A profile of addiction: the midbrain transcriptome in cocaine abuse

描述(由申请人提供)：吸毒成瘾是一种慢性和复发性疾病，与受影响的个人和整个社会的巨大成本有关。参与成瘾过程的神经递质和神经回路显示出药物诱导的长期适应，据信是基因表达持续变化的结果。该项目的长期目标是通过扩大我们对成瘾的分子机制的了解，为药物成瘾的药物治疗确定新的靶点。中脑多巴胺(DA)合成神经元的数量相对较少，对所有滥用药物都起到使能作用。DA神经元对精神刺激剂滥用的积极和消极强化特征的重要贡献为进一步研究药物暴露脑中这些神经元的分子特征提供了令人信服的理论基础。在这个发现驱动的项目中，我们将首次确定人类可卡因滥用者中脑基因表达的全面概况。在具体目标1中，我们将使用高通量表达微阵列分析来识别与可卡因滥用相关的基因表达变化。在特定的目标2中，我们将研究可卡因诱导的基因表达变化所产生的特定基因和基因途径。目标2将通过对目标1中产生的数据集进行详尽的生物信息学分析，再加上实验验证以及选定转录本和蛋白质的细胞定位和量化来实现。总体而言，在特定目标1和2中提出的实验将提供关于构成可卡因成瘾的分子基础的基因和基因网络表达的神经可塑性的重要线索，最终为药物成瘾的治疗提供新的靶点。

DESCRIPTION (provided by applicant): Drug addiction is a chronic and relapsing disorder associated with significant costs to both affected individuals and society at large. The neurotransmitters and neurological circuits involved in the process of addiction show long-lasting drug-induced adaptations, believed to result from persistent changes in gene expression. The long-term goal of this project is to identify novel targets for the pharmacotherapy of drug addiction by expanding our knowledge of the molecular mechanisms underlying addiction. A relatively small number of midbrain dopamine (DA)-synthesizing neurons play an enabling role for all drugs of abuse. The important contribution of DA neurons to both the positive and negative reinforcing features of psychostimulant abuse provides a compelling rationale for the further molecular characterization of these neurons in the drug-exposed brain. In this discovery- driven project, we will determine, for the very first time, a comprehensive profile of midbrain gene expression in human cocaine abusers. In Specific Aim 1, we will use high-throughput expression microarray analysis to identify changes in gene expression that are associated with cocaine abuse. In Specific Aim 2, we will investigate specific genes and gene pathways emerging from the determination of cocaine-induced changes in gene expression. Aim 2 will be accomplished using exhaustive bioinformatic analysis of the dataset generated in Aim 1, coupled with experimental validation and cellular localization and quantification of selected transcripts and proteins. Overall, the experiments proposed in Specific Aims 1 and 2 will provide important clues regarding the neuroplasticity in gene and gene network expression that form the molecular bases for cocaine addiction, ultimately providing novel targets for the treatment of drug addiction.