Antecedents & Consequences of Drug Abuse: Heritability, Stress & Neurplasticity

描述(由申请人提供)：最初对成瘾的敏感性及其对大脑和行为的影响可能取决于基因和环境的相互作用，在发育过程中和接触药物时。需要动物模型来分析这些变量，并发现成瘾的神经机制。这一应用程序由四个高度集成的项目组成，它们围绕着一个中心假设，即神经可塑性机制是成瘾所有阶段的关键决定因素--对吸毒的初始敏感性、其维持以及导致渴望和复发的长期后果。项目1使用了两个品系的大鼠，这些品系是有选择地培育出来的，是为了寻找新奇的特征(HR与LR)，这种特征预测了对药物的敏感性。这些大鼠将暴露在可卡因中，然后进行不同时期的禁欲，并在有或没有社会应激源的情况下进行测试。可卡因对神经重塑的广泛影响将通过评估一组神经可塑性基因在相关大脑回路中的表达和测量海马神经发生来指标化。选定的目标基因将被进一步鉴定。项目2研究了接触可卡因对HR系和LR系大鼠的神经影响，并询问先前接触可卡因是否会阻碍个体从随后的积极经历中获益的能力(丰富的环境)。这将通过树突形态、神经发生和基因表达来索引。项目3询问，在控制和应激条件下，增强海马神经发生的手法是否可以防止对可卡因的敏感性，以及这种保护效果在不同遗传背景的动物中是否会有所不同。项目4询问与压力相关的基因糖皮质激素受体(GR)的表达增加是否会增加对可卡因的易感性。它使用两个相关的小鼠转基因模型-结构性GR过度表达和可诱导GR过度表达来确定对药物敏感性影响最大的发育关键期。这项工作将为不同药物滥用倾向的人提供更好的成瘾诱导的脑重构的分子理解。这将导致新的、更好地量身定做的药物靶点，用于治疗成瘾药物的早期影响或逆转其可能引发复发的持久影响。 节目特点

DESCRIPTION (provided by applicant): Both the initial susceptibility to addiction and its consequences on brain and behavior likely depend on the interaction of genes and environment, during development and at the time of drug exposure. Animal models are needed to analyze these variables and discover the neural mechanisms of addiction. This application consists of four highly integrated projects that revolve around the central hypothesis that mechanisms of neural plasticity are key determinants of all phases of addiction--the initial susceptibility to drug-taking, its maintenance and the long-term consequences that lead to craving and relapse. Project 1 uses two lines of rats selectively bred for the novelty-seeking trait (HR vs. LR) that predicts susceptibility to drug-taking. These rats will be exposed to cocaine, followed by various periods of abstinence, and tested with or without a social stressor. Cocaine's broad impact on neural remodeling will be indexed by assessing expression of a panel of neuroplasticity genes in relevant brain circuits, and measuring hippocampal neurogenesis. Selected target genes will be further characterized. Project 2 studies the neural impact of cocaine exposure in HR-bred and LR-bred rats and asks whether prior exposure to the drug occludes the ability of the individual to profit from subsequent positive experience (enriched environment). This will be indexed by dendritic morphology, neurogenesis and gene expression. Project 3 asks whether a manipulation that enhances hippocampal neurogenesis can protect against susceptibility to cocaine under control and stressful conditions, and whether this protective effect may be different in animals with different genetic backgrounds. Project 4 asks whether increased expression of a stress-related gene, the glucocorticoid receptor (GR) increases susceptibility to cocaine. It uses two related mouse transgenic models -a constitutive GR overexpressor and an inducible GR overexpressor to determine critical periods in development with the greatest impact on drug susceptibility. This work will provide a better molecular understanding of addiction-induced brain remodeling in individuals with different propensities for drug abuse. This should lead to novel, better-tailored drug targets for treating the early impact of addictive drugs or reversing their persistent effects that can trigger relapse. PROGRAM CHARACTERISTICS