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

来路

基本信息

批准号：
8101236
负责人：
HUDA AKIL
金额：
$ 124.1万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-25 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8101236
关键词：
Antecedents Consequences Drug Abuse Heritability

项目摘要

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

描述（由申请人提供）：对成瘾的最初易感性及其对大脑和行为的影响可能取决于发育过程中和药物暴露时基因和环境的相互作用。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，这些项目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——吸毒的最初易感性、吸毒的维持以及导致渴望和吸毒的长期后果。复发。项目 1 使用了两个品系的老鼠，这些老鼠是为了寻求新奇特征（HR 与 LR）而选择性培育的，这种特征可以预测对吸毒的易感性。这些老鼠将接触可卡因，然后进行不同时期的禁欲，并在有或没有社会压力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相关大脑回路中一组神经可塑性基因的表达并测量海马神经发生来索引。选定的靶基因将被进一步表征。项目 2 研究了 HR 繁殖和 LR 繁殖的大鼠中接触可卡因的神经影响，并询问先前接触药物是否会阻碍个体从随后的积极经历（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来索引。项目 3 询问增强海马神经发生的操作是否可以在受控和应激条件下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 询问应激相关基因糖皮质激素受体 (GR) 表达的增加是否会增加对可卡因的易感性。它使用两种相关的小鼠转基因模型 - 组成型 GR 过表达蛋白和诱导型 GR 过表达蛋白来确定对药物敏感性影响最大的发育关键时期。这项工作将为具有不同药物滥用倾向的个体中成瘾引起的大脑重塑提供更好的分子理解。这应该会产生新的、更适合的药物靶标，用于治疗成瘾药物的早期影响或扭转其可能引发复发的持续影响。项目特点

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

High novelty-seeking predicts aggression and gene expression differences within defined serotonergic cell groups.

高度的新奇寻求预示着特定血清素能细胞群内的攻击性和基因表达差异。

DOI：
发表时间：
2011-10-24
期刊：
影响因子：
2.9
作者：
Kerman, Ilan A;Clinton, Sarah M;Bedrosian, Tracy A;Abraham, Antony D;Rosenthal, Devin T;Akil, Huda;Watson, Stanley J
通讯作者：
Watson, Stanley J

Pattern of forebrain activation in high novelty-seeking rats following aggressive encounter.

攻击性遭遇后高度寻求新奇的老鼠的前脑激活模式。

DOI：
发表时间：
2011-11-08
期刊：
影响因子：
2.9
作者：
Clinton, Sarah M;Kerman, Ilan A;Orr, Hailey R;Bedrosian, Tracy A;Abraham, Antony D;Simpson, Danielle N;Watson, Stanley J;Akil, Huda
通讯作者：
Akil, Huda

Medicine. The future of psychiatric research: genomes and neural circuits.

药品。

DOI：
发表时间：
2010-03-26
期刊：
影响因子：
0
作者：
Akil, Huda;Brenner, Sydney;Kandel, Eric;Kendler, Kenneth S;King, Mary;Scolnick, Edward;Watson, James D;Zoghbi, Huda Y
通讯作者：
Zoghbi, Huda Y

GSearcher: agile attribute querying for biological networks.

GSearcher：生物网络的敏捷属性查询。