The hangover gene defines a stress pathway required for ethanol tolerance development

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Abstract
Improbable as it may seem, Drosophila fruit flies can be used as a model for alcohol-induced behaviours. Exposed to ethanol vapour in a device known as an inebriometer (it looks like a glass condenser), they lose control of their posture and sink to the bottom of the tube within 20 minutes. Repeated alcohol consumption leads to tolerance, but not in flies with a newly identified mutation. Flies with this hangover mutation also have a shortened life span and are more susceptible to stresses such as heat and insecticides. There is growing recognition that cellular and systemic stress contributes to drug- and addiction-related behaviours in mammals, and these studies suggest that this role may be conserved in evolution. Repeated alcohol consumption leads to the development of tolerance, simply defined as an acquired resistance to the physiological and behavioural effects of the drug. This tolerance allows increased alcohol consumption, which over time leads to physical dependence and possibly addiction1,2,3. Previous studies have shown that Drosophila develop ethanol tolerance, with kinetics of acquisition and dissipation that mimic those seen in mammals. This tolerance requires the catecholamine octopamine, the functional analogue of mammalian noradrenaline4. Here we describe a new gene, hangover, which is required for normal development of ethanol tolerance. hangover flies are also defective in responses to environmental stressors, such as heat and the free-radical-generating agent paraquat. Using genetic epistasis tests, we show that ethanol tolerance in Drosophila relies on two distinct molecular pathways: a cellular stress pathway defined by hangover, and a parallel pathway requiring octopamine. hangover encodes a large nuclear zinc-finger protein, suggesting a role in nucleic acid binding. There is growing recognition that stress, at both the cellular and systemic levels, contributes to drug- and addiction-related behaviours in mammals. Our studies suggest that this role may be conserved across evolution.

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