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

大脑的多巴胺系统涉及认知、运动活动、动机和奖励。这些系统和它们之间的连接是非常可塑的，在整个生命过程中都会发生变化。反复暴露于兴奋剂药物，如安非他明，导致多巴胺系统的变化，导致对这些药物的影响以及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标是确定在成年期引起多巴胺功能和行为敏感性变化的机制，使个体更容易（或更少）受到随后暴露于药物或压力源的影响。为此，我将研究安非他明如何在成人大脑中引起这种变化。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。成年人大脑中多巴胺系统变化的持久性表明，在发育过程中，通常参与组织神经元布线的因素被重新激活，从而导致了电路的重组。Netrin-1是一种在发育过程中神经元连接的组织中起着重要作用的蛋白质，我们最近发现Netrin-1受体在成人大脑中的多巴胺神经元中高度表达，并且它们的表达受到反复暴露于安非他明的调节。这项研究计划的目的是确定netrin-1受体功能的变化在成人安非他明诱导的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.