Ethanol induces maladaptive impulse control and decreased seeking behaviors in mice

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.

Chronic Alcohol Exposure Induces Aberrant Mitochondrial Morphology and Inhibits Respiratory Capacity in the Medial Prefrontal Cortex of Mice

“…Chronic intermittent alcohol exposure also increases mPFCassociated maladaptive impulse and reward-seeking behaviors (Starski et al, 2019a). More specifically, the infralimbic and prelimbic cortex are involved in ethanol seeking, Pavlovian fear conditioning, and learning alternatives (Palombo et al, 2017;Mukherjee and Caroni, 2019).…”

“…Alcohol vapor or air was delivered in Plexiglas inhalation chambers, as previously described (Griffin et al, 2009). We have used the vapor chamber system previously to successfully maintain stable blood alcohol concentration (BAC) in mice (Hong et al, 2019;Starski et al, 2019a). Mice were exposed to alcohol vapor or room air using vapor administration chambers for 16 h from 1600 to 0900, followed by 8 h of room air in their home cages.…”

“…Moreover, projections from mPFC to subcortical sites, including the extended amygdala and nucleus accumbens, were disrupted in AUDs, causing abnormalities in impulsivity and associative learning (Klenowski, 2018). According to our previous study, chronic intermittent alcohol (CIA) exposure triggers abnormal impulse and reward-seeking behaviors, which are associated with the mPFC and underlying changes in proteomic profiles (Starski et al, 2019a).…”

An ultra-low frequency spike timing dependent plasticity-based approach for treating alcohol use disorder

“…A standard two-bottle choice paradigm was used to assess alcohol consumption 63 . Briefly, two bottles were presented daily: one containing water and the other alcohol 64 . The position of the alcohol and water bottles was swapped daily to reduce confounds produced by location preference.…”

Low alcohol preferring mice have reduced task engagement during a waiting task for alcohol, which is enhanced by intermittent alcohol drinking

“…While determining clear correlations between behavioral factors in human studies remains challenging, rodent studies give the ability to dissect important contributors to behavioral engagement for alcohol. However, to date, studies examining the relation of alcohol and impulsivity have primarily determined 5-CSRTT responding for sugar in relation to alcohol exposure (25)(26)(27)(28)(29)(30)(31).…”