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Summary: Drug-Induced Epigenetic Changes
Produce Drug Tolerance
Yan Wang1,6
, Harish R. Krishnan1,2
, Alfredo Ghezzi3
, Jerry C. P. Yin4,5
, Nigel S. Atkinson1,6*
1 Section of Neurobiology, The University of Texas at Austin, Austin, Texas, United States of America, 2 Institute for Neuroscience, The University of Texas at Austin, Austin,
Texas, United States of America, 3 Department of Biology, Brandeis University, Waltham, Massachusetts, United States of America, 4 Department of Genetics, University of
Wisconsin-Madison, Madison, Wisconsin, United States of America, 5 Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin, United States of
America, 6 The Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America
Tolerance to drugs that affect neural activity is mediated, in part, by adaptive mechanisms that attempt to restore
normal neural excitability. Changes in the expression of ion channel genes are thought to play an important role in
these neural adaptations. The slo gene encodes the pore-forming subunit of BK-type Ca2þ
-activated Kþ
channels, which
regulate many aspects of neural activity. Given that induction of slo gene expression plays an important role in the
acquisition of tolerance to sedating drugs, we investigated the molecular mechanism of gene induction. Using
chromatin immunoprecipitation followed by real-time PCR, we show that a single brief sedation with the anesthetic
benzyl alcohol generates a spatiotemporal pattern of histone H4 acetylation across the slo promoter region. Inducing
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