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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.

第三节一页的摘要，描述R33阶段的研究计划对最初的药物产生特别强烈(但通常是隐藏的)监管反应的个人根据终结性结果衡量标准，挑战最初可能表现为对药物不敏感。是这样的个人容易因反复接触毒品而获得多动反应(S)，使他们处于毒品使用升级和形成毒瘾的风险增加。成瘾的变态模型假设药物诱导的变态反应导致高反应性和/或其他失调反应的增长促进成瘾的发展；即，异位状态激励不断升级的药物使用，创造以失控和强制吸毒为特征的恶性循环。虽然只有一小部分人吸毒成瘾，给社会带来的总代价是巨大的。因此，理解造成成瘾易感性个体差异的原因机制具有很高的优先地位。我们先前发现，初始药物敏感性的个体差异预示着未来的药物耐受性、药物自身给药以及向异位平衡失调的过渡。在R21的初步阶段，我们的实验室开发了使用雄性和雌性大鼠验证了一种新型的同居乙醇蒸气暴露系统，该系统允许可靠的提供特定乙醇蒸气浓度以产生适当的血液乙醇水平以进行研究初始敏感度、乙醇蒸气获得性、慢性程度的个体差异耐受性的发展，并区分居住的温度梯度内的调节行为和失调行为仪器。在R33阶段，SA4测试了个体对酒精初始敏感性的差异这一假设可靠地预测酒精蒸气自我给药的持续差异。SA5测试了这样的假设个体对酒精的初始敏感度差异可预测异位平衡失调的发展在温度梯度中反复接触酒精。SA6测试了一个假设，即非药物挑战可以替代最初的酒精挑战，以确定预测可靠的个体间反应差异异位平衡失调的发展。我们研究的翻译影响将会增强，如果个体发生异位的可能性可以在不需要最初的药物挑战的情况下进行评估。拟议的研究将通过使用严格的实验设计来提供可靠和公正的结果以及包括连续测量变量的方法，如行为和代谢率在自然主义或酒精诱导的监管挑战期间的反应。这项创新性的研究是基于强大的概念框架，对于推进我们的知识和实践具有重要的理论和实践意义对成瘾易感性的潜在机制的理解。