Dopaminergic Brain Function in Alcoholics

酗酒者的多巴胺能脑功能

• 批准号: 6678828
• 负责人: GENE-JACK WANG
• 金额: $ 45.66万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6678828
• 关键词: alcoholism /alcohol abuse; brain metabolism; clinical research; disease /disorder proneness /risk; dopamine; dopamine receptor; electrocardiography; frontal lobe /cortex; genetic susceptibility; glucose metabolism; human subject; interview; magnetic resonance imaging; neurochemistry; positron emission tomography; psychological tests; questionnaires

DESCRIPTION (provided by applicant): The importance of genetics in alcoholism is well established but the neurobiological mechanisms underlying predisposition are poorly understood and are likely to be multi-factorial. In our studies in alcoholics we have documented reductions in striatal DA D2 receptors (D2-R) and in metabolic activity in orbitofrontal cortex (OFC). Since these abnormalities persisted with detoxification we questioned whether they reflected predisposing factors for alcoholism. Pilot studies in subjects at high risk for alcoholism (HR) (positive family history for alcoholism) revealed decreases in OFC activity but increases in D2-R. These results coupled with our findings that increasing D2-R reduces alcohol intake in rats and the fact that after all the HR subjects were not alcoholics even though they had a family history for alcoholism led us to hypothesize that while decreased OFC may be a predisposing factor elevated D2-R may be protective. Here we propose to test these hypotheses, which are based on the postulate that predisposition for alcoholism reflects the balance between vulnerability and protective factors. Specific hypotheses are as follows: (1) A vulnerability factor in HR subjects is decreased OFC activity since this region is implicated in the lack of control and compulsive drug consumption characteristic of addictions including alcoholism, (2) A protective factor in HR subjects is high D2-R, which we postulate protects them against alcoholism by regulating the response of brain reward circuits to alcohol intoxication, (3) HR subjects will have reduced behavioral and regional brain metabolic responses to alcohol intoxication when compared with subjects at low risk for alcoholism (LR) (negative family history of alcoholism). Alcohol induced metabolic and behavioral effects will be modulated by D2-R levels and activity in OFC. To test these hypotheses we will use PET to measure D2-R availability using [11C] raclopride and to measure regional brain glucose metabolism using 18FDG at baseline and during alcohol intoxication (0.75 g/kg) in 60 HR and 60 LR subjects. To increase the probability of recruiting subjects with a high likelihood of having inherited the predisposition for alcoholism subjects will be pre-selected by their P300, which serves as an endophenotypic marker for vulnerability (HR subjects will have low P300 amplitudes and LR normal P300). A better understanding of the neurobiological mechanisms underlying protective and predisposing factors in alcoholism would allow development of better preventive interventions and may help in the design of corrective therapeutic strategies

描述（由申请人提供）：遗传学在酒精中毒中的重要性已得到充分证实，但对易感性的神经生物学机制了解甚少，可能是多因素的。在我们对酗酒者的研究中，我们记录了纹状体DA D2受体（D2-R）和眶额皮质（OFC）代谢活动的减少。由于这些异常在解毒过程中持续存在，我们怀疑它们是否反映了酗酒的易感因素。在酒精中毒（HR）高风险（酒精中毒家族史阳性）受试者中进行的初步研究显示，OFC活性降低，但D2-R增加。这些结果加上我们的发现，即增加D2-R减少了大鼠的酒精摄入量，以及尽管HR受试者有酗酒家族史，但他们毕竟不是酗酒者，这一事实使我们假设，虽然OFC减少可能是一个诱发因素，但D2-R升高可能是保护性的。在这里，我们建议测试这些假设，这是基于假设，即酗酒倾向反映了脆弱性和保护因素之间的平衡。具体假设如下： (1)HR受试者中的一个脆弱因素是OFC活性降低，因为该区域与缺乏控制和包括酒精中毒在内的成瘾特征的强迫性药物消费有关。（2）HR受试者中的一个保护因素是高D2-R，我们假设其通过调节大脑奖励回路对酒精中毒的反应来保护他们免受酒精中毒，（3）当与处于低酒精中毒风险（LR）（酒精中毒的阴性家族史）的受试者相比时，HR受试者对酒精中毒的行为和局部脑代谢反应将降低。酒精诱导的代谢和行为效应将受到眶额皮层D2-R水平和活性的调节。 为了检验这些假设，我们将在60名HR和60名LR受试者中使用PET测量使用[11 C]雷氯必利的D2-R可用性，并使用18 FDG测量基线和酒精中毒期间（0.75 g/kg）的局部脑葡萄糖代谢。为了增加招募具有高度遗传酒精中毒倾向的可能性的受试者的概率，将通过其P300预先选择受试者，P300用作脆弱性的内表型标志物（HR受试者将具有低P300振幅和LR正常P300）。 更好地了解酒精中毒保护和诱发因素的神经生物学机制将有助于开发更好的预防干预措施，并有助于设计纠正治疗策略