Summary: The slowpoke Gene Is Necessary for Rapid Ethanol
Tolerance in Drosophila
R.B. Cowmeadow, H.R. Krishnan, and N.S. Atkinson
Background: Ethanol is one of the most commonly used drugs in the world. We are interested in the
compensatory mechanisms used by the nervous system to counter the effects of ethanol intoxication.
Recently, the slowpoke BK-type calcium-activated potassium channel gene has been shown to be involved
in ethanol sensitivity in Caenorhabditis elegans and in rapid tolerance to the anesthetic benzyl alcohol in
Methods: We used Drosophila mutants to investigate the role of slowpoke in rapid tolerance to sedation
with ethanol vapor. Rapid tolerance was defined as a reduction in the sedative phase caused by a single
previous sedation. The ethanol and water contents of flies were measured to determine if pharmacody-
namic changes could account for tolerance.
Results: A saturated ethanol air stream caused sedation in 20 min and resulted in rapid tolerance that
was apparent 4 hr after sedation. Two independently isolated null mutations in the slowpoke gene elimi-
nated the capacity for tolerance. In addition, a third mutation that blocked expression specifically in the
nervous system also blocked rapid tolerance. Water measurements showed that both ethanol and mock
sedation caused equivalent dehydration. Furthermore, a single prior exposure to ethanol did not cause a
change in the ethanol clearance rate.
Conclusions: Rapid tolerance, measured as a reduction in the duration of sedation, is a pharmacokinetic
response to ethanol that does not occur without slowpoke expression in the nervous system in Drosophila.