The Role of miRNAs in Cocaine Addiction

描述（由申请人提供）：了解药物成瘾的分子机制对于开发治疗这种使人衰弱的疾病的新方法至关重要。最近的研究表明，老鼠上瘾行为的发展与基因表达的稳定变化有关。成瘾的遗传基础提出了一个问题，即在成瘾中起关键作用的基因及其调节因子的本质。我们发现，小鼠可卡因成瘾的形成与纹状体中大量mirna的表达变化有关，纹状体是负责药物成瘾的大脑区域。鉴于mirna在基因表达调控中的强大作用，我们假设可卡因调控的mirna有助于建立支持成瘾的基因表达网络。为了评估可卡因诱导的mirna对可卡因成瘾的发展和维持的贡献，我们建议解决纹状体特异性改变的单个mirna对成瘾的影响。小鼠成瘾的两种最明确的症状，如可卡因诱导的致敏和奖励，将用于解决miRNA在动物行为中的作用。我们将测试受慢性可卡因治疗影响的miRNA水平的纠正是否会影响体内成瘾行为的发展。通过将基于RNA的细胞渗透性特异性miRNA抑制剂注射到纹状体中，可以实现可卡因治疗诱导的miRNA失活。反过来，通过使用表达腺相关病毒（AAV）的miRNA，可以实现可卡因抑制的纹状体特异性miRNA的正常化。鉴定在可卡因成瘾的发展和维持中起作用的特定mirna可能有助于揭示在健康和疾病中控制多巴胺信号的分子网络。此外，通过合成miRNA拮抗剂靶向成瘾相关的miRNA可能会开发出一种新的、高度特异性的成瘾治疗方法。

DESCRIPTION (provided by applicant): Understanding of the molecular mechanisms of drug addiction is essential for the development of novel approaches for the treatment of this debilitating disease. Recent findings showed that development of addictive behavior in mice is associated with stable changes in gene expression. The genetic basis of addiction raises the question about the nature of genes and their regulators that play a critical role in addiction. We found that establishment of cocaine addiction in mice is associated with expression changes of numerous miRNAs in the striatum, a brain area responsible for drug addiction. Given the potent role of miRNAs in regulation of gene expression, we hypothesize that cocaine regulated miRNAs contribute to the establishment of the gene expression network that supports addiction. To evaluate the contribution of cocaine induced miRNAs to the development and maintenance of cocaine addiction we propose to address the impact of striatum specific alteration of individual miRNAs on addiction. The two most well defined symptoms of addiction in mice such as cocaine induced sensitization and reward will be used to address the role of miRNA on animal behavior. We will test whether correction of miRNA levels affected by chronic cocaine treatment affects the development of addictive behavior in vivo. Inactivation of miRNA that are induced by cocaine treatment will be achieved by injection of the RNA based cell-permeable specific miRNA inhibitors into the striatum. In turn, striatum specific normalization of miRNA that are suppressed by cocaine will be achieved by using miRNA expressing adenoassociated virus (AAV). Identification of specific miRNAs that play a role in the development and maintenance of cocaine addiction may help to reveal molecular networks controlling dopamine signaling in health and disease. Furthermore, targeting of the addiction-associated miRNAs by synthetic miRNA antagonists may lead to development of novel and highly specific approach for treatment of addiction. PUBLIC HEALTH RELEVANCE: The widespread and sociomedical impact of drug addiction dictates the necessity to develop efficient and selective drugs for the treatment of this harmful disease. In our studies we propose to explore the possibility of selective correction of gene function for the purpose of anti-addictive therapy. We found that the development of addiction is associated with aberrant expression of miRNAs, a novel class of highly potent and equally selective regulators of gene expression. We will test whether normalization of the miRNA expression, altered by cocaine treatment, will normalize brain function and cure addiction.