Ethanol tolerance: In vivo spectroscopy and drinking in monkeys

描述（由申请方提供）：拟定研究的总体目标是在三个非人灵长类动物研究项目之间建立接口，以建立乙醇磁共振波谱（MRS）作为耐受性的转化指标。在俄勒冈州国家灵长类动物研究中心（ONPRC）猕猴种群中，我们先前已经评估了对乙醇中毒的先天耐受性的遗传基础，表征了过量乙醇自我给药的发展，并开发了通过体内MRS直接测量非人灵长类动物脑乙醇的程序。我们建议研究乙醇MRS作为耐受性的量度，通过直接确定它与醉酒行为指标的关系，以及它如何随着大量饮酒而变化。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。我们已经开发了一个框架来解释这一发现的浓度和亲和力的饱和乙醇结合位点（或结合位点的集合）在大脑内。我们的数据证实了早期的光谱结果，从人类的调查，并提供了一个机会，扩展这些早期的研究结果，将现代分析策略和以前未被识别的生物物理模型的乙醇结合与大分子成分的相互作用。在这种情况下，我们将提供第一次直接比较乙醇MRS措施的耐受性，建立良好的行为测量急性耐受性，和获得性耐受性的发展。这些测量值中的每一个都将根据自我给予过量乙醇的倾向进行解释，这也将在我们的非人灵长类动物研究中直接测量。首先，我们将检验以下假设：对乙醇致醉作用的高度先天耐受性可通过BEC校正的乙醇MRS信号强度增加的内表型检测。其次，我们将测试的假设，即BEC校正的乙醇MRS信号强度增加作为一个个体的过渡从乙醇幼稚状态过度乙醇自我管理的状态。通过这项工作，我们的目标是开发一种翻译工具，用于监测乙醇暴露后的神经适应性，这些神经适应性与未来酒精滥用的耐受性和倾向性特别相关。 公共卫生相关性：这项工作的目标是开发一种磁共振波谱（MRS）工具来表征脑组织中乙醇分子成分之间的直接相互作用的程度。以前的研究工作已经揭示了我们希望开发的技术的有前途的能力，但是它们是使用人类受试者进行的，因此不可能以令人信服的方式操纵实验条件，将MRS结果与酗酒相关的行为联系起来。我们已经取得了一些初步的研究结果，使用非人类灵长类动物的主题，我们建议追求证明，在体内MRS可用于识别个人，是固有的耐受酒精的中毒作用，并在更大的风险发展酒精使用障碍。

DESCRIPTION (provided by applicant): The overall objective of the proposed studies is to create an interface between three non-human primate research programs to establish ethanol magnetic resonance spectroscopy (MRS) as a translational measure of tolerance. Within the Oregon National Primate Research Center (ONPRC) macaque monkey population, we have previously assessed the genetic basis of innate tolerance to ethanol intoxication, characterized the development of excessive ethanol self-administration, and developed procedures for directly measuring non- human primate brain ethanol via in vivo MRS. We propose to investigate ethanol MRS as a measure of tolerance, by directly determining how it relates to behavioral measures of intoxication, and how it changes with heavy ethanol drinking. 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-naive state to a state of excessive ethanol self-administration. Through this work, we aim to develop a translational tool for monitoring neuroadaptations following ethanol exposure that are specifically related to tolerance and propensity for future alcohol abuse. PUBLIC HEALTH RELEVANCE: The goal of this work is to develop a magnetic resonance spectroscopy (MRS) tool to characterize the extent of direct interaction between ethanol molecular constituents of brain tissue. Previous research efforts have revealed promising capabilities of the technique we wish to develop, however they were carried out using human subjects, and thus it was not possible to manipulate the experimental conditions in such a way as to convincingly link the MRS findings to behaviors related to alcoholism. We have made some preliminary findings using non-human primate subjects that we propose to pursue to demonstrate that in vivo MRS can be used to identify individuals that are inherently tolerant to the intoxicating effects of ethanol and at greater risk of developing an alcohol use disorder.