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：酗酒和依赖是一系列不适应行为，对公共健康有巨大影响，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存，但尽管它们经常在临床实践中使用，5-羟色胺再摄取抑制剂(SSRI)治疗酒精使用障碍的临床试验一直没有成功。在临床试验中，不同类型的酗酒者对SSRIs治疗的反应存在差异(较轻的“A型”酒精依赖与较严重的“B型”酒精依赖)。在SSRI的临床试验中，A型酗酒者的饮酒行为减少，而B型酗酒者的饮酒量增加。文献没有为这种差异提供解释，因此，还不清楚这些研究结果如何应用于临床。酒精研究非常适合退伍军人群体，因为退伍军人中有酒精依赖的比例很高。计划目标：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，为这次培训提供了理想的基础设施。他将得到这些领域的知名专家Arthur Brody M.D.和Edythe London Ph.D.的指导。这些导师有几项由NIH和VA赠款资助的酒精和其他成瘾障碍研究正在进行中，这些研究与VA PET研究基础设施有很强的联系。被提名者计划在获奖期结束时提交NIH R01和/或退伍军人事务部功绩审查补助金。从长远来看，他计划建立一个独立的研究生涯，研究治疗和理解物质使用障碍的神经药理学方法，主要专注于酒精。设计：该项目计划研究20个人 每组(A型酒精依赖、B型酒精依赖和健康对照受试者)进行双盲、安慰剂对照、受试者内的门诊研究，静脉注射西酞普兰(40毫克和生理盐水，按平衡顺序)和[18F]FolyPride PET扫描。该项目的目的：1)通过[18F]FolyPride PET扫描，确定静脉注射西酞普兰(40毫克)与静脉注射生理盐水相比，纹状体D2/3受体D2/3受体可获得性的变化(以放射性示踪剂的结合潜能来衡量)；2)确定静脉注射西酞普兰(40毫克)与盲目输注生理盐水对照组相比，是否影响线索诱导的酒精渴望的措施；以及3)评估静脉注射西酞普兰(40毫克)与静脉注射生理盐水对照的纹状体D2/3受体可用性的变化是否与受试者酒精渴望的措施有关。干预说明(S)/治疗(S)：通过电话筛选招募感兴趣的参与者。合格的参与者将被邀请参加用于PET扫描注册目的的结构磁共振成像(SMRI)扫描，以及在WLAVA为期两天的实验课程，在那里他们将接受静脉注射西酞普兰(40毫克和生理盐水，双盲)。在每次注射后，参与者将接受情绪测量以及基线和线索诱导的饮酒渴望的评估。随后，参与者将接受[18F]FolyPride PET扫描(~90分钟)，以评估纹状体D2/3受体的可用性。在完成输液和正电子发射计算机断层扫描后，参与者将退出研究。

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.