Predicting addictive vulnerability to alcohol: Initial sensitivity, tolerance, allostasis and self-administration

预测酒精成瘾脆弱性：初始敏感性、耐受性、动态平衡和自我管理

基本信息

批准号：
10019315
负责人：
Douglas S Ramsay
金额：
$ 18.47万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10019315
关键词：
Acute Alcohol consumption Alcohol dependence Alcohols Behavioral Behavioral Genetics Blood Blood alcohol level measurement Chronic Closure by clamp Consumption Data Data Analyses Dependence Development Drug Addiction Drug Exposure Drug Modelings Drug Tolerance Drug Withdrawal Symptoms Drug usage Ethanol Etiology Exhibits Experimental Designs Exposure to Food Future Goals Growth Homeostasis Hyperactive behavior Individual Individual Differences Inhalant dose form Inhalation Knowledge Measurement Measures Mediating Methodology Methods Modeling National Institute on Alcohol Abuse and Alcoholism Nitrous Oxide Outcome Measure Pathogenesis Pharmaceutical Preparations Pharmacology Phase Physiological Play Predictive Factor Prevention Rattus Regulation Research Risk Role Self Administration Societies Specific qualifier value Sweetening Agents System Temperature Testing Variant Water Withdrawal Work addiction alcohol exposure alcohol research alcohol sensitivity alcohol use disorder allostasis base cost design drug sensitivity genetic selection individual response individual variation inhalation drug abuse innovation insight inter-individual variation metabolic rate motivated behavior natural hypothermia non-drug novel pre-clinical pre-clinical research prevent response translational impact vapor

项目摘要

Individuals who generate especially vigorous (but usually hidden) regulatory responses to an initial drug challenge can appear to be initially insensitive to the drug based on summative outcome measures. Such individuals are vulnerable to acquiring hyperactive response(s) over repeated drug exposures, putting them at increased risk to escalate drug use and develop drug addiction. The allostatic model of addiction posits that drug-induced allostatic changes cause the growth of hyper-responsive and/or otherwise dysregulated responses that promote the development of addiction; i.e., an allostatic state motivates escalating drug use, creating a vicious cycle characterized by loss of control and compulsive drug-taking. While only a modest percentage of drug-exposed individuals become addicted, the aggregate costs to society are immense. Thus, understanding the causal mechanisms responsible for individual differences in addictive vulnerability has high priority. We have found that individual variation in initial drug sensitivity predicts future drug tolerance, drug self-administration, and the transition to allostatic dysregulation. The R21 phase proposes to develop a novel live-in ethanol-vapor exposure chamber for rats that also can be used for ethanol vapor self-administration. Specific Aim 1 (SA1) builds the apparatus and tests its reliability to deliver a specified ethanol vapor concentration and clear it from the chamber. SA2 will measure the relationship between inhaled ethanol vapor concentration and blood ethanol levels and validate the functionality of the apparatus by assessing individual differences in initial sensitivity, acquisition of self-administration, and degree of chronic tolerance development. SA3 validates the use of alcohol vapor in a live-in thermal gradient apparatus. In the R33 phase, SA4 tests the hypothesis that individual differences in initial sensitivity to alcohol reliably predict persistent differences in alcohol vapor self-administration. SA5 tests the hypothesis that individual differences in initial sensitivity to alcohol predict the development of allostatic dysregulation over repeated alcohol exposures in a thermal gradient. SA6 tests the hypothesis that a non-drug challenge can substitute for an initial alcohol challenge in identifying reliable inter-individual response variation that predicts the development of allostatic dysregulation. The translational impact of our research will be enhanced if an individual's likelihood of developing allostasis could be assessed without requiring an initial drug challenge. The proposed studies will provide robust and unbiased results through the use of rigorous experimental designs and methods that include continuous measurements of variables such as behavioral and metabolic-rate responses during naturalistic or alcohol-induced regulatory challenges. This innovative research is based on a strong conceptual framework and is of theoretical and practical importance for advancing our knowledge and understanding of the mechanisms underlying addictive vulnerability.

对初始药物产生特别强烈（但通常是隐藏的）监管反应的个人根据总结性结果衡量，挑战最初可能对药物不敏感。这样的个体很容易因反复接触药物而产生过度活跃的反应，使他们处于危险境地增加吸毒和吸毒成瘾的风险。成瘾的变稳态模型假设药物引起的稳态变化导致高反应性和/或其他失调的生长促进成瘾发展的反应；即，失衡状态会促使药物使用不断增加，形成以失控和强迫性吸毒为特征的恶性循环。虽然只是微不足道的接触毒品的人成瘾的比例很高，社会的总成本是巨大的。因此，了解导致成瘾脆弱性个体差异的因果机制具有很高的意义优先事项。我们发现初始药物敏感性的个体差异可以预测未来的药物耐受性、药物耐受性自我管理，以及向稳态失调的转变。 R21阶段建议开发一种新颖的大鼠居住乙醇蒸气暴露室，也可用于乙醇蒸气自我给药。具体目标 1 (SA1) 构建设备并测试其可靠性以输送指定的乙醇蒸汽浓缩并将其从腔室中清除。 SA2将测量吸入的乙醇蒸气之间的关系浓度和血液乙醇水平，并通过评估个人来验证设备的功能初始敏感性、自我给药获得性和慢性耐受程度的差异发展。 SA3 验证了酒精蒸汽在内置热梯度装置中的使用。在R33阶段， SA4 检验了以下假设：最初对酒精的敏感度存在个体差异，可以可靠地预测持续的酒精敏感度酒精蒸气自我管理的差异。 SA5 检验初始个体差异的假设对酒精的敏感性可预测反复暴露于酒精的情况下会发生稳态失调的情况热梯度。 SA6 测试非药物挑战可以替代初始酒精的假设识别可靠的个体间反应变化以预测非稳态发展的挑战失调。如果个人的可能性无需进行初始药物挑战即可评估发生的动态平衡。拟议的研究将通过使用严格的实验设计和方法提供稳健和公正的结果包括对变量的连续测量，例如行为和代谢率反应自然主义或酒精引起的监管挑战。这项创新研究基于强大的概念框架，对于提高我们的知识和理解具有重要的理论和实践意义成瘾脆弱性的潜在机制。