slo K(+) channel gene regulation mediates rapid drug tolerance.
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 naive 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.
Ghezzi
Alfredo
A
Section of Neurobiology, University of Texas, Austin, TX 78712, USA.
Al-Hasan
Yazan M
YM
Larios
Leo E
LE
Bohm
Rudolf A
RA
Atkinson
Nigel S
NS
D000818:Animals; D019905:Benzyl Alcohol / Q000494:pharmacology; D016292:Procedural Sedation; D004330:Drosophila; D029721:Drosophila Proteins; D004361:Drug Tolerance; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006948:Hyperkinesis; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009154:Mutation; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D019076:Transgenes
D029721:Drosophila Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; C494844:slo protein, Drosophila; D019905:Benzyl Alcohol