The role of circadian genes in tolerance to ethanol in Drosophila melanogaster

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Pohl, Jascha Benjamin, 1981-

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Alcoholism is a devastating inheritable disease that causes a large fiscal and societal impact worldwide. The fruit fly, Drosophila melanogaster, has proven to be a useful model system in identifying genetic factors underlying ethanol-associated behaviors. Many genes have been identified in the fly that are involved in the acquisition of tolerance, or the reduced response of an effect of a drug caused by previous exposure. In this thesis, I investigated whether circadian genes are involved in tolerance to ethanol in the fly. Circadian genes had previously been implicated in cocaine sensitization in flies, as well as some ethanol responses in mammals. I developed a novel assay using a bootstrapping paradigm to analyze tolerance to ethanol in the fly that allows for the investigation of multiple components of tolerance. I then used this assay to test whether circadian genes were necessary for the acquisition of tolerance in the fly. Interestingly, only some circadian genes affect tolerance to ethanol. These results argues that circadian genes are involved in tolerance to ethanol, but because some mutants are arrhythmic but still acquire tolerance, that they are acting in a role outside of the circadian system. While in the course of this work, I intended to investigate if these mutations affected ethanol preference in a two-choice assay. Before employing this assay, however, we wished to determine if flies prefer ethanol for its pharmacological effect or for its value as a food. Weperformed experiments in which flies had a choice between food supplemented with ethanol and food supplemented with an isocaloric carbohydrate. When presented with the isocaloric alternative, flies no longer demonstrated preference for ethanol. Flies will even stop showing preference for ethanol when switched to a balanced assay after preference has already been attained. We conclude that the flies prefer ethanol not because of its effect as a drug, but as a food source.




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