KCa2 channel positive modulation reduces alcohol drinking in female C57BL/6J mice

Abstract

Although men have historically exhibited higher levels of alcohol use disorder (AUD) diagnosis, the gap between men and women has been diminishing quickly. Preclinical screening for pharmacological treatments for AUD has typically focused solely on males, ignoring the possibility that males and females may differ mechanistically for the same behavioral phenotype. To ensure the efficacy of treatment targets across the sexes, it is crucial to study the pharmacological effects of AUD treatments in males and females. While positive K_Ca2 channel modulation can reduce ethanol consumption and seeking behaviors, withdrawal-induced hyperexcitability, and negative affective behaviors in male rodents, the effect of K_Ca2 channel modulation on female ethanol consumption has not been reported. To determine the efficacy of K_Ca2 channel positive modulation in female C57BL/6J mice, we assessed the ability of the K_Ca2 channel positive modulator 1-EBIO to affect locomotor activity, voluntary home cage ethanol intake prior to and following chronic intermittent ethanol (CIE) exposure, and voluntary home cage sucrose drinking. There were no significant changes to distance traveled in an open field apparatus following administration of 1-EBIO in our locomotor assay. In ethanol drinking mice, 1-EBIO significantly reduced ethanol consumption in air controls and CIE exposed mice, without altering water consumption. While administration of 1-EBIO did not affect consumption of sucrose in male mice, 1-EBIO significantly increased sucrose intake in females. Together, these data provide further evidence that K_Ca2 channel positive modulation is a promising therapeutic target to reduce ethanol drinking in males and females alike.