Wininger, Katheryn

AbstractDisruptions in circadian rhythms are risk factors for excessive alcohol drinking. The ethanol‐sensitive adenosine equilibrative nucleoside transporter type 1 (ENT1, slc29a1) regulates ethanol‐related behaviors, sleep, and entrainment of circadian rhythms. However, the mechanism underlying the increased ethanol consumption in ENT1 knockout (KO) mice in constant light (LL) and whether there are sex differences in ethanol consumption in ENT1 mice are less studied. Here, we investigated the effects of loss of ENT1, LL, and sex on ethanol drinking using two‐bottle choice. In addition, we monitored the locomotor activity rhythms. We found that LL increased ethanol drinking and reduced accumbal ENT1 expression and adenosine levels in male but not female mice, compared with control mice. Interestingly, only LL‐exposed male, not female, ENT1 KO mice exhibited higher ethanol drinking and a longer circadian period with a higher amplitude compared with wild‐type (WT) mice. Furthermore, viral‐mediated rescue of ENT1 expression in the NAc of ENT1 KO mice reduced ethanol drinking, demonstrating a possible causal link between ENT1 expression and ethanol drinking in males. Together, our findings indicate that deficiency of ENT1 expression contributes to excessive ethanol drinking in a sex‐dependent manner.

Abstract Waiting impulsivity is a risk factor for many psychiatric disorders including alcohol use disorder (AUD). Highly impulsive individuals are vulnerable to alcohol abuse. However, it is not well understood whether chronic alcohol use increases the propensity for impulsive behavior. Here, we establish a novel experimental paradigm demonstrating that continuous binge‐like ethanol exposure progressively leads to maladaptive impulsive behavior. To test waiting impulsivity, we employed the 5‐choice serial reaction time task (5‐CSRTT) in C57BL/6J male mice. We assessed premature responses in the fixed and variable intertrial interval (ITI) 5‐CSRTT sessions. We further characterized our ethanol‐induced impulsive mice using Open Field, y‐maze, two‐bottle choice, and an action‐outcome task. Our results indicate that continuous binge‐like ethanol exposure significantly increased premature responses when mice were tested in variable ITI sessions even during a prolonged abstinent period. Ethanol‐induced impulsive mice exhibited anxiety‐like behavior during chronic exposures. This behavior was also observed in a separate cohort that was subjected to 20 days of abstinence. Ethanol‐treated mice were less motivated for a sucrose reward compared with air‐exposed control mice, while also demonstrating reduced responding during action‐outcome testing. Overall, ethanol‐treated mice demonstrated increased impulsive behavior, but a reduced motivation for a sucrose reward. Although waiting impulsivity has been hypothesized to be a trait or risk factor for AUD, our findings indicate that maladaptive impulse control can also be potentiated or induced by continuous chronic ethanol exposure in mice.