Activation of anoctamin-1 calcium-activated chloride channels reduces voluntary alcohol consumption in rats

Abstract

Repeated episodes of binge drinking can lead to an alcohol use disorder, yet the underlying pharmacological mechanisms are still not fully understood. Nevertheless, emerging evidence indicates that Ca²⁺-dependent signaling effectively reduces alcohol consumption without affecting water intake. Therefore, activating anoctamin1 (ANO1), a Ca²⁺-activated chloride channel and a component of Ca²⁺-dependent signaling, can similarly decrease alcohol drinking while maintaining normal water intake. This study investigates how activation of ANO1 channels with EACT affects voluntary alcohol consumption in male and female Sprague-Dawley rats using the intermittent alcohol access method in a two-bottle choice paradigm. Rats were trained to drink 7.5 % ethanol or water for four weeks before administering either EACT (2.5, 5, and 10 mg/kg). Afterward, their alcohol intake, preference, and water intake were systematically recorded 2 and 24 h after exposure to water and 7.5 % ethanol solution. The results indicated that female rats consumed more alcohol than males. Furthermore, activating ANO1 channels with EACT significantly decreased alcohol intake and preference in males, only at the 5 mg/kg dose; in females, this effect was observed as a linear response at both the 5 and 10 mg/kg doses, highlighting distinct sex-related differences. Additionally, the inhibitory effect of EACT on alcohol consumption was associated with increased water intake in females, suggesting a potential influence of EACT on thirst homeostasis. Collectively, these findings highlight the differential effects of EACT on alcohol intake, preference, and water intake based on sex, and underscore the complexity of consummatory behavior mechanisms.