slo K+ channel gene regulation mediates rapid drug tolerance

doi:10.1073/pnas.0405584101

slo K⁺ channel gene regulation mediates rapid drug tolerance

Section of Neurobiology, University of Texas, Austin, TX 78712

Edited by Charles F. Stevens, The Salk Institute for Biological Studies, La Jolla, CA, and approved October 25, 2004 (received for review July 30, 2004)

Abstract

Changes in neural activity caused by exposure to drugs may trigger homeostatic mechanisms that attempt to restore normal neural excitability. In Drosophila, a single sedation with the anesthetic benzyl alcohol changes the expression of the slo K⁺ channel gene and induces rapid drug tolerance. We demonstrate linkage between these two phenomena by using a mutation and a transgene. A mutation that eliminates slo expression prevents tolerance, whereas expression from an inducible slo transgene mimics tolerance in naïve animals. The behavioral response to benzyl alcohol can be separated into an initial phase of hyperkinesis and a subsequent phase of sedation. The hyperkinetic phase causes a drop in slo gene expression and makes animals more sensitive to benzyl alcohol. It is the sedative phase that stimulates slo gene expression and induces tolerance. We demonstrate that the expression level of slo is a predictor of drug sensitivity.

Footnotes

↵ † To whom correspondence should be addressed at: University of Texas, 1 University Station C0920, Austin, TX 78712-0248. E-mail: nigela{at}mail.utexas.edu.
↵ * Present address: Division of Neuroscience, Children's Hospital, and Department of Neurobiology, Harvard Medical School, Boston, MA 02115.
Author contributions: A.G., Y.M.A.-H., R.A.B., and N.S.A. designed research; A.G., Y.M.A.-H., L.E.L., and R.A.B. performed research; A.G., Y.M.A.-H., and N.S.A. analyzed data; and A.G., Y.M.A.-H., and N.S.A. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.