A PET Study of Ventral Striatum Dopamine Release Deficits

腹侧纹状体多巴胺释放缺陷的 PET 研究

• 批准号: 7622301
• 负责人: John H. Krystal
• 金额: $ 17.66万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7622301
• 关键词: Abstinence; Address; Age; Age-Years; Alcohol dependence; Alcoholism; Amphetamines; Animals; Appendix; Behavioral; Binding; Biological; Biological Markers; Blood; Bolus Infusion; Brain; Chronic; Consumption; Corpus striatum structure; DNA; Daily; Dextroamphetamine; Disease; Dopamine; Dopamine D2 Receptor; Drug Metabolic Detoxication; Equilibrium; Ethnic Origin; Family history of; Foundations; Gender; Habits; Hand; Human; Impairment; Individual; Lead; Long-Term Effects; Measures; Molecular; Motivation; Participant; Partition Coefficient; Patients; Pharmaceutical Preparations; Population; Populations at Risk; Positive Reinforcer; Positron-Emission Tomography; Predisposing Factor; Prevention strategy; Raclopride; Reporting; Research; Research Personnel; Resolution; Rewards; Risk; Risk Factors; Sampling; Scanning; Severities; Smoking; Substance Addiction; Substance abuse problem; Synapses; Testing; Therapeutic; Toxic effect; Ventral Striatum; addiction; alcohol exposure; base; design; drinking; healthy volunteer; motivational processes; neuroimaging; presynaptic; problem drinker; radiotracer; receptor; receptor binding; receptor density; reinforcer; reward circuitry; reward processing; socioeconomics; transmission process

During CTNA-1 we used high resolution Positron Emission Tomography (PET) and the D2 receptor radiotracer [11 C]raclopride to study two parameters of DA transmission: D2 receptor density and amphetamine-induced intrasynaptic DA release in the ventral striatum in currently abstinent alcoholic subjects and healthy controls and found: 1) decreased D2 receptors in all striatal subregions in recently detoxified alcohol dependent patients compared to controls, 2) a relationship between the decrease in D2 receptors and the severity of daily drinking in all striatal subregions, and 3) a regionally selective decrease in amphetamine induced DA release in the ventral striatum in alcohol dependent subjects compared to controls. Low DA transmission in the ventral striatum and low striatal D2 receptors availability may both be predisposing factors to developing alcohol dependence or could alternatively reflect the effects of long term use on the reward circuitry in the brain. We now propose now to examine dopamine transmission with PET and [11 C]raclopride and the amphetamine challenge in +FH versus -FH matched healthy volunteers. The striatal [11 CJraclopride binding potential (BP) and the specific to nonspecific equilibrium partition coefficient (V3") will be measured and compared between the two groups (SA1). Amphetamine-induced reduction in [11 C]raclopride V3" will be compared between the two groups (SA2). In the high risk group we predict that decreased D2 will be related to severity of drinking measured by the amount of daily consumption. This will not be the case for -FH subjects indicating that low D2 is a marker for vulnerability rather than toxicity (SAS).This study builds on our current findings and extends the study of dopaminergic transmission to a high risk population. Confirming these alterations in at risk subjects prior to the onset of alcoholism will be a first step in understanding the biological basis of vulnerability. This could lead to developing a biomarker for identifying at risk subjects and possibly designing specific therapeutic strategies for prevention.

在 CTNA-1 期间，我们使用高分辨率正电子发射断层扫描 (PET) 和 D2 受体 放射性示踪剂 [11 C]雷氯必利用于研究 DA 传输的两个参数：D2 受体密度和 安非他明诱导当前戒酒者腹侧纹状体突触内 DA 释放 受试者和健康对照者发现：1）最近所有纹状体亚区域的 D2 受体减少 戒毒酒精依赖患者与对照组相比，2) D2 减少之间的关系 受体和所有纹状体亚区域日常饮酒的严重程度，以及 3) 区域选择性减少 与酒精依赖者相比，苯丙胺诱导的腹侧纹状体中 DA 释放 控制。腹侧纹状体中 DA 传输低和纹状体 D2 受体可用性低可能都与 酒精依赖的诱发因素或可以反映长期的影响 用于大脑中的奖励电路。我们现在建议用 PET 检查多巴胺传输 [11C]雷氯必利和+FH与-FH中的安非他明挑战与健康志愿者相匹配。这 纹状体 [11 CJraclopride 结合电位 (BP) 和特异性与非特异性平衡分配系数 (V3") 将在两组 (SA1) 之间进行测量和比较。安非他明诱导的减少 [11 C]雷氯必利 V3”将在两组之间进行比较 (SA2)。在高风险组中，我们预测 D2 的减少与每日饮酒量衡量的饮酒严重程度有关。这将 -FH 受试者的情况并非如此，表明低 D2 是脆弱性而非毒性的标志 （SAS）。这项研究建立在我们当前的研究结果的基础上，并将多巴胺能传递的研究扩展到了高水平 危险人群。在酗酒发生之前确认高危受试者的这些变化将是首要任务 理解脆弱性的生物学基础的一步。这可能会导致开发一种生物标志物 识别有风险的受试者并可能设计具体的预防治疗策略。