ETHANOL TOLERANCE: IN VIVO SPECTROSCOPY AND DRINKING IN MONKEYS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 拟议研究的总体目标是建立乙醇磁共振波谱(MRS)作为耐受性的翻译测量。在静脉注射乙醇后的一系列体内MRS实验中，我们观察到乙醇MRS信号的大小是乙醇浓度的非线性函数。我们开发了一个框架，根据大脑中可饱和的乙醇结合部位(或结合部位的集合)的浓度和亲和力来解释这一发现。我们的数据证实了人类调查的早期光谱结果，并通过纳入现代分析策略和先前未知的乙醇与大分子成分结合作用的生物物理模型，提供了扩展这些早期发现的机会。在此背景下，我们将提供乙醇MRS耐受性测量、公认的急性耐受性行为测量和获得性耐受性发展之间的第一次直接比较。这些测量中的每一项都将被解释为自我服用过量乙醇的倾向，这也将在我们的非人类灵长类研究中直接测量。首先，我们将检验这一假设，即通过BEC校正的乙醇MRS信号强度增加的内表型，可以检测到对乙醇中毒效应的高度先天耐受性。其次，我们将检验这一假设，即BEC校正的乙醇MRS信号强度随着个体从乙醇-天然状态转变到过量乙醇自我给药状态而增加。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall objective of the proposed studies is to establish ethanol magnetic resonance spectroscopy (MRS) as a translational measure of tolerance. In a series of in vivo MRS experiments following intravenous ethanol administration, we have observed that the size of the ethanol MRS signal is a non-linear function of ethanol concentration. We have developed a framework to interpret this finding in terms of the concentration and affinity of a saturable ethanol binding site (or collection of binding sites) within the brain. Our data corroborate early spectroscopic results from human investigations, and provide an opportunity to extend these earlier findings by incorporating modern analysis strategies and a previously unrecognized biophysical model of ethanol binding interactions with macromolecular constituents. Within this context, we will provide the first direct comparison between ethanol MRS measures of tolerance, well-established behavioral measurements of acute tolerance, and the development of acquired tolerance. Each of these measurements will be interpreted in terms of the propensity to self-administer excessive quantities of ethanol, which will also be directly measured in our non-human primate study. First, we will test the hypothesis that a high degree of innate tolerance to the intoxicating effects of ethanol is detectable through an endophenotype of increased BEC-corrected ethanol MRS signal intensity. Second, we will test the hypothesis that BEC-corrected ethanol MRS signal intensity increases as an individual transitions from an ethanol-na¿ve state to a state of excessive ethanol self-administration.