Molecular mechanisms of alcohol tolerance in the fruit fly

Large conductance calcium-activated potassium channels have been shown to be potentiated by physiologically relevant acute doses of ethanol. Here I show that ethanol sedation increased transcription of the slowpoke gene, which encodes a largeconductance calcium-activated potassium channel, in the nervous system of the fruit fly Drosophila melanogaster, six hours after ethanol sedation. Twenty-four hours after sedation, neural slowpoke expression was decreased. Sedation with ethanol also induced tolerance that developed within four hours of sedation and persisted for at least seven days. Drosophila lacking slowpoke expression only in the nervous system were unable to acquire tolerance and flies which over-expressed slowpoke displayed resistance to the sedating effects of ethanol. The expression of several other ion channels was also increased six hours after ethanol sedation, however no other ion channel mutant tested showed a deficit in the capacity to acquire tolerance. Wild-type and slowpoke mutant flies showed no differences in ethanol metabolism following ethanol sedation that could account for the tolerance or lack of it. Therefore the slowpoke gene appears to play a unique role in the phenomenon of tolerance.