M Hernández¹, R Sultana¹, D-J Paredes¹, AM Barkley-Levenson¹

Recent genome wide association studies (GWAS) have identified numerous novel hits for problematic alcohol use and alcohol consumption. However, follow-up studies are still needed to demonstrate a causal relationship between implicated genes and alcohol-related traits. Here, we describe the functional validation of Dpp6, which is a novel genetic association for problematic alcohol use and alcohol drinking. Dpp6 encodes an auxiliary subunit of A-type voltage-gated potassium channels and is involved in modulating dendritic excitability and synaptic plasticity. We have found that global knockout of Dpp6 does not alter ethanol binge-like drinking or total consumption in a chronic intermittent two-bottle choice procedure, but does produce an escalation in ethanol preference over time in this procedure compared to wild type (WT) littermates. Knockout mice also show greater binge-like sucrose intake in a single bottle procedure, but do not differ from WT in sucrose preference in a two-bottle choice test. However, we do see a significant increase in ethanol sensitivity in the knockout mice compared to WTs across multiple behaviors (ethanol conditioned place preference, locomotor sedation, and ethanol-induced anxiolysis) following ethanol injections, suggesting that route of administration may be relevant for the genotypic differences observed in this model. Taken together, these findings confirm that loss of Dpp6 does impact multiple ethanol-associated behavioral phenotypes, even without significantly altering voluntary ethanol consumption.

¹Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.

Funding support: NIH-NIAAA grant R00AA027835, NIH-NIGMS grant K12GM088021