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

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，异位状态激发药物使用的升级， 造成以失控和强制吸毒为特征的恶性循环。虽然只是一个谦虚的 吸毒成瘾的人比例很高，给社会带来的总代价是巨大的。因此， 了解成瘾易感性个体差异的原因机制有很高的意义。 优先考虑。我们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，以及向平衡失调的过渡。R21阶段建议开发一种新的 供大鼠居住的乙醇蒸汽暴露室内，也可用于乙醇蒸汽自我给药。 特定目标1(SA1)制造该装置并测试其输送特定乙醇蒸气的可靠性 集中并将其从密封室中清除。SA2将测量吸入的乙醇蒸气与 浓度和血液酒精水平，并通过评估个体来验证仪器的功能 初始敏感度、自我管理习得和慢性耐受程度的差异 发展。SA3验证了酒精蒸气在内置式温度梯度装置中的使用。在R33阶段， SA4测试了一种假设，即个体对酒精的初始敏感性差异可靠地预测了持久性 酒精蒸气自我给药的差异。SA5测试了一种假设，即初始阶段的个体差异 对酒精的敏感性可预测反复酒精暴露后的变态平衡失调的发生 温度梯度。SA6测试了非药物挑战可以替代初始酒精的假设 确定可靠的个体间反应变异以预测变态反应的发展面临的挑战 监管失调。我们研究的翻译影响将会增强，如果一个人的可能性 可以在不需要最初的药物挑战的情况下对发展中的异物作用进行评估。拟议的研究将 通过使用严格的实验设计和方法提供可靠和公正的结果 包括连续测量变量，如行为和代谢率反应 自然主义或酒精引发的监管挑战。这项创新性的研究建立在强大的概念性基础上 框架，对于增进我们对……的认识和理解具有重要的理论和实践意义 令人上瘾的脆弱性背后的机制。

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.