PSYCHOSTIMULANT REWARD AND SENSITIZATION

精神刺激性药物会上瘾，即使在长期戒毒后也会复发， 可能性很大。精神刺激性药物的行为和神经化学反应 与药物暴露的数量一致被认为在成瘾和复发方面起着重要作用。一把钥匙 科学成分6的假说是看似不同的中枢神经系统改变 与上瘾相关的两种方式是相互协调的，这些方式很难通过单独研究每种方式来定义。 动物核心组件3将开发两组选择性繁殖的小鼠，并用于帮助 确定影响甲基苯丙胺(MA)自我给药的基因和基因组合 神经适应。在具体目标1中，敏化和自我管理之间的遗传关系将 在为增加和降低对运动敏感化(A)敏感性而培育的小鼠品系中进行检查 神经适应措施)，由MA产生，并在为高和低口服MA自我给药而培育的不同品系中； 来自Science Component 5的可操作的颅内MA自我管理模型将是 用于验证口服自我给药模型。在特定的目标2中，将执行全基因组扫描以 确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)相互作用提供了对可能影响 这些复杂的特征。在特定的目标3中，将检查大脑中的基因表达模式 使用微阵列方法对来自特定神经解剖位置的组织进行选择，以获得全局 图中哪些基因表达的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Pilot 8A通知。最后，在具体目标4中，其他特征 可能与选择性状相关的基因将在选定的品系中进行检测。为 例如，对应激诱导的MA诱导的条件性位置偏爱的恢复的敏感性将是 审查；将使用延迟贴现程序评估冲动方面的可能差异； 将与组件5合作检查神经化学相关性。临床前遗传学 调查结果将被翻译给我们的临床研究人员。神经解剖通路的共同含义 跨科学组成部分的发现可能导致识别协调的路径， 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.