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

描述（由申请人提供）：成瘾的初始易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，在发育期间和药物暴露时。需要动物模型来分析这些变量并发现成瘾的神经机制。该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使用了两种有选择地培育的大鼠，以寻求新奇的特性（HR vs. LR）来预测对药物的易感性。这些老鼠将被暴露在可卡因中，随后是不同时期的禁欲，并在有或没有社会压力的情况下进行测试。可卡因对神经重塑的广泛影响将通过评估相关脑回路中一组神经可塑性基因的表达和测量海马神经发生来确定。选择的靶基因将进一步表征。项目2研究可卡因暴露对hr和lr大鼠的神经影响，并询问先前的药物暴露是否会阻碍个体从随后的积极体验（丰富的环境）中获益的能力。这将通过树突形态、神经发生和基因表达进行索引。项目3询问在控制和压力条件下，增强海马神经发生的操作是否可以防止对可卡因的易感性，以及这种保护作用在不同遗传背景的动物中是否可能不同。项目4研究应激相关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。采用两种相关的小鼠转基因模型——组成型GR过表达者和诱导型GR过表达者来确定对药物敏感性影响最大的发育关键时期。这项工作将为不同药物滥用倾向个体的成瘾诱导脑重塑提供更好的分子理解。这应该会导致新的、更合适的药物靶点来治疗成瘾性药物的早期影响，或者逆转它们可能引发复发的持续影响。

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