Extinction of cue-elicited cocaine seeking

描述（由申请人提供）：药物成瘾是一种脑部疾病，其特征是不顾已知的不良后果，强迫寻求和服用药物。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，并显著促进高复发倾向。这种疾病的有效治疗策略的发展取决于对药物诱导行为发展和消失的分子机制的透彻理解。我们一直在研究多巴胺D1受体和D1受体承载神经元中表达的即时早期基因产物c-Fos通过调节细胞信号传导和基因表达来介导脑多巴胺系统中持续神经适应的发展。我们建立并分析了新的基因工程小鼠模型，发现D1受体和携带D1受体的神经元中表达的c-Fos介导了可卡因的运动致敏和强化效应。此外，这些分子调节可卡因诱导的树突重塑、电生理反应以及大脑中细胞信号传导和基因表达的变化。特别相关的是，在小鼠D1受体携带神经元中缺乏c-Fos表达导致诱导没有变化，但延迟了可卡因诱导的条件位置偏好的消退。此外，习得后伏隔核的突触抑制被诱导，这种抑制在行为消失后明显被逆转。灭绝训练也改变了c- fos调节的某些谷氨酸受体亚基在伏隔核中的表达。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诱导的可卡因寻找的消失，D1受体介导和c-Fos调控的神经元兴奋性、细胞信号传导和基因表达的变化在消失过程中起关键作用。本提案的总体目标是检验上述假设。在Aim 1中，我们提出通过一种新的D1受体神经元特异性诱导的c-Fos小鼠模型，基因上调D1受体神经元中c-Fos的表达，并研究c-Fos的上调是否有助于可卡因诱导的条件位置偏好的消失。在目标2和3中，我们建议使用两种互补的c-Fos小鼠模型来鉴定D1受体介导和c-Fos调节的神经元兴奋性、信号和基因调控的变化，这些变化与获取和消失过程相关。基于它们在线索诱发的可卡因寻找回路中的关键作用，我们将重点研究伏隔核和杏仁核基底外侧。这项工作的成功完成将为c-Fos通过调节大脑中表达多巴胺D1受体的神经元的特异性变化，在消除线索引发的药物寻找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消失的机制提供新的见解，并为药物滥用治疗提供潜在的新靶点。公共卫生相关性：这项工作将确定神经元回路、细胞信号和基因表达的特定变化如何促进药物寻找行为的消失。这些实验可能为药物滥用的药理和分子干预治疗提供潜在的新靶点。

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.