Mechanisms underlaying drug-induced behavioral sensitization in the adult brain: possible role of guidance cues

大脑中的多巴胺系统与认知、运动活动、动机和奖励有关。这些系统和它们的连接是非常可塑性的，在一生中都在经历变化。反复接触兴奋剂，如苯丙胺，会导致多巴胺系统的变化，导致对这些药物的影响以及对激活多巴胺系统的其他生活事件的敏感性长期增加。我的研究项目的总体目的是确定导致成年后多巴胺功能和行为的敏感性发生变化的机制，使个人更容易(或更不容易)随后接触药物或应激源。为此，我将研究安非他明如何在成人大脑中引起这种变化。对这些过程的识别将对我们理解“经验”如何改变多巴胺回路，进而改变多巴胺介导的行为具有重要意义。成人大脑中多巴胺系统的持久变化表明，在发育过程中，通常参与组织神经元连接的因素重新激活了电路。Netrin-1是一种在发育过程中对神经元连接的组织起重要作用的蛋白质，我们最近的研究表明，Netrin-1受体由成年大脑中的多巴胺神经元高度表达，并且其表达受反复暴露于苯丙胺的调节。这项研究计划现在的目的是确定观察到的netrin-1受体功能的变化在苯丙胺诱导的成人多巴胺可塑性中所起的确切作用。

The dopamine systems of the brain are involved in cognition, motor activity, motivation and reward. These systems and their connections are remarkably plastic, undergoing changes throughout life. Repeated exposure to stimulant drugs, such as amphetamine, results in changes in dopamine systems resulting in long-lasting increases in sensitivity to the effects that these drugs, and to other life events that activate the dopamine systems. The general aim of my research project is to identify mechanisms that bring about changes in sensitivity in dopamine function and behavior in adulthood, rendering individuals more (or less) vulnerable to subsequent exposure to drugs or to stressors. To this end I will study how amphetamine induces such changes in the adult brain. Identification of these processes will have important implications for our understanding of how 'experience' can alter dopamine circuitry and, in turn, dopamine-mediated behaviors. The enduring nature of changes in the dopamine system in the adult brain suggests reorganization of the circuitry by re-activation of factors that are normally involved in organizing neuronal wiring during development. Netrin-1 is a protein that plays a fundamental role in the organization of neuronal connectivity during development and we have recently shown that netrin-1 receptors are highly expressed by dopamine neurons in the adult brain and that their expression is regulated by repeated exposure to amphetamine. This research proposal is now aimed at identifying the precise role that the changes in netrin-1 receptor function observed play in amphetamine-induced dopamine plasticity in the adult.