Inflexible and Indifferent Alcohol Drinking in Male Mice

Background:  Alcoholism is characterized by compulsive alcohol intake, but this critical feature of alcoholism is seldom captured in preclinical studies. Here, we evaluated whether alcohol‐preferring C57BL/6J mice develop compulsive alcohol drinking patterns, using adulteration of the alcohol solution with quinine, in a limited access choice paradigm. We assessed 2 independent aspects of compulsive drinking: (i) inflexible alcohol intake by testing whether mice would drink bitter alcohol solutions if this was their only source of alcohol and (ii) indifferent drinking by comparing intake of aversive and nonaversive alcohol solutions. Methods:  Male C57BL/6J mice consumed alcohol for 2 or 8 consecutive weeks. The alcohol solution was then adulterated with graded quinine concentrations, and the effect on alcohol intake was determined. Results:  C57BL/6J mice rapidly developed compulsive alcohol drinking patterns. Adulteration of the alcohol solution with an aversive quinine concentration failed to reduce intake, indicative of inflexible drinking behavior, after only 2 weeks of alcohol experience, although quinine adulteration did suppress the acquisition of alcohol drinking in naïve mice. After 8 weeks of alcohol consumption, the mice also became indifferent to quinine. They consumed an aversive, quinine‐containing alcohol solution, despite the simultaneous availability of an unadulterated alcohol solution. Prolonged alcohol ingestion did not alter the sensitivity to the bitter taste of quinine itself. Conclusion:  These findings demonstrate the staged occurrence in mice of 2 distinct behavioral characteristics of alcoholism, i.e., inflexible and indifferent alcohol drinking.