Role of Translin/Trax in Dopamine Signaling

项目概要-巴拉班 确定更有效的预防和治疗吸毒成瘾的战略至关重要， 依赖于破译介导和调节行为的信号通路的进展， 滥用药物的影响。最近的研究表明，microRNA系统在 这个过程然而，我们才刚刚开始了解它对神经元信号的影响。近几 研究中，我们发现translin/trax RNase复合物介导了一个子集的降解， microRNAs。因此，为了进一步了解microRNA系统在 多巴胺信号，我们已经检查了translin基因敲除小鼠是否表现出改变的行为反应， 可卡因。 我们发现，可卡因增加自发活动的能力在这些 小鼠此外，微透析研究表明，可卡因能够提高细胞核中的DA， 在translin KO小鼠中，β-淀粉样蛋白变钝。此外，快速扫描循环伏安法研究表明， translin缺失阻断可卡因增强DA诱发释放的能力，而不干扰其 阻断多巴胺转运体的能力由于最近的研究把注意力集中在穷人身上， 可卡因增强诱发的DA释放的能力被认为在介导其 加强性能，我们计划进行研究，旨在了解如何translin删除损害 这种效果。特别是，我们将评估这种表型是否是：1）由于translin/trax RNA酶的丢失， 活动，和2）由于损失translin从DA神经元。此外，我们将使用自我管理 测定以评估translin缺失是否损害可卡因的增强性质。

Project Summary - Baraban Identification of more effective strategies to prevent and treat drug addiction is critically dependent on advances in deciphering the signaling pathways that mediate and regulate the behavioral effects of drugs of abuse. Recent studies indicate that the microRNA system plays a prominent role in this process. However, we are only beginning to understand its impact on neuronal signaling. In recent studies, we have found that the translin/trax RNase complex mediates degradation of a subset of microRNAs. Accordingly, to advance our understanding of the role of the microRNA system in dopamine signaling, we have checked whether translin KO mice display altered behavioral responses to cocaine. We have found that the ability of cocaine to increase locomotor activity is impaired in these mice. Furthermore, microdialysis studies revealed that cocaine's ability to elevate DA in the nucleus accumens is blunted in translin KO mice. In addition, fast scan cyclic voltammetry studies indicate that translin deletion blocks cocaine's ability to potentiate evoked release of DA without interfering with its ability to block the dopamine transporter. As recent studies have focused attention on the poorly understood ability of cocaine to potentiate evoked DA release as playing a key role in mediating its reinforcing properties, we plan to conduct studies aimed at understanding how translin deletion impairs this effect. In particular, we will assess whether this phenotype is: 1) due to loss of translin/trax RNase activity, and 2) due to loss of translin from DA neurons. Furthermore, we will use self-administration assays to assess whether translin deletion impairs the reinforcing properties of cocaine.