High Alcohol–Preferring Mice Show Reaction to Loss of Ethanol Reward Following Repeated Binge Drinking

Abstract

Background Beyond yielding high blood ethanol (EtOH) concentrations (BECs), binge‐drinking models allow examination of drinking patterns which may be associated with EtOH’s rewarding effects, including front‐loading and consummatory successive negative contrast (cSNC), a decrease in intake when only water is available to subjects expecting EtOH. The goals of the current study were to broaden our understanding of these reward‐related behaviors during binge EtOH access in high alcohol–preferring (HAP) replicate lines (HAP2 and HAP3) of mice selectively bred to prefer alcohol. We hypothesized that both lines would show evidence of front‐loading during binge EtOH access and that we would find a cSNC effect in groups where EtOH was replaced with water, as these results have been shown previously in HAP1 mice. Methods HAP replicate 2 and replicate 3 female and male mice were given 2 hours of EtOH or water access in the home cage for 15 consecutive days using "drinking in the dark" (DID) procedures. Mice received the same fluid (either 20% unsweetened EtOH or water) for the first 14 days. However, on the 15th day, half of the mice from these 2 groups were provided with the opposite assigned fluid (EtOH groups received water and vice versa). Intake was measured in 1‐minute bins using specialized sipper tubes, which allowed within‐session analyses of binge‐drinking patterns. Results EtOH front‐loading was observed in both replicates. HAP3 mice displayed front‐loading on the first day of EtOH access, whereas front‐loading developed following alcohol experience in HAP2 mice, which may suggest differences in initial sensitivity to EtOH reward. Consummatory SNC, which manifests as lower water intake in mice expecting EtOH as compared to mice expecting water, was observed in both replicates. Conclusions These findings increase confidence that defined changes in home cage consummatory behavior are driven by the incentive value of EtOH. The presence of cSNC across HAP replicates indicates that this reaction to loss of reward is genetically mediated, which suggests that there is a biological mechanism that might be targeted.

Shortening time for access to alcohol drives up front-loading behavior, bringing consumption in male rats to the level of females

“…Nevertheless, it can be challenging to test the effect of alcohol drinking on the nervous system in rodents because adult female rodents tend to drink significantly more g/kg alcohol than their male counterparts [ 42 , 59 – 63 , 84 , 85 ]. Studies that show no sex differences in alcohol consumption can also be found, which may reflect differences in species, strain, age, drinking paradigm, and study design [ 46 , 47 , 63 , 65 , 86 – 88 ]. While it is well known in the field that adult female rats drink more alcohol than males, the specific differences in patterns of drinking between males and females and their effects on the brain are not well understood.…”

“…For example, others have described “front-loading” as a burst of rapid drinking behavior at the start of the session when rodents first have access to alcohol [ 35 – 48 ]. Front-loading is found to be specific to rewarding substances, as mice that previously exhibited front-loading behavior to alcohol did not show this same behavioral response for water [ 45 – 47 ]. Other rewarding substances are capable of inducing front-loading in mice and rats, including sweet high-fat liquids and sodium solution to sodium-depleted rats, which makes front-loading behavior a consistent behavioral phenotype for seeking and consuming rewards [ 37 , 38 ].…”

Three Weeks of Binge Alcohol Drinking Generates Increased Alcohol Front‐Loading and Robust Compulsive‐Like Alcohol Drinking in Male and Female C57BL/6J Mice

“…In experiment 2, we assessed whether repeated QuA exposures alters the pattern of compulsive‐like QuA drinking after 3 weeks of daily DID, because we utilized a within‐subjects design in experiment 1 which resulted in 2 QuA exposures. Since alcohol front‐loading is thought to represent motivation to drink alcohol because the consumption occurs prior to the absorptive effects of alcohol (Ardinger et al, 2020; Linsenbardt and Boehm, 2014, 2015; Wilcox et al, 2014), we also sought to determine the pattern of front‐loading in QuA‐drinking mice. Finally, we determined BACs following QuA drinking.…”

Shortening Time for Alcohol Access Drives Up Front-Loading Behavior, Bringing Consumption in Male Rats to the Level of Females

“…Additionally, front-loading can be suppressed with conditioned taste aversion with a bitter solution (LiCl) in the first 9 minutes of access (Baird et al, 2005). Reward expectation can induce front-loading to non-rewarding solutions in alcohol-exposed mice that receive water when alcohol is expected (Ardinger et al, 2020). Increasing the effort to obtain alcohol with an FR3 schedule suppressed the total alcohol intake in both males and females; however subtle sex differences in front-loading remained, as females showed front-loading while it was notably reduced in males.…”

“…Operant self-administration in rodents is useful for modeling voluntary alcohol consumption in humans, while maintaining a level of experimental control needed for precise tracking and manipulation of alcohol drinking behavior (Brown et al, 1998;Elmer et al, 1987aElmer et al, , 1987bGeorge, 1987;Samson, 1986, 1985;June and Gilpin, 2010;Risinger et al, 1998); reviewed in (Green and Grahame, 2008;Jeanblanc et al, 2019). We used this approach to map out the dynamic microstructural patterns in drinking in male and female adult rats to explore various aspects of drinking behavior such as rapid drinking at the start of a session i.e., "front-loading" (Ardinger et al, 2020;Baird et al, 2005;D'Aquila et al, 2012;Davis, 1996;Lardeux et al, 2013;Linsenbardt and Boehm, 2015;Robinson and McCool, 2015). We also manipulated operant parameters of alcohol availability to further probe these sex differences in drinking patterns.…”