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。这些系统及其联系具有显著的可塑性，在一生中都在发生变化。反复接触兴奋剂药物，如安非他命，会导致多巴胺系统的变化，从而导致对这些药物和其他激活多巴胺系统的生活事件的敏感性长期增加。我的研究项目的总体目标是确定成年后多巴胺功能和行为敏感性变化的机制，使个体在随后的药物或压力源暴露中更容易（或更少）受到伤害。为此，我将研究安非他明如何在成人大脑中引起这种变化。识别这些过程将对我们理解“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变化的持久性表明，在发育过程中，通过重新激活通常参与组织神经元线路的因素，神经回路进行了重组。Netrin-1是一种蛋白质，在发育过程中神经元连接的组织中起着重要作用，我们最近发现，在成人大脑中，Netrin-1受体在多巴胺神经元中高度表达，并且它们的表达受反复暴露于安非他明的调节。这项研究计划现在旨在确定netrin-1受体功能的变化在安非他明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.