Role of c-fos in cocaine actions

药物成瘾是一种慢性复发性疾病，其特征是强迫寻求和服用 一种不顾已知的不良后果的药物。吸毒成瘾的一个突出特点是它是一种长期的 持久的状况。有效的治疗策略取决于对本病的透彻了解。 药物诱导行为持续性背后的分子机制。基因的变化 通过特定的多巴胺(DA)受体亚型表达被认为在 调节对反复药物暴露的持久神经适应。即刻早期基因产物c-Fos 是将重复的可卡因刺激与大脑DA的持续性神经适应相结合的理想候选者 系统通过调节基因的表达。我们用新的遗传学手段研究了这些假设。 构建了小鼠模型，发现DAD1受体既介导了运动敏化，又介导了运动敏化 以及可卡因的强化作用。D1R也介导可卡因诱导的神经生理学 脑内的反应、树突重塑和基因表达的变化，包括c-fos和基因 启动子区域含有AP-1结合位点。此外，d1中c-Fos的正确表达 受体产生神经元参与可卡因诱导的行为敏感化和树突重塑 基因表达也会发生变化。值得注意的是，d1受体基因和c-fos的突变有几个共同点。 反复注射可卡因的常见后果。这些发现使我们假设c- Fos是一种重要的细胞内信号转导分子，位于D1受体下游，参与细胞内信号传导。 可卡因的行为效应以及c-Fos调控的基因表达变化参与持续性 对反复接触可卡因的神经适应。这项提案的总体目标是检验上述内容 假设。我们建议通过联合检测c-Fos在可卡因行为效应中的作用 行为敏感化和自我给药范式在新的DA D1受体神经元上的应用- 特异性c-fos突变和诱导型c-fos小鼠模型。我们还建议鉴定d1受体介导的 以及c-Fos调控的基因表达变化，这些变化在可卡因戒断后持续很长时间。成功 拟议工作的完成将建立一个关于c-fos对如何重复的分子框架。 可卡因暴露对持续性行为改变和特定基因调节的神经适应 在脑内表达DAD1受体的神经元中的表达。这些实验可能会提供新的 对药物成瘾的潜在机制和治疗药物滥用的新战略的洞察。

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 long- lasting 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 neuron- specific 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.