Department of Psychiatry, Huntsman Mental Health Institute, School of Medicine, University of Utah, Salt Lake City, Utah, USA.
Neuroscience Graduate Program, University of Utah, Salt Lake City, Utah, USA.
Genes Brain Behav. 2024 Feb;23(1):e12884. doi: 10.1111/gbb.12884.
Tolerance occurs when, following an initial experience with a substance, more of the substance is required subsequently to induce identical behavioral effects. Tolerance is not well-understood, and numerous researchers have turned to model organisms, particularly Drosophila melanogaster, to unravel its mechanisms. Flies have high translational relevance for human alcohol responses, and there is substantial overlap in disease-causing genes between flies and humans, including those associated with Alcohol Use Disorder. Numerous Drosophila tolerance mutants have been described; however, approaches used to identify and characterize these mutants have varied across time and labs and have mostly disregarded any impact of initial resistance/sensitivity to ethanol on subsequent tolerance development. Here, we analyzed our own, as well as data published by other labs to uncover an inverse correlation between initial ethanol resistance and tolerance phenotypes. This inverse correlation suggests that initial resistance phenotypes can explain many 'perceived' tolerance phenotypes, thus classifying such mutants as 'secondary' tolerance mutants. Additionally, we show that tolerance should be measured as a relative increase in time to sedation between an initial and second exposure rather than an absolute change in time to sedation. Finally, based on our analysis, we provide a method for using a linear regression equation to assess the residuals of potential tolerance mutants. These residuals provide predictive insight into the likelihood of a mutant being a 'primary' tolerance mutant, where a tolerance phenotype is not solely a consequence of initial resistance, and we offer a framework for understanding the relationship between initial resistance and tolerance.
当在经历一种物质的初始体验后，需要更多的该物质才能引起相同的行为效应时，就会发生耐受性。目前对耐受性的了解还不够充分，许多研究人员转向模式生物，特别是黑腹果蝇，以揭示其机制。果蝇与人的酒精反应有很高的翻译相关性，并且果蝇和人类之间存在大量的致病基因重叠，包括与酒精使用障碍相关的基因。已经描述了许多果蝇耐受突变体；然而，用于识别和表征这些突变体的方法在时间和实验室之间有所不同，并且大多忽略了对乙醇的初始抗性/敏感性对随后的耐受性发展的任何影响。在这里，我们分析了我们自己的以及其他实验室发表的数据，以揭示初始乙醇抗性与耐受性表型之间的反比关系。这种反比关系表明，初始抗性表型可以解释许多“感知”的耐受性表型，因此将此类突变体归类为“继发性”耐受性突变体。此外，我们表明，耐受性应该作为在初始和第二次暴露之间镇静时间的相对增加来测量，而不是镇静时间的绝对变化。最后，基于我们的分析，我们提供了一种使用线性回归方程来评估潜在的耐受性突变体残差的方法。这些残差提供了对突变体成为“原发性”耐受性突变体的可能性的预测性洞察，其中耐受性表型不仅仅是初始抗性的结果，我们提供了一个理解初始抗性和耐受性之间关系的框架。
