative (related person); Role; Saline; Series; Signal Transduction; Signaling Molecule; Slice; Synaptic Transmission; Synaptic plasticity; Testing; Training; Up-Regulation; Wild Type Mouse; Work; adverse outcome; base; chromatin remodeling; dopamine system; drug induced behavior; drug seeking behavior; effective therapy; inhibitor/antagonist; insight; interest; mouse model; neuroadaptation; neuronal excitability; novel; preference; public health relevance; receptor-mediated signaling; research study; response; reward circuitry; synaptic depression; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Drug addiction is a brain disease that is characterized by the compulsive seeking and taking of a drug despite known adverse consequences. A prominent feature of drug addiction is that drug-associated cues can elicit drug-seeking behaviors and contribute significantly to the high propensity to relapse. The development of effective treatment strategies of this disease depends on a thorough understanding of molecular mechanisms underlying the development and extinction of drug-induced behaviors. We have been investigating the notion that the dopamine D1 receptor and the immediate early gene product c-Fos expressed in D1 receptor-bearing neurons mediate the development of persistent neuroadaptation in the brain dopamine system by regulating cell signaling and gene expression. We generated and analyzed novel genetically engineered mouse models and found that the D1 receptor and c-Fos expressed in D1 receptor-bearing neurons mediate the locomotor sensitization and reinforcing effects of cocaine. Moreover, these molecules regulate cocaine-induced dendritic remodeling, electrophysiological responses, and changes in cell signaling and gene expression in the brain. Of particular relevance, a lack of c-Fos expression in D1 receptor-bearing neurons in mice results in no change in the induction but a delayed extinction of cocaine-induced conditioned place preference. Further, synaptic depression is induced in the nucleus accumbens following the acquisition, and this depression is apparently reversed after extinction of the behavior. Extinction training also modifies c-Fos-regulated expression of certain glutamate receptor subunits in the nucleus accumbens. These findings led us to hypothesize that up- regulation of c-Fos expression in D1 receptor-bearing neurons facilitates the extinction of cue-elicited cocaine seeking, and that D1 receptor-mediated and c-Fos-regulated changes in neuronal excitability, cell signaling and gene expression play key roles in the extinction process. The overall goal of this proposal is to test the above hypothesis. In Aim 1, we propose to genetically up-regulate c-Fos expression in D1 receptor-bearing neurons by using a novel D1 receptor neuron-specific inducible c-Fos mouse model, and investigate whether up-regulation of c-Fos facilitates the extinction of cocaine-induced conditioned place preference. In Aims 2 and 3, we propose to identify D1 receptor-mediated and c-Fos-regulated changes in neuronal excitability, signaling and gene regulation that are associated with the acquisition and extinction processes using the two complementary c-Fos mouse models. Based on their key involvement in the circuitry underlying cue-elicited cocaine seeking, we will focus on the nucleus accumbens and basolateral amygdala. Successful completion of the proposed work will establish a molecular framework for the role of c-Fos in the extinction of cue-elicited drug seeking by regulating specific changes in dopamine D1 receptor-expressing neurons in the brain. We expect these experiments to provide novel insights into mechanisms underlying facilitation of extinction of drug seeking, identifying potential new targets for the treatment of drug abuse. PUBLIC HEALTH RELEVANCE: The proposed work will identify how specific changes in neuronal circuits, cellular signaling and gene expression may facilitate the extinction of drug seeking behaviors. These experiments may provide potential new targets for pharmacological and molecular interventions for the treatment of drug abuse.

描述（由申请人提供）：药物成瘾是一种脑部疾病，其特征是尽管已知有不良后果，仍会强迫性地寻求和服用药物。毒瘾的一个显着特征是，与药物相关的线索可以引发寻求药物的行为，并显着导致复发的高倾向。该疾病有效治疗策略的制定取决于对药物诱发行为发生和消失的分子机制的透彻理解。我们一直在研究这样的观点：多巴胺 D1 受体和 D1 受体神经元中表达的立即早期基因产物 c-Fos 通过调节细胞信号传导和基因表达来介导大脑多巴胺系统中持久神经适应的发展。我们生成并分析了新型基因工程小鼠模型，发现 D1 受体神经元中表达的 D1 受体和 c-Fos 介导可卡因的运动敏化和增强作用。此外，这些分子还调节可卡因诱导的树突重塑、电生理反应以及大脑中细胞信号和基因表达的变化。特别重要的是，小鼠 D1 受体神经元中 c-Fos 表达的缺乏导致可卡因诱导的条件性位置偏好的诱导没有变化，但延迟消失。此外，在获得后，在伏隔核中诱发突触抑制，并且这种抑制在行为消失后明显逆转。消退训练还可以改变伏隔核中某些谷氨酸受体亚基的 c-Fos 调节表达。这些发现使我们推测，携带 D1 受体的神经元中 c-Fos 表达的上调促进了线索引发的可卡因寻求的消退，并且 D1 受体介导和 c-Fos 调节的神经元兴奋性、细胞信号传导和基因表达的变化在消退过程中发挥着关键作用。该提案的总体目标是检验上述假设。在目标 1 中，我们建议通过使用新型 D1 受体神经元特异性诱导 c-Fos 小鼠模型，从基因上上调 D1 受体神经元中的 c-Fos 表达，并研究 c-Fos 的上调是否有助于可卡因诱导的条件性位置偏好的消失。在目标 2 和 3 中，我们建议使用两种互补的 c-Fos 小鼠模型来识别 D1 受体介导和 c-Fos 调节的神经元兴奋性、信号传导和基因调节的变化，这些变化与获得和消退过程相关。基于它们在线索引发的可卡因寻找的回路中的关键参与，我们将重点关注伏核和基底外侧杏仁核。成功完成拟议的工作将为 c-Fos 通过调节大脑中表达多巴胺 D1 受体的神经元的特定变化，在线索引发的药物寻找消退中的作用建立一个分子框架。我们期望这些实验能够为促进药物寻求灭绝的潜在机制提供新的见解，从而确定治疗药物滥用的潜在新目标。公共健康相关性：拟议的工作将确定神经元回路、细胞信号和基因表达的具体变化如何促进药物寻求行为的消失。这些实验可能为治疗药物滥用的药理学和分子干预提供潜在的新靶标。