<i>Dpp6</i> knockout mice exhibit increased ethanol conditioned place preference and acute ethanol‐induced anxiolytic behavior

BACKGROUND: 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. METHODS: To further assess the role of this gene in ethanol-related traits, we tested Dpp6 knockout (KO) and wild-type mice for ethanol (EtOH) conditioned place preference (CPP), locomotor activity, and ethanol-induced anxiolysis. RESULTS: Male homozygous KO mice (HOM) showed greater preference for the ethanol-paired (2 g/kg) 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 2 min. In a separate experiment, HOM mice showed enhanced locomotor activity following a 1.5 g/kg EtOH 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 min, 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. CONCLUSIONS: Ultimately, these findings validate a role for Dpp6 in modulating ethanol's rewarding, anxiolytic, and sedative effects in a sex-dependent manner.