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：
10682461
负责人：
Douglas S Ramsay
金额：
$ 50.2万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-10 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10682461
关键词：
Predicting addictive vulnerability alcohol Initial

项目摘要

Section 3. A one-page abstract describing the Research Plan for the R33 phase 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 previously found that individual variation in initial drug sensitivity predicts future drug tolerance, drug selfadministration, and the transition to allostatic dysregulation. In a preliminary R21 phase, our lab developed and validated a novel live-in ethanol vapor exposure system using male and female rats that allows the reliable delivery of a specified ethanol vapor concentration that produces appropriate blood ethanol levels to investigate individual differences in initial sensitivity, acquisition of ethanol vapor self-administration, degree of chronic tolerance development, and distinguish regulatory from dysregulatory behavior within 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.

第3节。描述R33阶段研究计划的一页摘要对初始药物产生特别有力（但通常是隐藏）的调节性反应的个人基于总结性结果指标，挑战似乎对药物不敏感。这样的个人容易对反复暴露的过度活跃反应，将其置于增加毒品使用并发展吸毒的风险增加。成瘾的同种模型假设药物诱导的同性化变化会导致高反应性和/或其他反应失调的增长促进成瘾的发展；即，一个同性恋状态激发了毒品使用的升级，创造了一个恶性循环的特征是失去控制和强迫毒品。虽然只有一个适中的百分比暴露于毒品的人会上瘾，社会的总成本是巨大的。那是理解的负责添加剂脆弱性个体差异的因果机制具有很高的优先级。我们先前发现，初始药物敏感性的个体变异可以预测未来的药物耐受性，药物自我给药以及向同层失调的过渡。在初步的R21阶段，我们的实验室发展了使用雄性和雌性大鼠验证了一种新型的实时乙醇蒸气暴露系统，该系统允许可靠递送指定的乙醇蒸气浓度，产生适当的血乙醇水平以调查初始灵敏度的个体差异，乙醇蒸气自我给药的获取，慢性程度耐受性发展，并区分调节性的活性梯度中的失调行为设备。在R33阶段，SA4检验了以下假设：初始敏感性的个体差异可靠地预测酒精蒸气自我给药的持续差异。 SA5检验了以下假设对酒精初始敏感性的个体差异预测了同种异体失调的发展在热梯度中重复酒精暴露。 SA6检验了一个假设，即非毒品挑战可以代替初始酒精挑战来识别可靠的个体间反应变化同性失调的发展。如果一个可以评估个人发展同性恋的可能性，而无需最初的毒品挑战。拟议的研究将通过使用严格的实验设计提供强大而公正的结果以及包括连续测量变量（例如行为和代谢率）的方法自然主义或酒精引起的监管挑战期间的反应。这项创新的研究基于强大的概念框架，对于促进我们的知识和了解额外脆弱性的基础机制。