Extinction of cue-elicited cocaine seeking

描述(申请人提供)：药物成瘾是一种脑部疾病，其特征是强迫寻求和服用药物，尽管已知有不良后果。毒品成瘾的一个显著特征是，与毒品相关的线索可以诱发寻求毒品的行为，并显著促进复发的高倾向。这种疾病的有效治疗策略的发展依赖于对药物诱导行为发生和消失的分子机制的透彻理解。我们一直在研究的观点是，多巴胺D_1受体和即刻早期基因产物c-Fos在D_1受体神经元中表达，通过调节细胞信号和基因表达，在脑多巴胺系统中介导持续性神经适应的发展。我们建立和分析了新的基因工程小鼠模型，发现D1受体和c-Fos在D1受体神经元中的表达介导了可卡因的运动敏化和增强效应。此外，这些分子还调节可卡因诱导的树突状重塑、电生理反应以及大脑中细胞信号和基因表达的变化。特别相关的是，在小鼠的d1受体神经元中缺乏c-Fos的表达导致诱导没有改变，但延迟了可卡因诱导的条件位置偏爱的消退。此外，在习得后，伏隔核会诱导出突触抑制，而这种抑制在行为消失后明显被逆转。消光训练还可以改变伏隔核中c-Fos调节的某些谷氨酸受体亚单位的表达。这些研究结果使我们推测，d1受体神经元c-Fos表达上调有助于线索诱导的可卡因寻找的消退，而d1受体介导和c-Fos调节的神经元兴奋性、细胞信号和基因表达的变化在消退过程中起关键作用。这一提议的总体目标是检验上述假设。在目标1中，我们提出了一种新的D1受体神经元特异性可诱导的c-Fos小鼠模型，在基因上上调d1受体神经元中c-Fos的表达，并探讨c-Fos上调是否有助于可卡因诱导的条件性位置偏爱的消退。在目标2和目标3中，我们建议使用两个互补的c-Fos小鼠模型来识别d1受体介导的和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。基于它们在线索诱导的可卡因寻找潜在回路中的关键参与，我们将重点关注伏隔核和杏仁基底外侧核。这项拟议工作的成功完成将建立一个分子框架，通过调节大脑中表达多巴胺D1受体的神经元的特定变化，c-Fos在线索诱导的药物寻找的消退中发挥作用。我们期望这些实验将为促进毒品寻求灭绝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。

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.