A Molecular Analysis of the Gateway Hypothesis in Mice

小鼠网关假说的分子分析

• 批准号: 7350792
• 负责人: DENISE B KANDEL
• 金额: $ 52.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7350792
• 关键词: Acetylation; Addictive Behavior; Address; Adolescence; Adolescent; Adult; Adverse event; Age; Age of Onset; Alcohols; Amygdaloid structure; Animal Model; Animals; Behavior; Behavioral; Biological; Biological Assay; Brain; Brain region; CREB-binding protein; CREB1 gene; Candidate Disease Gene; Cannabis; Cell Nucleus; Cell surface; Chromatin Structure; Chronic; Cigarette; Class; Cocaine; Corpus striatum structure; Data; Data Set; Development; Drug Addiction; Drug Experimentation; Drug Exposure; Drug abuse; Drug usage; Employee Strikes; Epidemiologic Studies; Epidemiology; Etiology; Experimental Designs; Exposure to; FOS gene; Gene Chips; Gene Expression; Gene Proteins; Gene-Modified; Genes; Genetic Transcription; Goals; Health; Histone Acetylation; Human; Illicit Drugs; Immediate-Early Genes; Individual; Lateral; Legal; Life; Logic; Maintenance; Marijuana; Mediating; Memory; Messenger RNA; Modeling; Modification; Molecular; Molecular Analysis; Molecular Target; Morphine; Mus; Nature; Nicotine; Nuclear; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Pilot Projects; Population; Process; Protein Isoforms; Public Health; Recruitment Activity; Research; Risk; Risk Factors; Rodent; Running; Signal Transduction Pathway; Smoke; Smoking; Staging; Study Section; Substance Abuse, Other; Substance abuse problem; Surveys; System; Testing; Tobacco; Transcriptional Activation; addiction; base; chromatin immunoprecipitation; design; drug of abuse; experience; genetic analysis; histone acetyltransferase; human CREBBP protein; insight; long term memory; mouse model; prevent; programs; promoter; psychologic; research study; response; social

DESCRIPTION (provided by applicant): The overall goal of the research is to test an epidemiological hypothesis, the Gateway Hypothesis, in molecular terms. The hypothesis describes the sequence of steps whereby use of one class of drug, e.g. cigarettes (nicotine), precedes the use of other drugs, such as cocaine. We propose to test the Gateway Hypothesis at the molecular level using a mouse model. Our approach is further based on the evidence that addiction shares molecular steps and molecular logic with long-term memory. We will address four specific aims: (1) To determine on a behavioral and transcriptional level whether there is the sequential order between nicotine and cocaine predicted by the Gateway Hypothesis, whether this sequence is unidirectional (from nicotine to cocaine) or bidirectional (from cocaine to nicotine), and whether nicotine can also enhance the response to drugs of abuse other that cocaine, such as morphine. (2) To determine the molecular mechanisms by which nicotine primes an animal to the effects of cocaine, we propose to use gene-chip analysis to selected target regions to survey patterns of mRNA in the striatum, particularly the nucleus accumbens, and the amygdala. We will use pharmacological analysis to dissect any possible signal transduction pathway that may mediate the priming effects, and genetically modified mice to explore some of the selected candidate genes emerging from the screen. (3) To identify molecular mechanisms that might contribute to maintaining the gateway effect, we will examine persistent histone acetylation focusing on promoters of FosB and c-Fos, using chromatin immunoprecipitation assays. (4) To characterize the nature and consequences of adolescent drug exposure in both behavioral and molecular terms, we will replicate selected experiments outlined in Aims 1-3 (a) on adolescent mice to compare these results to those obtained on adults, and (b) on adult mice preexposed to nicotine or cocaine to identify the consequences of adolescent drug exposure for drug responses in adulthood to the same or different drugs. Preliminary results from pilot studies support the proposed approach. In addition to testing certain fundamental hypotheses for understanding addiction, these molecular insights are potentially useful for two reasons: (1) They may provide new molecular targets for the treatment of addiction; (2) They are likely to provide new hypotheses about drug behavior in human populations that can be further explored in epidemiological data. Drug abuse represents one of the most important public health issues in the nation. Drug abuse begins in adolescence, with the use of one of the legal drugs, alcohol or tobacco (nicotine); those who use one of these drugs are at much greater risk of progressing to the use of illicit drugs, such as marijuana or cocaine. Those who start smoking in adolescence are much more likely to continue smoking as adults and to experience the adverse health consequences of smoking than individuals who start smoking later in life. The proposed research aims to elucidate the biological mechanisms that underlie the progression in drug use from nicotine to cocaine by using a mouse model. The findings of the research may make it possible to develop new drugs to prevent and treat substance abuse.

描述(由申请人提供)：这项研究的总体目标是从分子的角度检验流行病学假说，即Gateway假说。该假说描述了在使用可卡因等其他药物之前使用一类药物(如香烟(尼古丁))的步骤序列。我们建议使用小鼠模型在分子水平上检验Gateway假说。我们的方法进一步基于这样的证据，即成瘾与长期记忆具有共同的分子步骤和分子逻辑。我们将解决四个具体目标：(1)在行为和转录水平上确定Gateway假说预测的尼古丁和可卡因之间是否存在顺序顺序，这种顺序是单向的(从尼古丁到可卡因)还是双向的(从可卡因到尼古丁)，以及尼古丁是否也可以增强对可卡因以外的滥用药物的反应，如吗啡。(2)为了确定尼古丁启动动物对可卡因效应的分子机制，我们建议对选定的靶区进行基因芯片分析，以研究纹状体，特别是伏隔核和杏仁核中的mRNA模式。我们将使用药理学分析来剖析可能介导启动效应的任何可能的信号转导途径，并通过转基因小鼠来探索从筛选中出现的一些选定的候选基因。(3)为了确定可能有助于维持门户效应的分子机制，我们将使用染色质免疫沉淀试验，重点研究FosB和c-Fos启动子的持续组蛋白乙酰化。(4)为了从行为学和分子方面表征青少年药物暴露的性质和后果，我们将重复AIMS 1-3中概述的选定实验，(A)在青春期小鼠身上比较这些结果，(B)在预先暴露于尼古丁或可卡因的成年小鼠上，以确定青少年药物暴露对成年后对相同或不同药物的药物反应的后果。试点研究的初步结果支持拟议的方法。除了测试某些理解成瘾的基本假设外，这些分子洞察力可能有用的原因有两个：(1)它们可能为成瘾的治疗提供新的分子靶点；(2)它们可能提供关于人类群体药物行为的新假设，可以在流行病学数据中进一步探索。药物滥用是美国最重要的公共卫生问题之一。药物滥用始于青春期，开始使用合法药物中的一种，即酒精或烟草(尼古丁)；使用其中一种药物的人发展为使用大麻或可卡因等非法药物的风险要大得多。那些在青春期开始吸烟的人比那些在生活中较晚开始吸烟的人更有可能在成年后继续吸烟，并更有可能经历吸烟对健康的不利影响。这项拟议的研究旨在通过使用小鼠模型来阐明药物使用从尼古丁到可卡因的过程中的生物学机制。这项研究的发现可能会使开发预防和治疗药物滥用的新药成为可能。