From drug Use to Addiction: Unearthing the Switches

描述（由申请人提供）：药物成瘾神经生物学的一个关键问题是什么变化是负责从非依赖性药物使用到成瘾的过渡。新研究者的当前提议的目标是开始探索负责药物升级的神经生物学机制，并定义负责介导从药物使用到成瘾的变化的分子机制。为了实现这一目标，我们将测试以下假设：1）充分暴露于海洛因和可卡因导致扩展杏仁核的特定元素发生变化，从而产生快感设定点的升高，进而导致药物摄入量的进行性升高。一个亚假设是，这种向药物升级的转变的神经生物学基础反映了药物成瘾的发展; 2）这些神经生物学变化涉及翻译和翻译后水平的细胞效应，这些细胞效应改变了蛋白质表达水平和功能; 3）向成瘾的转变不是由于一个离散的神经化学变化而发生的; 4）这些变化代表了从吸毒过渡到成瘾的“开关”，即使是不同类别的滥用药物也是相似的。为了验证这些假设，我们提出了以下具体目的的研究：1）比较和对比与过量海洛因摄入相关的蛋白质表达和修饰的变化与可卡因摄入量增加相关的蛋白质表达和修饰的变化; 2）确定海洛因和可卡因摄入量增加过程中蛋白质表达和修饰变化的时间过程;和3）确定与戒断和再次暴露于海洛因或可卡因后复发相关的蛋白质表达和修饰的持续变化。我们提出的结合尖端的行为，神经解剖学和蛋白质组学的方法将允许识别的重要分子底物的过渡，从休闲吸毒成瘾。希望这些发现最终能改善这些毁灭性疾病的治疗方法。

DESCRIPTION (provided by applicant): A critical issue for the neurobiology of drug addiction is what changes are responsible for the transition from non-dependent drug use to addiction. The goal of the present proposal from a new investigator is to begin to explore the neurobiological mechanisms responsible for drug escalation and define the molecular mechanisms responsible for mediating the change from drug use to addiction. To achieve this goal, we will test the following hypotheses: 1) Sufficient exposure to heroin and cocaine leads to changes in specific elements of the extended amygdala to produce elevations in hedonic set point that in turn leads to progressive elevation in drug intake. A subhypothesis is that the neurobiological basis of this transition to drug escalation reflects the development of drug addiction; 2) These neurobiological changes involve cellular effects at the translational and post translational levels that alter protein expression levels and function; 3) The transition to addiction does not occur as a result of one discrete neurochemical change; rather, a series of layered changes developing over the course of the drug escalation process; and 4) These changes represent the "switches" responsible for the transition from drug use to addiction, and are similar even for different classes of abused drugs. To test these hypotheses, we propose studies with the following Specific Aims: 1) To compare and contrast changes in protein expression and modification associated with excessive levels of heroin intake with those associated with escalated cocaine intake; 2) To define the time course of changes in protein expression and modification during the development of heroin and cocaine escalation; and 3) To define persistent changes in protein expression and modification associated with abstinence and with relapse upon re-exposure to heroin or cocaine. Our proposed combination of cutting-edge behavioral, neuroanatomical, and proteomic approaches will permit the identification of important molecular substrates of the transition from casual drug use to addiction. It is hoped that these findings will eventually lead to improved treatments for these devastating conditions.