MR SPECTROSCOPY OF ALCOHOL IN THE BRAIN

申请人摘要：作为我们正在进行的研究的一部分 酒精(Etoh)对大脑的影响，这项提议的目标是 研究酒精诱导人体耐受的机制 最先进的体内磁共振(MR)方法。三大 假设将被检验：1)酒精耐受性与减少有关 乙醇摄入后脑膜中乙醇的区隔作用 耐受受试者的磷脂膜与耐受者的比较 非耐受性控制，增加了刚性，但在6小时后不能解决 -9个月的禁欲；以及3)增加了膜的硬度，降低了 乙醇在脑膜中的区隔是相关现象。这些 假说是基于其他人的磁共振波谱(MRS)工作，以及 我们发现：游离醇的质子(1H)MRS信号相对较弱 在大脑中(与暂时和谐的血液酒精相比 浓度)，脑内乙醇信号较强，慢性、重度 饮酒(HD)受试者与轻度/不饮酒(LD)受试者在 血液酒精浓度相似，磷(31P)MRS降低 HD受试者脑膜磷脂的信号。它是 认为这些发现可能是由于磷脂刚性增加所致 HD受试者的膜，无水乙醇和 HD患者与LD患者相比磷脂信号强度降低 控件是相关的，并且这两个观察结果都是 对酒精的耐受性。这一建议旨在复制和推广 这些早期的发现使用多体积质子(1H)和31P磁共振 光谱成像法：1)测定游离乙醇浓度 HD和LD受试者摄入乙醇后的脑内；2)测定 是否存在可能关联的第二个(MR不可见)Etoh池 3)估计LD和Ld中这一池的相对数量 HD受试者；4)HD和LD受试者和戒毒者的大脑中测定 酗酒者(AA)T2松弛时间(反映膜 刚性)和磷脂信号的浓度，以及5)至 确定在增加的乙醇信号之间是否存在关联 在急性乙醇注射和磷脂MRS信号减少后 HD受试者。这些研究将给出高等教育的机制解释 乙醇磁共振在酒精耐受受试者中的能见度，并将导致更大的 对酒精耐受背后的细胞机制的理解。他们 可以为研究结构之间的关联提供一种工具 酒精戒断过程中的细胞膜变化和过度兴奋性 为客观、定量的酒精体内测量奠定了基础 耐受性；这可能对预测酗酒者的脆弱性很有价值 故态复萌。最后，拟议的研究可提供确定 是否存在反映先天耐受性的遗传性膜刚性 在酒精中毒遗传风险较高的受试者群体中对酒精的敏感性。 评论A

APPLICANT'S ABSTRACT: As part of our ongoing efforts of studying the effects of alcohol (EtOH) on the brain, it is the goal of this proposal to investigate the mechanism of alcohol-induced tolerance in humans using state-of-the-art in-vivo magnetic resonance (MR) methodology. Three major hypotheses will be tested: 1) alcohol-tolerance is associated with reduced compartmentation of EtOH in brain membranes after EtOH consumption; 2) phospholipid membranes of tolerant subjects, compared to those of nontolerant controls, have increased rigidity which does not resolve after 6 - 9 months of abstinence; and 3) increased membrane rigidity and reduced compartmentation of EtOH in brain membranes are associated phenomena. These hypotheses are based on MR spectroscopy (MRS) work performed by others and by ourselves showing: a relatively weak proton (1H) MRS signal of free EtOH in the brain (compared to temporaily concordant blood alcohol concentrations), stronger EtOH signal in the brain of chronic, heavily drinking (HD) subjects compared to light/non-drinking (LD) controls at similar blood alcohol concentrations, and a reduced phosphorus (31P) MRS signal from membrane phospholipids in the brain of HD subjects. It is thought that these findings may be due to increase rigidity of phospholipid membranes in HD subjects, that the reduced visibility of EtOH and the reduced phospholipid signal intensities in HD subjects compared to LD controls are related, and that both observations are expressions of tolerance to alcohol. This proposal is aimed at replicating and extending these earlier findings using multi-volume proton (1H) and 31P MR spectroscopic imaging methods to: 1) measure the concentration of free EtOH in the brains of HD and LD subjects after EtOH ingestion; 2) determine whether there is a second (MR-invisible) pool of EtOH possibly associated with brain membranes; 3) estimate the relative amount of this pool in LD and HD subjects; 4) determine in the brains of HD and LD subjects and abstinent alcoholics (AA) both the T2 relaxation times (which reflect membrane rigidity) and the concentrations of phospholipid signals, and 5) to determine whether an association exists between the increased EtOH signal after acute EtOH administration and the reduced phospholipid MRS signal in HD subjects. The studies will give a mechanistic explanation for higher EtOH MR-visibility in alcohol-tolerant subjects, and will lead to a greater understanding of the cellular mechanisms underlying alcohol tolerance. They may provide a tool for investigating the association between structural membrane changes and hyperexcitability during alcohol withdrawal and may form the basis for an objective, quantitative invivo measure of alcohol tolerance; this may be valuable for predicting an alcoholic's vulnerability to relapse. Finally, the proposed studies may provide means for determining whether there is an inherited membrane rigidity reflecting innate tolerance to alcohol in subject groups at genetic high risk of alcoholism. REVIEW A