A profile of addiction: the midbrain transcriptome in cocaine abuse

成瘾概况：可卡因滥用中的中脑转录组

• 批准号: 8203965
• 负责人: Magen Marie Johnson
• 金额: $ 3.54万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-19 至 2013-08-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203965
• 关键词: Affect; Area; Bioinformatics; Brain; Brain region; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Coupled; Data; Data Set; Development; Disease; Dopamine; Drug Addiction; Drug Exposure; Drug abuse; Exhibits; Gene Expression; Gene Expression Profile; Genes; Goals; Human; Individual; Investigation; Knowledge; Mediating; Microarray Analysis; Midbrain structure; Molecular; Neurologic; Neuronal Plasticity; Neurons; Neurotransmitters; Outcome; Pathway interactions; Pharmaceutical Preparations; Play; Process; Proteins; Regulation; Relapse; Relative (related person); Rewards; Role; Series; Societies; Techniques; Testing; Time; Transcript; Translating; Validation; addiction; base; case control; cost; dopaminergic neuron; drug addiction pharmacotherapy; drug craving; drug of abuse; insight; neurochemistry; neurotransmission; novel; psychostimulant; research study; response; stimulant abuse; therapeutic target

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. PUBLIC HEALTH RELEVANCE: Drug addiction is associated with significant costs to both affected individuals and society at large. The persistence of drug craving and the likelihood of relapse seem to be due to long- lasting changes in the extent to which many genes are turned on or off within critical regions of the brain. This project will reveal for the first time a complete picture of gene activity in one such area by studying the brains of individuals dying of cocaine abuse, with the goal of identifying new targets for the treatment of drug addiction.

描述（由申请人提供）：吸毒成瘾是一种慢性且复发性的疾病，给受影响的个人和整个社会带来巨大的损失。成瘾过程中涉及的神经递质和神经回路表现出持久的药物诱导适应，据信这是基因表达持续变化的结果。该项目的长期目标是通过扩展我们对成瘾分子机制的了解来确定药物成瘾药物治疗的新靶点。相对较少数量的中脑多巴胺（DA）合成神经元在所有药物滥用中发挥着促进作用。 DA 神经元对精神兴奋剂滥用的正向和负向增强特征的重要贡献为进一步对药物暴露大脑中这些神经元的分子表征提供了令人信服的理由。在这个以发现为驱动的项目中，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。在具体目标 2 中，我们将研究通过确定可卡因诱导的基因表达变化而出现的特定基因和基因途径。目标 2 将通过对目标 1 中生成的数据集进行详尽的生物信息分析，并结合实验验证以及所选转录本和蛋白质的细胞定位和定量来实现。总体而言，具体目标 1 和 2 中提出的实验将为基因和基因网络表达的神经可塑性提供重要线索，这些基因和基因网络表达形成可卡因成瘾的分子基础，最终为药物成瘾的治疗提供新的靶点。 公共卫生相关性：吸毒成瘾会给受影响的个人和整个社会带来巨大的损失。药物渴望的持续存在和复发的可能性似乎是由于大脑关键区域内许多基因开启或关闭程度的长期变化所致。该项目将通过研究死于可卡因滥用的个体的大脑，首次揭示此类区域基因活动的完整图景，目的是确定治疗毒瘾的新靶点。