Ethanol tolerance: In vivo spectroscopy and drinking in monkeys

乙醇耐受性：猴子体内光谱学和饮酒

• 批准号: 7690953
• 负责人: Christopher D Kroenke
• 金额: $ 19.48万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690953
• 关键词: Acute; Affect; Affinity; Alcohol abuse; Alcohol consumption; Alcoholic Intoxication; Alcoholism; Animals; Behavior; Behavior assessment; Binding; Binding Sites; Brain; Collection; Data; Development; Dose; Ethanol; Funding; Future; Genetic; Goals; Grant; Human; Individual; Infusion procedures; Intoxication; Intravenous; Investigation; Link; Lipids; Macaca; Macaca mulatta; Magnetic Resonance Spectroscopy; Measurement; Measures; Methods; Modeling; Molecular; Monitor; Monkeys; N-acetylaspartate; Neurobiology; Oregon; Pattern; Population; Populations at Risk; Primates; Procedures; Property; Proteins; Protocols documentation; Reporting; Research; Risk; Self Administration; Self-Administered; Series; Signal Transduction; Site; Spectrum Analysis; System; Techniques; Testing; Work; alcohol effect; alcohol exposure; alcohol measurement; alcohol use disorder; base; behavior measurement; behavioral impairment; brain tissue; cohort; drinking; endophenotype; experience; human subject; in vivo; neuroadaptation; neuroimaging; nonhuman primate; programs; public health relevance; receptor; research study; tool

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.

描述（由申请人提供）：拟议研究的总体目标是在三个非人类灵长类动物研究计划之间建立界面，以建立乙醇磁共振光谱（MRS）作为公差的转化度量。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，表征了过度乙醇自我给药的发展，并开发了直接测量非人类灵长类动物脑乙醇的方法，该程序通过Vivo MRS进行测量。我们建议通过直接确定它与中毒行为度量以及它如何随大乙醇饮用的方式变化来研究乙醇MRS作为耐受性的度量。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功能。我们已经开发了一个框架来解释这一发现，以大脑内饱和乙醇结合位点（或结合位点的收集）的浓度和亲和力。我们的数据证实了人类研究的早期光谱结果，并通过纳入现代分析策略和以前未被认可的乙醇结合相互作用与大分子成分的乙醇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。在这种情况下，我们将提供乙醇MRS公差测量，良好的急性公差行为测量和获得的公差的发展之间的首次直接比较。这些测量中的每一个都将根据自我管理过量量的倾向的倾向来解释，这也将在我们的非人类灵长类动物研究中直接测量。首先，我们将测试以下假设：通过增加乙醇MRS信号强度的内表型，可以检测到对乙醇醉酒作用的天生耐受性。其次，我们将检验以下假设：BEC校正的乙醇MRS信号强度随着个体从乙醇态到过度乙醇自我给药状态的过渡而增加。通过这项工作，我们旨在开发一种转化工具，用于监测乙醇暴露后的神经加热，这与耐受性和对未来酒精滥用的倾向特别相关。 公共卫生相关性：这项工作的目的是开发磁共振光谱（MRS）工具，以表征脑组织乙醇分子成分之间直接相互作用的程度。先前的研究工作揭示了我们希望开发的技术的有希望的能力，但是它们是使用人类受试者进行的，因此无法以令人信服地将MRS发现与与酒精中毒相关的行为联系起来，以操纵实验条件。我们已经使用非人类灵长类动物受试者提出了一些初步发现，我们提出要证明，体内MRS可以用来识别对乙醇的陶醉效果固有的宽容的个体，并且患有饮酒障碍的风险更大。