Dopaminergic Brain Function in Alcoholics

描述(由申请人提供)：遗传学在酒精中毒中的重要性已经得到了很好的证实，但潜在的易感性的神经生物学机制却知之甚少，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)和眼眶额叶皮质(OFC)代谢活动的减少。由于这些异常在戒毒过程中持续存在，我们质疑它们是否反映了酒精中毒的诱因。对酒精中毒(HR)高危人群(酒精中毒阳性家族史)的初步研究显示，OFC活动减少，但D2-R增加。这些结果，再加上我们的发现，增加D2-R减少了大鼠的酒精摄入量，以及毕竟HR受试者不是酒鬼，即使他们有酗酒的家族史，这一事实使我们假设，虽然OFC减少可能是一个易感因素，但增加D2-R可能具有保护作用。在这里，我们建议检验这些假设，这些假设是基于酒精中毒的易感性反映了脆弱性和保护性因素之间的平衡这一假设。具体假设如下： (1)HR受试者的一个易感因素是FC活性降低，因为该区域与包括酒精中毒在内的成瘾的缺乏控制和强迫药物消费特征有关；(2)HR受试者的一个保护因素是高D2-R，我们假设这是通过调节大脑奖赏回路对酒精中毒的反应来保护他们免受酒精中毒的影响；(3)与酒精中毒低风险(LR)受试者相比，HR受试者对酒精中毒的行为和局部大脑代谢反应会降低(无酒精中毒家族史)。酒精诱导的代谢和行为效应将受到OFC中D2-R水平和活性的调节。 为了验证这些假设，我们将使用正电子发射计算机断层扫描(PET)来测量D2-R的利用度，使用[11C]雷氯普利，并使用18FDG测量60名HR和60名LR受试者在基线和酒精中毒期间(0.75g/kg)的局部脑葡萄糖代谢。为了增加招募有酗酒倾向遗传倾向的受试者的可能性，受试者将通过他们的P300预先选择，P300作为易感性的内表型标记(HR受试者的P300波幅较低，而LR的P300正常)。 更好地了解酒精中毒中潜在的保护和易感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，并可能有助于设计纠正治疗策略。

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