Ethanol tolerance: In vivo spectroscopy and drinking in monkeys

描述（由申请人提供）：拟议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一个接口，以建立乙醇磁共振光谱（MRS）作为耐受性的转化测量。在俄勒冈国家灵长类动物研究中心（ONPRC）的猕猴种群中，我们之前已经评估了对乙醇中毒先天耐受性的遗传基础，描述了过度乙醇自我给药的发展，并开发了通过体内MRS直接测量非人类灵长类动物脑乙醇的程序。我们建议通过直接确定乙醇MRS与中毒行为测量的关系来研究乙醇MRS作为耐受性的测量。以及它是如何随着大量饮酒而变化的。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。我们的数据证实了人类研究的早期光谱结果，并通过结合现代分析策略和以前未被认识到的乙醇与大分子成分结合相互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，建立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。每一项测量都将被解释为自我管理过量乙醇的倾向，这也将在我们的非人类灵长类动物研究中直接测量。首先，我们将通过增加的BEC校正乙醇MRS信号强度的内表型来检测对乙醇中毒作用的高度先天耐受性的假设。其次，我们将验证以下假设：当个体从乙醇初始状态过渡到过度的乙醇自我给药状态时，经becc校正的乙醇MRS信号强度会增加。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与未来酒精滥用耐受性和倾向特别相关的神经适应。

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.