Project 2: Acute Cocaine Sensitivity and Chronic Sensitization

项目2 -可卡因敏感性和致敏作用 成瘾是一种慢性复发性疾病，开始于最初的接触，随后逐渐升级， 不受控制地使用药物。然而，并不是每个接触毒品的人都会上瘾。在 人类，对精神兴奋剂的初始敏感性已被证明可以预测随后的慢性药物使用， 重复使用后的神经适应被认为有助于药物渴望和复发的风险。急性 对精神兴奋剂运动激活和慢性运动敏感化已经发展为动物 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已经被 部分原因是遗传差异。然而，识别特定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小鼠种群， 研究复杂性状，协作杂交（CC）和多样性异交（DO）。这些人群有 增加遗传和表型变异性和重组，从而导致更精确的作图。使用 结合行为表型和基因表达分析，CC和DO将用于识别 基因和基因网络，有助于急性运动敏感性和 致敏将进一步表征表现出极端表型的CC品系，以确定是否 药代动力学变化是行为差异的原因，或者可卡因敏感性是否与 树突棘密度在丘脑核。CSNA汇集了一组科学家， 在成瘾相关行为的各个方面的专业知识，和一个共同的目标-确定潜在的 成瘾相关表型的遗传学，并推进我们对共同遗传病因学的理解， 是成瘾的特殊过程的基础利用一个综合实验平台，我们将能够发现 初始药物反应、致敏作用、神经适应和 成瘾相关行为。

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.