Reinforcement History Dependent Effects of Low Dose Ethanol on Reward Motivation in Male and Female Mice

Abstract

Alcohol use disorders (AUDs) are more prevalent in men than in women, though AUD diagnoses in women are growing rapidly, making an understanding of sex differences in alcohol-related behaviors increasingly important. The development of AUDs involves the transition from casual, low levels of alcohol drinking to higher, maladaptive levels. The ability of low dose alcohol to drive reward and drug seeking may differ in males and females, and this could underlie differences in susceptibility to AUD. In this study we sought to determine whether a history of chronic, low dose ethanol exposure (0.5 g/kg; i.p.) could drive sucrose reward seeking and motivation, and whether this differed between male and female mice. Adult mice were trained to lever press for a liquid sucrose reward on two reinforcement schedules: a random interval (RI) schedule and a variable ratio (VR) schedule. After training, mice were tested on each of these levers for reward motivation using a progressive ratio test. We found that a history of low dose ethanol exposure increased sucrose reward motivation in male mice, but only on the RI lever and only when exposure occurred proximal to learning. Female mice were more motivated for sucrose on the RI lever than the VR lever regardless of ethanol exposure condition. These findings indicate that training on different reinforcement schedules affects reward motivation. Further, we show that males are more susceptible to the effects of low dose ethanol on sucrose reward motivation than females. These data broaden our understanding of sex differences in reward seeking as a result of ethanol exposure.

Sex and individual differences in the effect of chronic low‐dose ethanol on behavioral strategy selection

“…Previously published findings from our lab showed that chronic low‐dose ethanol exposure had no effect on basal reward seeking during training, regardless of reinforcement schedule or sex (Bryant et al., 2022). However, a history of low‐dose ethanol exposure proximal to learning increased reward seeking on a progressive ratio task, and this was associated with alterations in reward magazine checking behavior.…”

“…Exposure timing‐dependent effects of ethanol on sucrose reward motivation have been observed under the same training and exposure conditions (Bryant et al., 2022), so this suggests that the effects of ethanol and exposure timing on behavioral strategy selection and motivation may occur via distinct underlying mechanisms. While there were no population level differences observed here, there was a lot of individual variability in sensitivity.…”

“…All mice were group housed for the duration of the study. A subset of the behavioral findings from these animals and experiments have been previously published (Bryant et al., 2022). This study presents new analyses of this published dataset in addition to unpublished findings in regard to contingency sensitivity and related behaviors.…”

“…After training, mice were tested for inflexible behavior on a contingency degradation (CD) test. Progressive ratio (PR) testing occurred following CD testing as described and presented in a previously published manuscript (Bryant et al., 2022). As the PR test occurred following the CD test, there is no impact of this additional testing on the results presented here.…”

“…While it is known that chronic high‐dose ethanol exposure can promote the development of inflexible behaviors such as habits (Dickinson et al., 2002; O'Tousa & Grahame, 2014; Vandaele & Ahmed, 2021) that are hallmarks of AUD (McKim et al., 2016; Sjoerds et al., 2013), the consequences of lower doses of ethanol are less well‐characterized. A smaller but growing body of evidence suggests that chronic low‐dose ethanol can also impact the development of inflexible reward seeking (Bryant et al., 2022; Corbit et al., 2012).…”