Modeling Concurrent Hedonic Disruption During Excessive Drinking and Abstinence-Related Negative Affect in a Novel Selectively Bred Mouse Line: The Crossed High Alcohol Preferring X High Drinking in the Dark (cHAPxHDID) Mice

Abstract

Background

Alcohol use disorder (AUD) is often comorbid with depressive disorders such as major depressive disorder (MDD). These comorbidities are often modeled by allowing C57BL/6 (B6) mice to drink alcohol and testing for depressive- and anxiety-like phenotypes 2–3 weeks into abstinence; however, it should be noted that B6 mice are both inbred, which may limit external validity, and show modest intakes compared to humans with AUD. We have created a new selectively bred line of high alcohol-preferring mice, the crossed High Alcohol Preferring X High Drinking-in-the-Dark mice (cHAPxHDIDs). The cHAPxHDID mice have not been explored as a model of AUD + MDD comorbidity, nor has their drinking propensity been characterized in any publication to date.

Methods

We used male and female cHAPxHDID mice and a home cage 2-bottle choice (2BC) paradigm (water/water v. 10% ethanol/water) for 5 weeks across three experiments. We characterized the cHAPxHDIDs' 2BC drinking by measuring intake over a day, along with blood ethanol concentrations (BECs). Additionally, we ran behavioral tests for negative affect at different timepoints in abstinence. Finally, we also probed for the emergence and sustenance of anhedonia during the drinking period with a modified 1% sucrose preference test (SPT).

Results

We found that cHAPxHDID mice drink excessively, especially at the onset of the dark cycle, and achieve average BECs higher than 300 mg/dL. Ethanol drinkers showed increased latency in the novelty-suppressed feeding test (NSFT) at 6 days into abstinence. Alcohol-drinking mice reduced their sucrose intake during the drinking period beginning in Week 2, which normalizes at 48 h into abstinence.

Conclusions

The cHAPxHDIDs show some evidence of depressive symptomatology after and during drinking. They drink excessive amounts of alcohol voluntarily, reaching high and sustained BECs. Taken together, our data suggest that the cHAPxHDIDs may be a promising model for excessive drinking and its mood-related comorbidities.