Translational study on CHRNA5 variation and alcohol reward mechanisms
CHRNA5变异与酒精奖励机制的转化研究
基本信息
- 批准号:10413132
- 负责人:
- 金额:$ 36.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-20 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAffectAlcohol consumptionAlcoholsAllelesAnimalsAreaAttentionBehaviorBehavioralBrainChronic DiseaseClinical ResearchCognitiveComplementConsumptionCorpus striatum structureCuesDependenceDiseaseDopamineDopaminergic CellDrosophila acetylcholine receptor alpha-subunitElectrophysiology (science)EthanolEtiologyFoodFunctional Magnetic Resonance ImagingFunctional disorderGenesGeneticGenetic PolymorphismGenetic studyGenetically Modified AnimalsGenotypeGoalsHealthHeterogeneityHumanIncentivesIndividualIntramural Research ProgramIntravenousLaboratoriesLinkMeasuresMediatingMicrodialysisModelingMusNational Institute of Drug AbuseNational Institute on Alcohol Abuse and AlcoholismNeurobiologyNeuronsNicotineNicotine DependenceNicotinic ReceptorsNucleus AccumbensParticipantPatient RecruitmentsPennsylvaniaPharmacogeneticsPhenotypePlayPre-Clinical ModelPropertyProspective StudiesPsychological reinforcementRecording of previous eventsResearchResearch PersonnelRestReversal LearningRewardsRiskRodent ModelRoleScanningSelf AdministrationSignal TransductionSingle Nucleotide PolymorphismSliceSmokingSystemTobaccoTransgenic MiceUnited StatesUnited States National Institutes of HealthUniversitiesVariantVentral Tegmental AreaWild Type MouseWorkaddictionalcohol behavioralcohol effectalcohol exposurealcohol reinforcementalcohol responsealcohol rewardalcohol seeking behavioralcohol use disorderbaseburden of illnesscholinergicclinical phenotypecomorbidityconditioned place preferencedopamine systemdopaminergic neurondrinkingendophenotypeexperimental studyflexibilityfunctional MRI scangenetic linkagegenetic varianthedonichuman subjectin vivoincentive salienceinterestneural correlateneuroimagingnon-smokingnull mutationpre-clinicalpreventable deathpublic health relevancerelating to nervous systemresponseselective expressionsexskillstobacco abusetraittranslational studyvirtual
项目摘要
Alcohol use disorder (AUD) is the third leading cause of preventable death in the United States. This
disease has a negative impact on health, work, and relationships of the affected individuals. Research on the
genetic and environmental determinants of the response to alcohol, and their relationship to the risk of
developing AUD is critical to reducing the substantial societal burden of AUD. Genetic studies have shown
association of AUD with gene variation in several loci. However, due to the heterogeneity in the AUD clinical
phenotype and small effect sizes, there has been an increasing interest in examining the influence of gene
variation on quantitative endophenotypes such as alcohol seeking, consumption, and brain circuit alterations.
The present application focuses on the potential influence of gene variation in CHRNA5, the gene
encoding the α5 subunit of nicotinic acetylcholine receptors, on alcohol self-administration and brain circuit
alterations. The rs16969968 missense single-nucleotide polymorphism (SNP) in CHRNA5 is associated with
nicotine addiction and smoking-related consequences. However, despite the widely prevalent co-abuse of
tobacco and alcohol, little work has been done to examine the effect of this SNP on alcohol use, dependence, or
alcohol response. The goal of this proposal is to examine the influence of CHRNA5 variation on alcohol
responses using an integrated translational pharmacogenetic approach that leverages the expertise of
investigators at the NIAAA and NIDA intramural programs with the project PI to combine clinical research on
human subjects and pre-clinical analyses in rodent models. A prospective study will compare alcohol self-
administration behavior and neuroimaging responses in humans that are homozygous for the G-allele and those
that are A-allele carriers of the CHRNA5 rs16969968 SNP. We will study the potential interaction of alcohol and
nicotine by comparing smoking and non-smoking drinkers. To better understand the mechanistic link between
CHRNA5 and alcohol response, we will conduct behavioral and functional studies in genetically modified
animals expressing the α5 gene variants or an α5 null mutation. Similar to the human studies, we will study
alcohol self-administration in nicotine-naïve vs. nicotine-treated animals. Furthermore, we will study how
CHRNA5 variation influences the effects of alcohol on the dopaminergic system by measuring ethanol-induced
electrophysiological responses and dopamine release.
Examination of the role of CHRNA5 variation in alcohol response will provide a greater understanding of
the cholinergic mechanisms underlying the neurobiology of alcohol, with the goal of providing an expanded
etiological spectrum for alcohol reward response phenotypes.
酒精使用障碍(AUD)是美国可预防死亡的第三大原因。这
疾病对受影响个人的健康、工作和人际关系产生负面影响。研究
对酒精反应的遗传和环境决定因素,以及它们与
发展AUD对于减少AUD的重大社会负担至关重要。遗传学研究表明
AUD与几个位点的基因变异相关。然而,由于AUD临床的异质性,
表型和小效应大小,人们越来越感兴趣的是检查基因的影响,
定量内表型的变化,如酒精寻求,消费和脑回路改变。
本申请集中于CHRNA 5中基因变异的潜在影响,
编码烟碱型乙酰胆碱受体α5亚单位,对酒精自我给药和脑回路的影响
改变。CHRNA 5中rs 16969968错义单核苷酸多态性(SNP)与
尼古丁成瘾和吸烟相关的后果。然而,尽管广泛流行的共同滥用,
烟草和酒精,很少有工作已经做了检查这种SNP对酒精使用,依赖,或
酒精反应这项提案的目的是研究CHRNA 5变异对酒精的影响。
使用整合的转化药物遗传学方法,利用
NIAAA和NIDA内部项目的研究人员与PI项目一起联合收割机临床研究,
人类受试者和啮齿动物模型中的临床前分析。一项前瞻性研究将比较酒精自我-
G-等位基因纯合子的人和那些
CHRNA 5 rs 16969968 SNP的A等位基因携带者。我们将研究酒精和
通过比较吸烟和不吸烟的饮酒者。为了更好地理解
CHRNA 5和酒精反应,我们将在转基因小鼠中进行行为和功能研究。
表达α5基因变体或α5无效突变的动物。与人类研究类似,我们将研究
尼古丁初治动物与尼古丁给药动物的酒精自我给药。此外,我们将研究如何
CHRNA 5变异通过测量乙醇诱导的多巴胺能系统影响乙醇的作用
电生理反应和多巴胺释放。
研究CHRNA 5变异在酒精反应中的作用将使我们更好地理解
酒精神经生物学的胆碱能机制,目的是提供一个扩展的
酒精奖励反应表型的病因谱。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mutation of the α5 nicotinic acetylcholine receptor subunit increases ethanol and nicotine consumption in adolescence and impacts adult drug consumption.
- DOI:10.1016/j.neuropharm.2022.109170
- 发表时间:2022-09-15
- 期刊:
- 影响因子:4.7
- 作者:Quijano Carde, Natalia A;Shaw, Jessica;Carter, Christina;Kim, Seung;Stitzel, Jerry A;Venkatesh, Shyamala K;Ramchandani, Vijay A;De Biasi, Mariella
- 通讯作者:De Biasi, Mariella
Behavioral characterization of withdrawal following chronic voluntary ethanol consumption via intermittent two-bottle choice points to different susceptibility categories.
- DOI:10.1111/acer.14785
- 发表时间:2022-04
- 期刊:
- 影响因子:0
- 作者:Carde, Natalia A. Quijano;De Biasi, Mariella
- 通讯作者:De Biasi, Mariella
Antagonism of GluK1-containing kainate receptors reduces ethanol consumption by modulating ethanol reward and withdrawal.
- DOI:10.1016/j.neuropharm.2021.108783
- 发表时间:2021-11-01
- 期刊:
- 影响因子:4.7
- 作者:Quijano Cardé NA;Perez EE;Feinn R;Kranzler HR;De Biasi M
- 通讯作者:De Biasi M
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Mariella De Biasi其他文献
Mariella De Biasi的其他文献
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{{ truncateString('Mariella De Biasi', 18)}}的其他基金
Educating Physician Scientists in Psychiatry (EPSP): Firing up the next generation of translational and clinical neuroscientists
精神病学医师科学家教育 (EPSP):培养下一代转化和临床神经科学家
- 批准号:
10353376 - 财政年份:2019
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Striatal mechanisms for e-cigarette reinforcement by flavorants
香料增强电子烟的纹状体机制
- 批准号:
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- 资助金额:
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Striatal mechanisms for e-cigarette reinforcement by flavorants
香料增强电子烟的纹状体机制
- 批准号:
10660974 - 财政年份:2019
- 资助金额:
$ 36.23万 - 项目类别:
Striatal mechanisms for e-cigarette reinforcement by flavorants
香料增强电子烟的纹状体机制
- 批准号:
10017928 - 财政年份:2019
- 资助金额:
$ 36.23万 - 项目类别:
Striatal mechanisms for e-cigarette reinforcement by flavorants
香料增强电子烟的纹状体机制
- 批准号:
10874294 - 财政年份:2019
- 资助金额:
$ 36.23万 - 项目类别:
Striatal mechanisms for e-cigarette reinforcement by flavorants
香料增强电子烟的纹状体机制
- 批准号:
10197866 - 财政年份:2019
- 资助金额:
$ 36.23万 - 项目类别:
Striatal mechanisms for e-cigarette reinforcement by flavorants
香料增强电子烟的纹状体机制
- 批准号:
10656610 - 财政年份:2019
- 资助金额:
$ 36.23万 - 项目类别:
Educating Physician Scientists in Psychiatry (EPSP): Firing up the next generation of translational and clinical neuroscientists
精神病学医师科学家教育 (EPSP):培养下一代转化和临床神经科学家
- 批准号:
10094259 - 财政年份:2019
- 资助金额:
$ 36.23万 - 项目类别:
Educating Physician Scientists in Psychiatry (EPSP): Firing up the next generation of translational and clinical neuroscientists
精神病学医师科学家教育 (EPSP):培养下一代转化和临床神经科学家
- 批准号:
10569533 - 财政年份:2019
- 资助金额:
$ 36.23万 - 项目类别:
Flavored e-cigarette use in adolescents: Behavioral, cellular, and epigenetic mechanisms
青少年使用调味电子烟:行为、细胞和表观遗传机制
- 批准号:
9521691 - 财政年份:2018
- 资助金额:
$ 36.23万 - 项目类别:
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