Role of c-fos in cocaine actions

描述(申请人提供)：毒瘾是一种慢性复发性疾病，其特征是强迫寻求和服用药物，尽管已知有不良后果。吸毒成瘾的一个突出特点是它是一种长期的状况。这种疾病的有效治疗策略依赖于对药物诱导行为持续性背后的分子机制的透彻理解。通过特定的多巴胺(DA)受体亚型的基因表达的变化被认为在介导对反复药物暴露的持久神经适应中发挥了关键作用。即刻早期基因产物c-Fos是通过调节基因表达，将重复的可卡因刺激与大脑DA系统中的持续性神经适应相结合的理想候选者。我们使用新的基因工程小鼠模型研究了这些假设，发现DA D1受体既介导了可卡因的运动敏化，也介导了可卡因的增强效应。D1R还介导可卡因诱导的神经生理反应、树突状细胞重塑和脑内基因表达的变化，包括c-fos及其启动子区域含有AP-1结合位点的基因。此外，在产生D1受体的神经元中，c-Fos的适当表达有助于可卡因诱导的行为敏化、树突重塑和基因表达的变化。值得注意的是，在反复注射可卡因后，D1受体基因和c-fos基因的突变有几个共同的后果。这些发现使我们推测，c-Fos是D1受体下游的一个重要的细胞内信号转导因子，参与了可卡因的行为效应，c-Fos调节的基因表达变化参与了反复接触可卡因的持续性神经适应。这一提议的总体目标是检验上述假设。我们建议将行为敏化和自我给药范式与新的DA D1受体神经元特异性c-fos突变体和可诱导的c-fos小鼠模型相结合，以确定c-fos在可卡因行为效应中的作用。我们还建议确定在可卡因戒断后持续较长时间的D1受体介导的和c-Fos调节的基因表达变化。这项拟议工作的成功完成将建立一个分子框架，研究c-Fos如何通过调节大脑中表达DA D1受体的神经元中的特定基因表达，来重复暴露于持续的行为变化和神经适应。这些实验可能为了解药物成瘾的潜在机制和治疗药物滥用的新策略提供新的见解。

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.