A Molecular Analysis of the Gateway Hypothesis in Mice
小鼠网关假说的分子分析
基本信息
- 批准号:8127966
- 负责人:
- 金额:$ 51万
- 依托单位:
- 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:2007-09-30 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAddictive BehaviorAddressAdolescenceAdolescentAdultAdverse eventAgeAge of OnsetAlcoholsAmygdaloid structureAnimal ModelAnimalsBehaviorBehavioralBiologicalBiological AssayBrainBrain regionCREB-binding proteinCREB1 geneCandidate Disease GeneCannabisCell NucleusCell surfaceChromatin StructureChronicCigaretteCocaineCorpus striatum structureDataData SetDevelopmentDrug AddictionDrug ExperimentationDrug ExposureDrug abuseDrug usageEmployee StrikesEpidemiologic StudiesEpidemiologyEtiologyExperimental DesignsExposure toFOS geneGene ChipsGene ExpressionGene ProteinsGene-ModifiedGenesGenetic TranscriptionGoalsHealthHistone AcetylationHumanIllicit DrugsImmediate-Early GenesIndividualLateralLegalLifeLogicMaintenanceMarijuanaMediatingMemoryMessenger RNAModelingModificationMolecularMolecular AnalysisMolecular TargetMorphineMusNatureNicotineNuclearNucleus AccumbensPatternPharmaceutical PreparationsPilot ProjectsPopulationProcessProtein IsoformsPublic HealthRecruitment ActivityResearchRiskRisk FactorsRodentSignal Transduction PathwaySmokingStagingStudy SectionSubstance abuse problemSubstance of AbuseSurveysSystemTestingTobaccoTranscriptional Activationaddictionbasechromatin immunoprecipitationcocaine usedesigndrug of abuseexperiencegenetic analysishistone acetyltransferasehuman CREBBP proteininsightlong term memorymouse modelpreventprogramspromoterpsychologicresearch studyresponsesocial
项目摘要
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):该研究的总体目标是从分子角度测试流行病学假设,即门户假设。该假说描述了使用一类药物(如香烟(尼古丁))先于使用其他药物(如可卡因)的步骤顺序。我们建议使用小鼠模型在分子水平上测试网关假说。我们的方法进一步基于成瘾与长期记忆共享分子步骤和分子逻辑的证据。我们将讨论四个具体目标:(1)在行为和转录水平上确定尼古丁和可卡因之间是否存在网关假说预测的顺序,这个顺序是单向的(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药物滥用的反应,如吗啡。(2)为了确定尼古丁引发动物可卡因效应的分子机制,我们建议使用基因芯片分析选定的目标区域,以调查纹状体,特别是杏仁核和杏仁核中mRNA的模式。我们将使用药理学分析来剖析可能介导引发效应的任何可能的信号转导途径,并使用转基因小鼠来探索筛选出的一些候选基因。(3)为了确定可能有助于维持网关效应的分子机制,我们将使用染色质免疫沉淀法研究持续的组蛋白乙酰化,重点关注FosB和c-Fos的启动子。(4)为了从行为和分子两个方面描述青少年药物暴露的性质和后果,我们将在目标1-3(a)中概述的青少年小鼠中重复选定的实验,以将这些结果与成年小鼠中获得的结果进行比较,以及(B)在预先暴露于尼古丁或可卡因的成年小鼠中重复选定的实验,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所提出的方法。除了测试某些理解成瘾的基本假设外,这些分子见解可能有两个原因:(1)它们可能为成瘾治疗提供新的分子靶点;(2)它们可能提供关于人群中药物行为的新假设,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,使用酒精或烟草(尼古丁)等法律的药物之一;使用这些药物之一的人有更大的风险发展到使用非法药物,如大麻或可卡因。那些在青春期开始吸烟的人更有可能在成年后继续吸烟,并比那些在生命后期开始吸烟的人更有可能经历吸烟的不良健康后果。这项拟议中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进展的生物学机制。这项研究的结果可能使开发新的药物来预防和治疗药物滥用成为可能。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DENISE B KANDEL其他文献
DENISE B KANDEL的其他文献
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{{ truncateString('DENISE B KANDEL', 18)}}的其他基金
PRESCRIPTION DRUG USE IN THE US POPULATION: GATEWAY EFFECTS AND FAMILY PATTERNS
美国人口中的处方药使用:门户效应和家庭模式
- 批准号:
9404447 - 财政年份:2015
- 资助金额:
$ 51万 - 项目类别:
PRESCRIPTION DRUG USE IN THE US POPULATION: GATEWAY EFFECTS AND FAMILY PATTERNS
美国人口中的处方药使用:门户效应和家庭模式
- 批准号:
9193073 - 财政年份:2015
- 资助金额:
$ 51万 - 项目类别:
PRESCRIPTION DRUG USE IN THE US POPULATION: GATEWAY EFFECTS AND FAMILY PATTERNS
美国人口中的处方药使用:门户效应和家庭模式
- 批准号:
9033105 - 财政年份:2015
- 资助金额:
$ 51万 - 项目类别:
A Molecular Analysis of the Gateway Hypothesis in Mice
小鼠网关假说的分子分析
- 批准号:
8539892 - 财政年份:2007
- 资助金额:
$ 51万 - 项目类别:
A Molecular Analysis of the Gateway Hypothesis in Mice
小鼠网关假说的分子分析
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7502028 - 财政年份:2007
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A Molecular Analysis of the Gateway Hypothesis in Mice
小鼠网关假说的分子分析
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7681755 - 财政年份:2007
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A Molecular Analysis of the Gateway Hypothesis in Mice
小鼠网关假说的分子分析
- 批准号:
7350792 - 财政年份:2007
- 资助金额:
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