BK channels play a counter-adaptive role in drug tolerance and dependence.

Alfredo Ghezzi, Jascha B Pohl, Yan Wang, Nigel S Atkinson

Section of Neurobiology and The Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX 78712, USA.

Proceedings of the National Academy of Sciences of the United States of America 2010 Sep 14

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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.

Citation

Alfredo Ghezzi, Jascha B Pohl, Yan Wang, Nigel S Atkinson. BK channels play a counter-adaptive role in drug tolerance and dependence. Proceedings of the National Academy of Sciences of the United States of America. 2010 Sep 14;107(37):16360-5