Role of c-fos in cocaine actions

描述（由申请人提供）：药物成瘾是一种慢性复发性疾病，其特征是不顾已知的不良后果，强迫寻求和服用药物。吸毒成瘾的一个显著特征是它是一种持续时间较长的状态。这种疾病的有效治疗策略取决于对药物诱导行为持久性质的分子机制的透彻理解。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反复药物暴露的持久神经适应中起关键作用。直接早期基因产物c-Fos是通过调节基因表达将重复可卡因刺激与脑DA系统持续神经适应结合起来的理想候选者。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受体介导了可卡因的运动致敏和强化效应。D1受体还介导可卡因诱导的神经生理反应、脑内树突重塑和基因表达变化，包括c-fos及其启动子区域含有AP-1结合位点的基因。此外，D1受体产生神经元中c-Fos的适当表达有助于可卡因诱导的行为致敏、树突重塑和基因表达改变。值得注意的是，反复注射可卡因后，D1受体基因和c-fos的突变有几个共同的后果。这些发现使我们假设c-Fos是D1受体下游的一个重要的细胞内信号换能器，有助于可卡因的行为影响，并且c-Fos调节的基因表达变化参与了对反复暴露于可卡因的持续神经适应。本提案的总体目标是检验上述假设。我们建议将行为致敏和自我给药模式与新型DA D1受体神经元特异性c-Fos突变和诱导型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D1受体介导和c- fos调控的基因表达变化在可卡因戒断后持续很长时间。这项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，将重复可卡因暴露与持续的行为改变和神经适应结合起来。这些实验可能为药物成瘾的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.