PSYCHOSTIMULANT REWARD AND SENSITIZATION

精神兴奋剂药物会使人上瘾，即使在长时间戒断后， 很有可能对精神兴奋剂药物的行为和神经化学反应， 与药物暴露量一致被认为在成瘾和复吸中起重要作用。一个关键 科学成分6的假设是，看似不同的中枢神经系统改变 与成瘾相关的各种因素的协调方式很难通过孤立地研究每一种因素来定义。 动物核心组件3将开发两组选择性繁殖的小鼠，用于帮助 鉴定影响甲基苯丙胺（MA）自我给药的基因和基因组合， 神经适应在具体目标1中，致敏和自我给药之间的遗传关系将 在为增加和减少对运动致敏的敏感性而饲养的小鼠品系中进行检查（a 神经适应的测量），以及在为高和低口服MA自我给药而繁殖的单独品系中; 科学组件5的操作性颅内MA自我给药模型将是 用于验证口服自我给药模型。在特定目标2中，将进行全基因组扫描， 鉴定影响每个所选性状的遗传基因座。此外，还将对数据进行搜索， 上位性（基因-基因）相互作用提供了重要的见解遗传相互作用，可能影响 这些复杂的特征。在具体目标3中，将在受试者的大脑中检查基因表达模式。 使用微阵列方法在来自特定神经解剖位置的组织上选择线，以获得全局 什么样的基因表达差异可能与药物敏感性的差异有关。 神经解剖位置将由组件5和飞行员8A通知。最后，在具体目标4中，其他特征 将在所选品系中检查可能与选择性状遗传相关的性状。为 例如，对压力诱导的MA诱导的条件性位置偏好的恢复的敏感性将是 检查;冲动性的可能差异将使用延迟折扣程序进行评估; 神经化学相关性将与组件5合作进行检查。临床前遗传学 我们将把结果翻译给我们的临床研究人员。神经解剖通路的共同含义 在科学组件中发现的信息可以识别协调的途径， 影响成瘾。

Psychostimulant drugs are addictive, and relapse to drug taking, even after prolonged periods of abstinence, is highly probable. The behavioral and neurochemical responses to psychostimulant drugs that change in concert with amount of drug exposure are thought to play an important role in addiction and relapse. A key hypothesis of Scientific Component 6 is that the seemingly diverse central nervous system alterations associated with addiction are coordinated in ways that are difficult to define by studying each in isolation. Two sets of selectively bred mice will be developed by the Animal Core Component 3 and used to help identify the genes and combinations of genes that influence methamphetamine (MA) self-administration and neuroadaptation. In Specific Aim 1, the genetic relationship between sensitization and self-administration will be examined in lines of mice bred for increased and reduced sensitivity to locomotor sensitization (a measure of neuroadaptation) produced by MA, and in separate lines bred for high and low oral MA self-administration; the operant intracranial MA self-administration model from Scientific Component 5 will be used to validate the oral self-administration model. In Specific Aim 2, full genome scans will be performed to identify genetic loci influencing each of the selected traits. In addition, data will be subjected to a search for epistatic (gene-gene) interactions to provide important insights into the genetic interplay that likely influences these complex traits. In Specific Aim 3, gene expression patterns will be examined in the brains of the selected lines using microarray methods on tissue from specific neuroanatomical locations to get a global picture of what gene expression differences may be associated with the differences in drug sensitivity. Neuroanatomic locations will be informed by Component 5 & pilot 8A. Finally, in Specific Aim 4, other traits that may be genetically correlated with the selection traits will be examined in the selected lines. For example, sensitivity to stress-induced reinstatement of MA-induced conditioned place preference will be examined; possible differences in impulsivity will be assessed using the Delay Discounting Procedure; neurochemical correlates will be examined in collaboration with Component 5. The preclinical genetic findings will be translated to our clinical investigators. Common implication of neuroanatomical pathways found across the Scientific Components could lead to the identification of coordinated pathways that influence addiction.