Alcohol and Comorbid Tobacco Use Disorders: PET Imaging of Glutamate System Effects
酒精和烟草使用障碍:谷氨酸系统影响的 PET 成像
基本信息
- 批准号:9285689
- 负责人:
- 金额:$ 66.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-10 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:AbstinenceAgeAlcohol consumptionAlcohol dependenceAlcohol withdrawal syndromeAlcoholsAnimal ModelAnimalsAutopsyBehaviorBindingBrainBrain imagingCigaretteClinicalClinical ResearchClinical TrialsComorbidityControl GroupsDevelopmentDiagnosisDiseaseDrug Metabolic DetoxicationEligibility DeterminationFrequenciesGlutamatesHumanImageInpatientsInterventionInvestigationLaboratoriesLiteratureMaintenanceMeasurementMeasuresMental disordersMetabotropic Glutamate ReceptorsModelingMoodsNeurotransmittersNicotineNucleus AccumbensOutpatientsParticipantPatternPersonsPharmaceutical PreparationsPharmacologyPlayPopulationPositron-Emission TomographyPre-Clinical ModelProceduresPublic HealthRecording of previous eventsRelapseReportingResearchResolutionRoleScanningSeveritiesSiteSmokerSmokingSmoking StatusStandardizationSystemTherapeuticTherapeutic EffectTobacco Use DisorderTobacco useUnit of MeasureWithdrawalWorkalcohol comorbidityalcohol cravingalcohol cuealcohol effectalcohol exposurealcohol preferring micealcohol seeking behavioralcohol use disorderbasebehavior measurementbehavioral outcomebenzonitrileburden of illnesschronic alcohol ingestioncomparison groupcravingdensitydrug developmentin vivometabotropic glutamate receptor 2metabotropic glutamate receptor 4metabotropic glutamate receptor 5metabotropic glutamate receptor type 1motivated behaviormu opioid receptorsnon-smokernovelpre-clinicalpreclinical studypublic health relevanceradioligandreceptorresponsetherapeutic evaluationtherapeutic targettomographytransmission process
项目摘要
DESCRIPTION (provided by applicant): Alcohol and tobacco use disorders are serious public health problems, but only a small number of medications are approved for treatment of either disorder. There is a pressing need to identify new neurotransmitter targets for medication development. There is clear preclinical and emerging clinical evidence that the glutamate (Glu) system plays a central role in development and maintenance of regular alcohol and nicotine use, withdrawal and reinstatement after a period of abstinence. Pre-clinical studies have demonstrated a specific role for the metabotropic glutamate receptor, type 5 (mGluR5). This study will examine the mGluR5 receptor in persons with alcohol use disorder (AUD) compared with age-matched healthy controls (HC) and persons with tobacco use disorder (TUD); it also will clarify the effects of smoking and TUD in the AUD population. Positron emission tomography (PET), using the specific mGluR5 radioligand [18F]FPEB, will quantify mGluR5 binding potential (BPND), a PET-derived measure that relates to receptor availability and density. Specifically, aim 1 will compare mGluR5 BPND in non-treatment seeking AUD (N=80) versus HC participants (N=40). Additionally, among AUD subjects, smokers (AUD+TUD; N=40) will be compared with nonsmokers (AUD only; N=40) (aim 2), and TUD only participants (N=40) will be compared with AUD+TUD (N=40) and HC participants (N=40) (aim 3). All participants will complete standardized assessment procedures to characterize alcohol and tobacco use history. Eligible AUD participants will be admitted to the Clinical Research Unit (CRU) and complete a three day, unmedicated alcohol detoxification; smokers will maintain their usual quantity/frequency of cigarette use; measures of alcohol withdrawal and craving as well as mood will be obtained. On day 4, AUD subjects complete PET measurement of mGluR5 BPND. On day 5, AUD subjects participate in an alcohol-motivated progressive ratio procedure to quantify extent of responding for and consumption of alcohol. In addition to the between-group comparisons, we will examine relationships between [18F]FPEB BPND and CRU measures of alcohol withdrawal and craving (aim 4), amount of alcohol-motivated responding (aim 5), as well as baseline assessment measures of amount and frequency of alcohol and tobacco use (aim 6). To date, therapeutic benefit of clinically approved or investigational AUD medications has been modest. However, there are multiple lines of evidence indicating that the mGluR5 site is highly sensitive in animal models, and shows promise as a target for treatment. This proposal will be the first to characterize mGluR5 in living humans with AUD, to clarify the modulating role of tobacco use in this population and to examine the relationship of mGluR5 to key behavioral measures of alcohol and tobacco use. Importantly, mGluR5 negative allosteric modulators (NAMs) are in development by several drug companies and are undergoing clinical trials for several psychiatric diseases. This proposed study will set the stage for future research to directly test the therapeutic effects of mGluR5 NAMs on brain mGluR5 occupancy and behavioral outcomes in AUD clinical population.
描述(由申请人提供):酒精和烟草使用障碍是严重的公共卫生问题,但只有少数药物被批准用于治疗这两种疾病。迫切需要确定新的神经递质靶点用于药物开发。有明确的临床前和新出现的临床证据表明,谷氨酸(Glu)系统在发展和维持常规酒精和尼古丁使用、戒断和戒断一段时间后的恢复中起着核心作用。临床前研究已经证明了代谢型谷氨酸受体5(mGluR 5)的特定作用。这项研究将检查酒精使用障碍(AUD)患者与年龄匹配的健康对照(HC)和烟草使用障碍(TUD)患者的mGluR 5受体;它还将阐明吸烟和TUD对AUD人群的影响。正电子发射断层扫描(PET),使用特定的mGluR 5放射性配体[18 F]FPEB,将量化mGluR 5结合潜力(BPND),PET衍生的措施,涉及受体的可用性和密度。具体而言,目标1将比较非寻求治疗的AUD(N=80)与HC受试者(N=40)的mGluR 5 BPND。此外,在AUD受试者中,将吸烟者(AUD+TUD; N=40)与不吸烟者(仅AUD; N= 40)进行比较(目的2),将仅TUD受试者(N=40)与AUD+TUD(N=40)和HC受试者(N=40)进行比较(目的3)。所有参与者将完成标准化评估程序,以描述酒精和烟草使用史。符合条件的AUD受试者将进入临床研究单位(CRU),并完成为期三天的无药酒精解毒;吸烟者将保持其通常的吸烟量/频率;将获得酒精戒断和渴望以及情绪的指标。在第4天,AUD受试者完成mGluR 5 BPND的PET测量。在第5天,AUD受试者参与酒精驱动的渐进比率程序,以量化对酒精的响应和消耗的程度。除了组间比较外,我们还将检查[18F]FPEB BPND和CRU酒精戒断和渴望(目标4),酒精动机反应量(目标5)以及酒精和烟草使用量和频率的基线评估指标(目标6)之间的关系。迄今为止,临床批准或试验性AUD药物的治疗获益不大。然而,有多条证据表明mGluR 5位点在动物模型中高度敏感,并显示出作为治疗靶点的前景。该提案将首次描述患有AUD的活体人类中的mGluR 5,以阐明烟草使用在该人群中的调节作用,并研究mGluR 5与酒精和烟草使用的关键行为指标的关系。重要的是,mGluR 5负变构调节剂(NAM)正在由几家制药公司开发,并正在进行几种精神疾病的临床试验。这项拟议的研究将为未来的研究奠定基础,以直接测试mGluR 5 NAM对AUD临床人群脑mGluR 5占用和行为结局的治疗作用。
项目成果
期刊论文数量(0)
专著数量(0)
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MARY E MCCAUL其他文献
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{{ truncateString('MARY E MCCAUL', 18)}}的其他基金
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$ 66.91万 - 项目类别:
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