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

对初始药物产生特别强烈（但通常是隐藏的）调节反应的个体 基于总结性结果测量，激发最初可能对药物不敏感。等 个体在反复暴露于药物时容易获得过度活跃的反应， 增加吸毒和吸毒成瘾的风险。成瘾的非稳态模型假定， 药物诱导的变应性变化引起高反应性和/或其他失调的 促进成瘾发展的反应;即，一种非稳态刺激了药物使用的升级， 形成了一个以失控和强迫性吸毒为特征的恶性循环。虽然只有一个温和的 尽管接触毒品的人中有50%上瘾，但社会的总成本是巨大的。因此，在本发明中， 了解成瘾易感性个体差异的因果机制， 要务我们已经发现，初始药物敏感性的个体差异预示着未来的药物耐受性， 自我管理，以及向非稳态失调的过渡。R21阶段提出开发一种新的 大鼠活体乙醇蒸汽暴露室，也可用于乙醇蒸汽自我给药。 具体目标1（SA 1）构建装置并测试其可靠性，以输送指定的乙醇蒸汽 浓度并将其从腔室中清除。SA2将测量吸入的乙醇蒸汽与 浓度和血液乙醇水平，并通过评估个体 初始敏感性、自我给药的获得和慢性耐受程度的差异 发展SA 3确认了在活体热梯度装置中使用酒精蒸汽。在R33阶段， SA4检验了对酒精初始敏感性的个体差异可靠地预测持续性的假设。 酒精蒸汽自我管理的差异。SA5检验了初始阶段的个体差异 对酒精的敏感性可以预测在反复酒精暴露的情况下， 热梯度SA6测试了非药物挑战可以替代初始酒精的假设 在确定可靠的个体间反应变化，预测发展的挑战 失调如果一个人的可能性，我们的研究的转化影响将得到加强， 可以在不需要初始药物攻击的情况下评估发生的变稳态。拟议的研究将 通过使用严格的实验设计和方法， 包括连续测量变量，例如行为和代谢率反应， 自然主义或酒精引起的监管挑战。这一创新性的研究是基于一个强大的概念 框架，并在理论和实践上的重要性，以促进我们的知识和理解， 上瘾的潜在机制

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.