title: BK channels play a counter-adaptive role in drug tolerance and dependence.
abstract: Disturbance of neural activity by sedative drugs has been proposed to trigger a homeostatic response that resists unfavorable changes in net cellular excitability, leading to tolerance and dependence. The Drosophila slo gene encodes a BK-type Ca(2+)-activated K(+) channel implicated in functional tolerance to alcohol and volatile anesthetics. We hypothesized that increased expression of BK channels induced by these drugs constitutes the homeostatic adaptation conferring resistance to sedative drugs. In contrast to the dogmatic view that BK channels act as neural depressants, we show that drug-induced slo expression enhances excitability by reducing the neuronal refractory period. Although this neuroadaptation directly counters some effects of anesthetics, it also causes long-lasting enhancement of seizure susceptibility, a common symptom of drug withdrawal. These data provide a possible mechanism for the long-standing counter-adaptive theory for drug tolerance in which homeostatic adaptations triggered by drug exposure to produce drug tolerance become counter-adaptive after drug clearance and result in symptoms of dependence.
authors.affiliation: Section of Neurobiology and The Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX 78712, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ghezzi
authors.forename: Jascha B
authors.initials: JB
authors.lastname: Pohl
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Atkinson
mesh_terms: D000220:Adaptation, Biological; D000818:Animals; D001522:Behavior, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D004361:Drug Tolerance; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; C494844:slo protein, Drosophila
references.citation: Neuron. 2001 Sep 27;31(6):1015-25
references.pmid: 11580900
references.citation: J Comp Physiol A. 1992 Aug;171(1):93-104
references.pmid: 1328625
references.citation: J Neurophysiol. 2000 Feb;83(2):998-1009
references.pmid: 10669511
references.citation: J Neurophysiol. 2001 Sep;86(3):1211-25
references.pmid: 11535671
references.citation: Bull World Health Organ. 1965;32(5):721-33
references.pmid: 5294186
references.citation: J Neurosci. 2000 Apr 15;20(8):2988-93
references.pmid: 10751451
references.citation: J Neurosci. 2001 May 15;21(10):3429-42
references.pmid: 11331373
references.citation: Alcohol Clin Exp Res. 2006 May;30(5):745-53
references.pmid: 16634842
references.citation: Nat Genet. 2005 Jul;37(7):733-8
references.pmid: 15937479
references.citation: Brain Res. 2000 Mar 31;860(1-2):21-8
references.pmid: 10727620
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10446-51
references.pmid: 8816820
references.citation: BMC Genomics. 2003 Aug 12;4(1):33
references.pmid: 12914675
references.citation: J Physiol. 1998 Feb 15;507 ( Pt 1):257-64
references.pmid: 9490848
references.citation: News Physiol Sci. 2002 Aug;17:156-61
references.pmid: 12136044
references.citation: J Biol Chem. 2000 Jul 7;275(27):20588-96
references.pmid: 10781603
references.citation: Invert Neurosci. 1996 Jun;2(1):51-60
references.pmid: 9372155
references.citation: Science. 1988 Nov 4;242(4879):715-23
references.pmid: 2903550
references.citation: J Neurophysiol. 1980 Aug;44(2):405-21
references.pmid: 6774064
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17276-81
references.pmid: 15569939
references.citation: Curr Opin Neurobiol. 1998 Jun;8(3):321-9
references.pmid: 9687354
references.citation: Alcohol Clin Exp Res. 2004 Oct;28(10):1469-80
references.pmid: 15597078
references.citation: Res Publ Assoc Res Nerv Ment Dis. 1968;46:206-25
references.pmid: 5749385
references.citation: J Physiol. 2007 May 1;580(Pt.3):859-82
references.pmid: 17303637
references.citation: J Neurosci. 2004 Sep 22;24(38):8322-32
references.pmid: 15385615
references.citation: Epilepsy Behav. 2009 Jun;15(2):92-7
references.pmid: 19249388
references.citation: Nat Neurosci. 2005 Dec;8(12):1752-9
references.pmid: 16261134
references.citation: Neuron. 2008 Jul 31;59(2):274-87
references.pmid: 18667155
references.citation: Psychol Rev. 1974 Mar;81(2):119-45
references.pmid: 4817611
references.citation: J Neurocytol. 1980 Dec;9(6):753-70
references.pmid: 6782199
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2053-8
references.pmid: 12566570
references.citation: Mol Pharmacol. 2002 Jul;62(1):135-42
references.pmid: 12065764
references.citation: Alcohol Clin Exp Res. 1999 Nov;23(11):1848-52
references.pmid: 10591603
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2141-6
references.pmid: 15677721
references.citation: J Neurosci. 2002 Dec 15;22(24):11065-79
references.pmid: 12486202
references.citation: Science. 1991 Aug 2;253(5019):551-5
references.pmid: 1857984
references.citation: J Neurosci. 2004 Feb 18;24(7):1594-603
references.pmid: 14973247