Abstract
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.
Original language | English (US) |
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Article number | e12884 |
Journal | Genes, Brain and Behavior |
Volume | 23 |
Issue number | 1 |
DOIs | |
State | Published - Feb 2024 |
Funding
We thank members of the Rothenfluh and Rodan labs for continued discussion and the reviewers for helpful suggestions. Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) were used in this study. This work was supported by the NIH: grants F31AA030209 to M.M.C, K01AA029200 to C.B.M., R01DK110358 to A.R.R., and R01AA026818 & R01AA019526-S1 to A.R. We thank members of the Rothenfluh and Rodan labs for continued discussion and the reviewers for helpful suggestions. Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) were used in this study. This work was supported by the NIH: grants F31AA030209 to M.M.C, K01AA029200 to C.B.M., R01DK110358 to A.R.R., and R01AA026818 & R01AA019526‐S1 to A.R.
Keywords
- Drosophila
- ethanol
- genetics
- sensitivity
- tolerance
ASJC Scopus subject areas
- Genetics
- Neurology
- Behavioral Neuroscience