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，其特征是强迫性寻求和服用药物，尽管已知有不良后果。药物成瘾的一个显著特征是药物相关线索可以诱发药物寻求行为，并显著促进高复吸倾向。有效的治疗策略的发展依赖于对药物诱导行为的发展和消退的分子机制的透彻理解。我们一直在研究的概念，多巴胺D1受体和立即早期基因产物c-Fos表达的D1受体轴承神经元介导的发展，在大脑多巴胺系统的持续神经适应，通过调节细胞信号和基因表达。我们生成并分析了新的基因工程小鼠模型，发现D1受体和c-Fos在D1受体神经元中表达介导可卡因的运动敏化和强化作用。此外，这些分子调节可卡因诱导的树突重塑，电生理反应，以及脑中细胞信号传导和基因表达的变化。特别相关的是，缺乏c-Fos表达的D1受体轴承神经元在小鼠中的结果没有变化的诱导，但延迟消退可卡因诱导的条件性位置偏爱。此外，在获得后，突触抑制在丘脑核中被诱导，并且这种抑制在行为消失后明显逆转。灭绝训练也改变了c-Fos调节的某些谷氨酸受体亚基在丘脑核中的表达。这些发现使我们假设，在D1受体携带神经元中c-Fos表达的上调促进线索诱发的可卡因寻求的消退，并且D1受体介导的和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起关键作用。本提案的总体目标是检验上述假设。在目的1中，我们提出了一种新的D1受体神经元特异性诱导的c-Fos小鼠模型，通过基因上调C-Fos表达的D1受体轴承神经元，并调查是否上调c-Fos促进可卡因诱导的条件性位置偏爱的消退。在目标2和3中，我们建议使用两种互补的c-Fos小鼠模型来鉴定与获得和消退过程相关的神经元兴奋性、信号传导和基因调控中D1受体介导和c-Fos调节的变化。基于它们在线索诱发的可卡因寻找的潜在回路中的关键参与，我们将重点关注脑桥核和基底外侧杏仁核。成功完成拟议的工作将建立c-Fos的作用的分子框架，通过调节多巴胺D1受体表达的神经元在大脑中的特定变化的线索引起的药物寻求灭绝。我们希望这些实验能够为药物寻求消失的潜在机制提供新的见解，确定治疗药物滥用的潜在新靶点。公共卫生相关性：拟议的工作将确定神经元回路，细胞信号传导和基因表达的特定变化如何促进寻求药物行为的消失。这些实验可能为药物滥用治疗的药理学和分子干预提供潜在的新靶点。