You et al KCNK13 Neuropharmacology final complete.pdf (1.91 MB)
Ethanol acts on KCNK13 potassium channels in the ventral tegmental area to increase firing rate and modulate binge–like drinking
journal contributionposted on 2019-03-29, 00:00 authored by Chang You, Antonia Savarese, Bertha J. Vandegrift, Donghong He, Subhash C. Pandey, Amy W. Lasek, Mark S. Brodie
Alcohol excitation of the ventral tegmental area (VTA) is important in neurobiological processes related to the development of alcoholism. The ionotropic receptors on VTA neurons that mediate ethanol-induced excitation have not been identified. Quinidine blocks ethanol excitation of VTA neurons, and blockade of two-pore potassium channels is among the actions of quinidine. Therefore two-pore potassium channels in the VTA may be potential targets for the action of ethanol. Here, we explored whether ethanol activation of VTA neurons is mediated by the two-pore potassium channel KCNK13. Extracellular recordings of the response of VTA neurons to ethanol were performed in combination with knockdown of Kcnk13 using a short hairpin RNA (shRNA) in C57BL/6 J mice. Real-time PCR and immunohistochemistry were used to examine expression of this channel in the VTA. Finally, the role of KCNK13 in binge-like drinking was examined in the drinking in the dark test after knockdown of the channel. Kcnk13 expression in the VTA was increased by acute ethanol exposure. Ethanol-induced excitation of VTA neurons was selectively reduced by shRNA targeting Kcnk13. Importantly, knockdown of Kcnk13 in the VTA resulted in increased alcohol drinking. These results are consistent with the idea that ethanol stimulates VTA neurons at least in part by inhibiting KCNK13, a specific two-pore potassium channel, and that KCNK13 can control both VTA neuronal activity and binge drinking. KCNK13 is a novel alcohol-sensitive molecular target and may be amenable to the development of pharmacotherapies for alcoholism treatment.
The authors gratefully acknowledge that this work was supported by PHS Grant R01AA05846 (MSB) and P50AA022538 (SCP; AWL; MSB). Contributions by Dr. Sarah B. Appel to initial work that served as a prelude to the studies reported here is acknowledged.
CitationYou, C., Savarese, A., Vandegrift, B. J., He, D. H., Pandey, S. C., Lasek, A. W., & Brodie, M. S. (2019). Ethanol acts on KCNK13 potassium channels in the ventral tegmental area to increase firing rate and modulate binge-like drinking. Neuropharmacology, 144, 29-36. doi:10.1016/j.neuropharm.2018.10.008