Dpp6 Homozygous Knockout Mice Exhibit Increased Ethanol Conditioned Place Preference and Acute Ethanol-Induced Anxiolytic Behavior

The gene DPP6 has been associated with behavioral phenotypes of alcohol use disorder (AUD) in recent human genome wide association studies. DPP6 encodes an auxiliary subunit that modulates A-type voltage-gated potassium channels, particularly Kv4.2. To further assess the role of this gene in ethanol-related traits, we tested Dpp6 knockout (KO) mice for ethanol conditioned place preference (CPP), locomotor activity, and ethanol-induced anxiolysis. Male homozygous KO mice (HOM) showed greater preference for the ethanol-paired context compared to wild type littermates (WT) and heterozygous KO mice (HET), while female mice showed no genotypic difference. HOM of both sexes exhibited greater novelty-induced hyperactivity in the CPP apparatus than HET and WT mice in the first two minutes. In a separate experiment, HOM mice showed enhanced locomotor activity following a 1.5 g/kg ethanol injection; however, they also displayed greater locomotor activity during habituation, suggesting basal locomotor differences. Following 1.5 and 2 g/kg injections, HOM mice exhibited EtOH-induced anxiolysis in the first 5 minutes, while the HET and WT mice did not. Lastly, HOM mice displayed a significant sedative response compared to WT animals following a 2 g/kg injection of ethanol. Ultimately, these findings validate a role for Dpp6 in modulating ethanols rewarding, anxiolytic, and sedative effects in a sex-dependent manner.