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Kcnn3 as a target for treating aberrant behaviors in stressed, ethanol-dependent mice

Audrey E. Padula, Jennifer A. Rinker, Fauzan Khan, Marcelo F. Lopez, Megan K. Mulligan, Robert W. Williams, Howard C. Becker, Patrick J. Mulholland
doi: https://doi.org/10.1101/734970
Audrey E. Padula
1Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425
2Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, 29425
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Jennifer A. Rinker
1Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425
2Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, 29425
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Fauzan Khan
1Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425
2Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, 29425
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Marcelo F. Lopez
2Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, 29425
3Department of Psychiatry & Behavioral Science, Medical University of South Carolina, Charleston, SC, 29425
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Megan K. Mulligan
4Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, 38163
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Robert W. Williams
4Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, 38163
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Howard C. Becker
2Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, 29425
3Department of Psychiatry & Behavioral Science, Medical University of South Carolina, Charleston, SC, 29425
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Patrick J. Mulholland
1Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425
2Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, 29425
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  • For correspondence: mulholl@musc.edu
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Abstract

Anxiety and mood disorders are often comorbid with alcohol use disorder (AUD) and are considered critical in the development, maintenance, and reinstatement of alcohol dependence and harmful alcohol-seeking behaviors. Because of this high comorbidity, it is necessary to determine shared and unique genetic factors driving heavy ethanol drinking and anxiety-related behaviors. We used a model of stress-induced escalation of drinking in ethanol dependent C57BL/6J mice to measure anxiety-like behaviors on the marble burying and novelty-suppressed feeding task (NSFT) during abstinence. In order to identify novel pharmacogenetic targets that may lead to more effective treatment, a targeted bioinformatics analysis was used to quantify the expression of K+ channel genes in the amygdala that covary with anxiety-related phenotypes in the well phenotyped and fully sequenced family of BXD strains. A pharmacological approach was used to validate the key bioinformatics finding in ethanol-dependent, stressed C57BL/6J mice during the NSFT. Amygdalar expression of Kcnn3 correlated significantly with just over 40 anxiety-associated phenotypes. Further examination of Kcnn3 expression revealed a strong eigentrait for anxiety-like behaviors in this family. Kcnn3 expression in the amygdala correlated negatively with binge-like and voluntary ethanol drinking. C57BL/6J mice treated with chronic intermittent ethanol exposure and repeated swim stress consumed more ethanol in their home cages and showed hypophagia on the NSFT during prolonged abstinence. Pharmacologically targeting KCNN3 protein with the KCa2 channel positive modulator 1-EBIO decreased ethanol drinking and reduced latency to approach food during the NSFT in ethanol-dependent, stressed mice. Collectively these validation studies provide central nervous system mechanistic links into to the covariance of stress, anxiety, and AUD in the BXD strains. Further this analytical approach is effective in defining targets for treating alcohol dependence and comorbid mood and anxiety disorders.

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Posted August 14, 2019.
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Kcnn3 as a target for treating aberrant behaviors in stressed, ethanol-dependent mice
Audrey E. Padula, Jennifer A. Rinker, Fauzan Khan, Marcelo F. Lopez, Megan K. Mulligan, Robert W. Williams, Howard C. Becker, Patrick J. Mulholland
bioRxiv 734970; doi: https://doi.org/10.1101/734970
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Kcnn3 as a target for treating aberrant behaviors in stressed, ethanol-dependent mice
Audrey E. Padula, Jennifer A. Rinker, Fauzan Khan, Marcelo F. Lopez, Megan K. Mulligan, Robert W. Williams, Howard C. Becker, Patrick J. Mulholland
bioRxiv 734970; doi: https://doi.org/10.1101/734970

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