Citalopram Effects on Craving and Dopamine Receptor Availability in Alcoholics

描述（由申请人提供）： 建议的研究背景摘要：酒精滥用和依赖代表了一系列适应不良的行为，对公共卫生产生了巨大的影响，特别是对美国退伍军人群体。抑郁症状经常与酒精使用障碍共病，但尽管在临床实践中经常使用，但使用5-羟色胺再摄取抑制剂（SSRIs）治疗酒精使用障碍的临床试验并不成功。在临床试验中，不同亚型的酗酒者对SSRIs治疗的反应存在差异（不太严重的“A型”与更严重的“B型”酒精依赖）。在SSRIs的临床试验中，A型酗酒者的饮酒行为减少，而B型酗酒者的饮酒行为增加。文献没有提供这种分歧的解释，因此，目前还不清楚这些研究结果如何在临床上应用。酒精研究非常适合退伍军人群体，因为有酒精依赖的退伍军人比例很高。 项目目标：被提名者在临床成瘾精神病学方面有很强的背景，他试图通过拟议的培训计划实现两个目标：1）成为人类酒精成瘾研究领域的专家，2）学习PET研究技术。被提名者在西洛杉矶退伍军人管理局医疗中心的工作环境，与加州大学洛杉矶分校的同事合作，为这种培训提供了理想的基础设施。他将由这些领域的著名专家亚瑟布罗迪医学博士指导，Edythe伦敦博士导师们有几个NIH和VA赠款资助的正在进行的研究，在酒精和其他成瘾性疾病的研究与VA PET研究基础设施的密切联系。被提名人计划在奖励期结束时提交NIH R 01和/或VA Merit Review补助金。从长远来看，他计划建立一个独立的研究生涯，研究神经药理学方法来治疗和理解物质使用障碍，主要集中在酒精。 设计：本项目拟研究20名个体， 3组（A型酒精依赖、B型酒精依赖和健康对照受试者）中的每一组，用于使用iv西酞普兰（40 mg和盐水，以平衡顺序）和[18 F]fallypride PET扫描的双盲、安慰剂对照、受试者内、门诊研究。该项目旨在：1）确定纹状体多巴胺受体D2/3受体可用性的变化通过[18F]fallypride PET扫描，与静脉注射盐水相比，静脉注射西酞普兰（40 mg）（测量为放射性示踪剂的结合潜力）; 2）确定与盲法盐水静脉注射对照输注相比，静脉注射西酞普兰（40 mg）是否影响线索诱导的对酒精的渴望的测量;和3）评估静脉注射西酞普兰（40 mg，与静脉注射生理盐水对照相比）时纹状体D2/3受体可用性的变化是否与受试者对酒精的渴望的测量有关。 干预/治疗描述：将通过电话筛选招募感兴趣的参与者。将邀请合格的参与者参加用于PET扫描登记目的的结构磁共振成像（sMRI扫描），以及在WLAVA进行的为期两天的实验，在那里他们将接受静脉注射西酞普兰（40 mg和生理盐水，双盲）。每次输注后，参与者将接受情绪测量以及基线和线索诱导的酒精渴望的评估。随后，参与者将接受[18F]fallypride PET扫描（约90分钟），以评估纹状体D2/3受体的可用性。完成输注和PET扫描后，受试者将退出研究。

DESCRIPTION (provided by applicant): Summary of Proposed Study Background: Alcohol abuse and dependence represent a spectrum of maladaptive behaviors with enormous public health impact, especially for the U.S. veteran population. Depressive symptoms are frequently comorbid with alcohol use disorders, but despite their frequent use in clinical practice, clinical trials with serotonin reuptake inhibiors (SSRIs) for alcohol use disorders have been unsuccessful. In clinical trials, a divergence in response to treatment with SSRIs among different subtypes of alcoholics is seen (less severe "Type A" vs. more severe "Type B" alcohol dependence). Type A alcoholics show decreased drinking behavior in clinical trials with SSRIs, whereas type B alcoholics show increased drinking. The literature does not offer an explanation for this divergence, and therefore, it is no clear how these research findings can be applied clinically. Alcohol research is well- suited to a veteran population because of the high proportion of veterans with alcohol dependence. Program Objectives: The nominee has a strong background in clinical addiction psychiatry, and he seeks to accomplish two objectives through the proposed training program: 1) to become an expert in the field of human alcohol addiction research, and 2) to learn techniques of PET research. The nominee's work environment at the West Los Angeles Veterans Administration Medical Center, in collaboration with colleagues at UCLA provides an ideal infrastructure for this training. He will be mentored by renowned experts in these areas, Arthur Brody M.D., and Edythe London Ph.D. The mentors have several NIH and VA grant-funded ongoing studies in alcohol and other addictive disorders research with strong ties to the VA PET research infrastructure. The nominee plans to submit an NIH R01 and/or VA Merit Review grant toward the end of the award period. Long term, he plans to found an independent research career studying neuropharmacological approaches to treating and understanding substance use disorders, focusing primarily on alcohol. Design: This project proposes to study 20 individuals in each of 3 groups (Type A alcohol dependence, Type B alcohol dependence, and healthy control subjects) for a double-blinded, placebo- controlled, within-subjects, outpatient study with iv citalopram (40 mg and saline, in counter-balanced order) and [18F]fallypride PET scanning. The project aims: 1) to determine the change in striatal dopamine receptor D2/3 receptor availability (measured as binding potential for the radiotracer) with iv citalopram (40 mg) as compared to iv saline by [18F]fallypride PET scanning; 2) To determine whether iv citalopram (40 mg) affects measures of cue-induced craving for alcohol compared to a blinded saline iv control infusion; and 3) to assess whether changes in striatal D2/3 receptor availability with iv citalopram (40 mg, compared to iv saline control) are related to measures of craving for alcohol among subjects. Description of Intervention(s)/Treatment(s): Interested participants will be recruited through phone screening. Qualified participants will be invited to participate in a structural magnetic resonance imaging (sMRI scan) for PET scan registration purposes, and two day-long experimental sessions at WLAVA, where they will undergo infusions with iv citalopram (40 mg and saline, double blinded). After each infusion, participants will undergo assessment of measures of mood and both baseline and cue- induced craving for alcohol. Subsequently, participants will undergo [18F]fallypride PET scanning (~90 min) to assess striatal D2/3 receptor availability. After completion of both infusions and PET scans, participants will be discharged from the study.