Kalirin-7 is essential in cocaine signaling: focus on nucleus accumbens

描述（由申请人提供）：吸毒成瘾是当今社会危害公众健康的一个主要因素，对使用非法药物的人及其家庭产生终身影响。滥用毒品最令人烦恼的问题之一是，即使经过适当的治疗，成瘾者也有很大的复吸倾向。在动物模型中，长期服药后最一致的发现之一是大脑特定区域的树突棘数量增加。即使在长期撤军之后，这些结构性变化仍然存在。在我们的实验室里，我们研究一种蛋白质，Kalirin-7，它与树突棘的形成和维持有关。我们的假设是，这种树突棘的增加在药物滥用的长期影响中起着重要作用，而加里林-7在结构变化中起着重要作用。我们将使用卡利林-7 （Kal7KO）基因缺陷的小鼠来确定它们对可卡因的行为或生化反应是否与野生型小鼠不同。初步研究表明，Kal7KO小鼠对可卡因的运动致敏作用超敏感，但对可卡因的位置偏好降低。我们现在正试图通过结合可卡因的位置偏好和受体拮抗剂的联合施用来阐明Kalirin-7调节的特定途径（目的1）。有趣的是，当使用增加Wt动物伏隔核树突棘的可卡因剂量方案时，Kal7KO动物没有表现出树突棘的增加。下一步，我们将使用由多巴胺1受体启动子驱动的表达GFP的小鼠来检测Kal7在纹状体神经元特定亚群中的表达和形态学影响（目的2）。纹状体中不同的神经元群在成瘾过程中起着不同的作用，了解它们的功能对理解成瘾至关重要。此外，我们最近发现Kal7KO动物改变了NMDA受体NR2B亚基的表面转运。NMDA受体的正常功能对于学习和记忆的正常可塑性至关重要，而NMDA受体功能的改变在药物成瘾的发展中起着重要作用。利用细胞培养模型和可卡因处理动物的组织，我们现在正在研究Kalirin-7和NR2B之间的特定相互作用，以及Kalirin-7如何改变这一关键受体的定位和运输（目的3）。当这些研究完成后，我们希望能够极大地扩展对神经元形态改变和受体运输在药物成瘾病理生理中所起作用的认识。

DESCRIPTION (provided by applicant): Drug addiction is a major detriment to public health in today's society, with lifelong effects on people who use illicit drugs and their families. One of the most vexing problems with drugs of abuse is that addicts have a tremendous propensity to relapse, even with proper treatment. In animal models, one of the most consistent findings after prolonged drug administration is an increase in the number of dendritic spines in specific regions of the brain. These structural changes remain even after long periods of withdrawal. In our lab, we work on a protein, Kalirin-7, that has been implicated in the formation and maintenance of dendritic spines. It is our hypothesis that this increase in dendritic spines plays a role in the long-term effects of drug abuse, and that Kalirin-7 is an essential player in the structural changes. We will be using a line of mice genetically deficient in Kalirin-7 (Kal7KO) to determine if their behavioral or biochemical response to cocaine is different from that of wildtype mice. Initial studies have shown that the Kal7KO mice are hypersensitive to the locomotor sensitization effects of cocaine, yet show decreased place preference for cocaine. We are now trying to clarify the specific pathways that Kalirin-7 modulates by combining place preference for cocaine with co-administration of receptor antagonists (Aim 1). Interestingly, when using a cocaine dosing regimen that increases dendritic spines in the nucleus accumbens of Wt animals, Kal7KO animals do not show an increase in dendritic spines. Moving forward, we will be using mice expressing GFP driven by the dopamine 1 receptor promoter to examine the expression and morphological effect of Kal7 in specific subsets of striatal neurons (Aim 2). The different populations of neurons in the striatum play different roles in the addiction process, and understanding of their function is critical for the understanding of addiction. Additionally, we have recently discovered that Kal7KO animals have altered surface trafficking of the NR2B subunit of NMDA receptors. Proper function of NMDA receptors is essential for the normal plasticity underlying learning and memory, and altered NMDA receptor function has been shown to play a role in the development of drug addiction. Using both cell culture models and tissue from cocaine treated animals we are now investigating the specific interaction between Kalirin-7 and NR2B, and how Kalirin-7 alters the localization and trafficking of this critical receptor (Aim 3). When these studies are finished, we hope to have greatly expanded the knowledge of the roles that alterations in neuronal morphology and receptor trafficking play in the pathophysiology of drug addiction.