From drug Use to Addiction: Unearthing the Switches

描述(由申请人提供)：对于药物成瘾的神经生物学来说，一个关键的问题是什么变化导致了从非依赖药物使用到成瘾的转变。由一位新的研究人员提出的这项提案的目标是开始探索导致药物升级的神经生物学机制，并确定负责调节从药物使用到成瘾转变的分子机制。为了实现这一目标，我们将检验以下假设：1)足够的海洛因和可卡因暴露会导致杏仁核延伸部分的特定元素发生变化，从而产生享乐设定点的升高，进而导致药物摄入量的进行性增加。一种假设是，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上的细胞效应，改变了蛋白质的表达水平和功能；3)向成瘾的转变不是作为一个离散的神经化学变化的结果；相反，是在药物升级过程中发展的一系列分层变化；以及4)这些变化代表着负责从使用药物向成瘾转变的“开关”，即使是对不同类别的滥用药物也是相似的。为了验证这些假说，我们建议进行以下特定目标的研究：1)比较与海洛因摄入量过高和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升级过程中蛋白质表达和修饰变化的时间进程；以及3)确定与戒断和再次接触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。我们提出的尖端行为学、神经解剖学和蛋白质组学方法的组合将允许识别从偶尔吸毒到成瘾转变的重要分子底物。人们希望，这些发现最终将导致改善对这些毁灭性疾病的治疗。

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.