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Author Notes:

Correspondence: Inyeong Choi, ichoi@emory.edu

I.C. led the project and wrote the manuscript. I.C. also performed alcohol-drinking behavior experiments.

J.R.S. and S.L. analyzed and interpreted data and edited the manuscript. C.E.G. performed electrophysiological recordings.

S.E.N., H.D.F., and J.C. (Emory) performed alcohol-related behavior experiments. J.M.L. performed perfusion/fxation.

Y.K. measured pH. L.A.J generated chronically alcohol-fed mice. J.C (UGA) and J.-K.L. collected brains from alcohol-fed and control mice. Z.J. performed qPCR in human brains.

C.A. and E.B. provided knockout mice. E.B. performed immunohistochemistry. All authors contributed to data analysis and interpretation.

The authors thank Dr. Michael Koval for providing brains of alcohol-fed and pair-fed mice, and Dr. Bryndis Birnir (Uppsala University, Sweden) for qPCR in post-mortem human brain tissues.

The authors also thank Jane H. Roenn (Aarhus University, Denmark) for expert technical assistance and Jason Lin for editing the manuscript.

The authors declare no competing interests.

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Research Funding:

Te work was supported by the National Institute of Health Pathway to Independence Award [AA021805] and the University of Georgia (J.R.S.) and by the NIH [GM078502-S], Emory University Research Committee and American Heart Association [14GRNT20480379] (I.C.).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • Intracellular pH Regulators
  • Cotransporter NBCN1
  • Functional characterization
  • Ethanol
  • SLC4A7
  • Expression
  • Quantification
  • Disruption
  • Modulation
  • Mechanism

Increased Alcohol Consumption in Mice Lacking Sodium Bicarbonate Transporter NBCn1

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Journal Title:

Scientific Reports

Volume:

Volume 10, Number 1

Publisher:

, Pages 11017-11017

Type of Work:

Article | Final Publisher PDF

Abstract:

The previous reports on an addiction vulnerability marker in the human SLC4A7 gene encoding the Na/HCO3 transporter NBCn1 suggest that this pH-regulating protein may affect alcohol-related behavior and response. Here, we examined alcohol consumption and sensitivity to the sedative effects of alcohol in male NBCn1 knockout mice. These mice displayed lower pH in neurons than wildtype controls, determined by intracellular pH in hippocampal neuronal cultures. Neurons from knockout mice had a higher action potential threshold and a more depolarized membrane potential, thus reducing membrane excitability. In a two-bottle free choice procedure, knockout mice consumed more alcohol than controls and consistently increased alcohol consumption after repeated alcohol deprivation periods. Quinine and sucrose preference was similar between genotypes. Knockout mice showed increased propensity for alcohol-induced conditioned place preference. In loss of righting reflex assessment, knockout mice revealed increased sensitivity to alcohol-induced sedation and developed tolerance to the sedation after repeated alcohol administrations. Furthermore, chronic alcohol consumption caused NBCn1 downregulation in the hippocampus and striatum of mice and humans. These results demonstrate an important role of NBCn1 in regulation of alcohol consumption and sensitivity to alcohol-induced sedation.

Copyright information:

© The Author(s) 2020.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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