Project 2: Acute Cocaine Sensitivity and Chronic Sensitization

项目摘要项目2--可卡因敏感度和敏感度 上瘾是一种慢性、复发性疾病，从最初的接触开始，然后逐渐升级和 无节制地使用这种药物。然而，并不是每个接触毒品的人都会上瘾。在……里面 人类，最初对精神刺激剂的敏感性已被证明可以预测随后的慢性药物使用，以及 反复使用后的神经适应被认为是导致药物渴求和复发风险的原因之一。急性 运动激活和对精神刺激物的慢性运动敏化已发展为动物 初始敏感性和神经适应性变化的模型。这些行为的个体差异一直是 有证据表明，部分原因是遗传差异。然而，识别特定的基因一直是一个挑战。 使用现有的动物模型。该项目利用了两个新的老鼠种群，这两个种群被设计成 研究复杂性状，合作杂交(CC)和多样性异交(DO)。这些人口有 增加了遗传和表型的可变性和重组，从而导致更精确的地图绘制。使用 结合行为表型和基因表达分析，CC和DO将被用来识别 导致急性运动敏感度和表型变异的基因和基因网络 敏化。将对表现极端表型的CC品系进行进一步鉴定，以确定 药动学差异是行为差异的原因，或者可卡因敏感性是否相关 伏隔核内有树突密度。CSNA汇集了一组科学家和 在与成瘾有关的行为的各个方面的专业知识，以及一个共同的目标-识别潜在的 成瘾相关表型的遗传学和促进我们对共同的遗传病因的理解 说明了上瘾的具体过程。使用一个综合的实验平台，我们将能够发现 药物初始反应、敏化、神经适应与免疫功能关系的生物学基础 与上瘾有关的行为。

PROJECT SUMMARY PROJECT 2 – COCAINE SENSITIVITY AND SENSITIZATION Addiction is a chronic, relapsing disease that begins with initial exposure, followed by escalating and uncontrolled use of the drug. However, not every individual who is exposed to drugs will develop addiction. In humans, initial sensitivity to psychostimulants has been shown to predict subsequent chronic drug use, and neuroadaptations following repeated use are thought to contribute to drug craving and risk of relapse. Acute locomotor activation and chronic locomotor sensitization to psychostimulants have been developed as animal models of initial sensitivity and neuroadaptive changes. Individual differences in these behaviors have been shown to be due, in part, to genetic differences. However, identifying specific genes has been a challenge using existing animal models. This Project utilizes two new mouse populations that have been designed to study complex traits, the Collaborative Cross (CC) and Diversity Outcross (DO). These populations have increased genetic and phenotypic variability and recombination that results in more precise mapping. Using a combination of behavioral phenotyping and gene expression analysis, the CC and DO will be used to identify genes and gene networks that contribute to phenotypic variation for both acute locomotor sensitivity and sensitization. CC lines that exhibit extreme phenotypes will be further characterized to determine whether pharmacokinetic variation is responsible for behavioral differences, or whether cocaine sensitivity correlates with dendritic spine density in the nucleus accumbens. The CSNA brings together a team of scientists with expertise in various aspects of addiction-related behavior, and a common goal – identifying the underlying genetics of addiction-related phenotypes and advancing our understanding of the shared genetic etiology that underlies specific processes of addiction. Using an integrative experimental platform we will be able to uncover the biological basis of the relationship between initial drug response, sensitization, neuroadaptation and addiction related behaviors.