Role of c-fos in cocaine actions

c-fos 在可卡因作用中的作用

• 批准号: 6967694
• 负责人: Ming Xu
• 金额: $ 10.51万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6967694
• 关键词: behavior test; behavioral /social science research tag; behavioral habituation /sensitization; cocaine; dopamine receptor; drug addiction; gene expression; genetically modified animals; immunoprecipitation; in situ hybridization; laboratory mouse; microarray technology; neuropsychology; operant conditionings; polymerase chain reaction; posttranslational modifications; protooncogene; psychological adaptation; psychological reinforcement; receptor expression; regulatory gene; self medication; substance abuse related behavior

DESCRIPTION (provided by applicant): Drug addiction is a chronic relapsing 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 it is a longlasting condition. Effective treatment strategies of this disease depend on a thorough understanding of the molecular mechanisms underlying the persistent nature of drug-induced behaviors. Changes in gene expression through specific dopamine (DA) receptor subtypes have been thought to play a key part in mediating enduring neuroadaptations to repeated drug exposure. The immediate early gene product c-Fos is an ideal candidate to couple repeated cocaine stimuli to persistent neuroadaptation in the brain DA system by regulating gene expression. We have investigated these assumptions using novel genetically engineered mouse models and found that the DA D1 receptor mediates both the locomotor sensitization and the reinforcing effects of cocaine. The D1 receptor also mediates cocaine-induced neurophysiological responses, dendritic remodeling and gene expression changes in the brain, including c-fos and genes containing AP-1 binding sites in their promoter regions. Furthermore, proper c-Fos expression in D1 receptor-producing neurons contributes to cocaine-induced behavioral sensitization, dendritic remodeling and gene expression changes. Noticeably, mutations of the D1 receptor gene and c-fos share several common consequences following repeated cocaine injections. These findings led us to hypothesize that c- Fos is a significant intracellular signal transducer downstream of the D1 receptor that contributes to the behavioral effects of cocaine, and that c-Fos-regulated gene expression changes participate in persistent neuroadaptation to repeated exposure to cocaine. The overall goal of this proposal is to test the above hypothesis. We propose to determine the role of c-Fos in the behavioral effects of cocaine by combining the use of behavioral sensitization and self-administration paradigms with novel DA D1 receptor neuronspecific c-fos mutant and inducible c-fos mouse models. We also propose to identify D1 receptor-mediated and c-Fos-regulated gene expression changes that persist long after cocaine withdrawal. Successful completion of the proposed work will establish a molecular framework on how c-Fos couples repeated cocaine exposure to persistent behavioral changes and neuroadaptation by regulating specific gene expression in DA D1 receptor-expressing neurons in the brain. These experiments may provide novel insights into mechanisms underlying drug addiction and new strategies for the treatment of drug abuse.

描述（由申请人提供）：药物成瘾是一种慢性复发疾病，尽管已知不良后果，但其特征是强迫寻求和服用药物。药物成瘾的一个突出特征是它是一种长期的条件。该疾病的有效治疗策略取决于对药物诱导行为持续性质的分子机制的透彻理解。人们认为，通过特定多巴胺（DA）受体亚型的基因表达变化被认为在介导持久的神经适应性的重复药物暴露中起着关键作用。直接的早期基因产物C-FOS是通过调节基因表达来持续的可卡因刺激以持续的神经适应的理想候选者。我们已经使用新型的基因工程小鼠模型研究了这些假设，发现DA D1受体介导了运动敏化和可卡因的增强作用。 D1受体还介导可卡因诱导的神经生理反应，树突重塑和基因表达在大脑中的变化，包括C-FOS和含有AP-1结合位点的基因。此外，在产生D1受体神经元中的适当C-FOS表达有助于可卡因诱导的行为敏化，树突重塑和基因表达变化。值得注意的是，D1受体基因和C-FOS的突变在重复的可卡因注射后有几种常见的后果。这些发现导致我们假设C-FOS是D1受体下游的重要细胞内信号传感器，这有助于可卡因的行为作用，并且C-FOS调节的基因表达变化参与持续的神经适应，以重复暴露于Cocaine。该提案的总体目标是检验上述假设。我们建议通过结合使用行为敏化和自我给药范式与新型DA D1 D1受体神经神经素C-FOS突变体和诱导C-FOS小鼠模型的使用，确定C-FOS在可卡因的行为效应中的作用。我们还建议鉴定D1受体介导的和C-FOS调节的基因表达变化，这些变化在可卡因戒断后很久持续存在。成功完成所提出的工作将建立一个分子框架，以了解C-Fos夫妇如何通过调节DA D1受体表达神经元中的特定基因表达来重复可卡因对持续的行为变化和神经适应。这些实验可能会提供有关药物成瘾基础机制和治疗药物滥用的新策略的新见解。