Affective Disruption During Forced Ethanol Abstinence in C57BL/6J and C57BL/6NJ Mice

• Published in: Alcoholism, clinical and experimental research clinical and experimental research, 2020-10, Vol.44 (10), p.2019-2030
• Main Authors: Hartmann, Matthew C., Haney, Megan M., Smith, Caitlin G., Kumar, Vivek, Rosenwasser, Alan M.
• Format: Article
• Language: English
• Subjects: Abstinence; Addictive behaviors; Affect - drug effects; Affective Behavior; Alcohol Abstinence; Alcohol Abstinence - psychology; Alcohol use; Alcohol withdrawal; Animals; B6J; B6NJ; Benzodiazepines; Central nervous system; CIE; Complications; Convulsions; Depression - etiology; Depression - genetics; Depression - psychology; Detoxification; Drinking behavior; Emotional behavior; Ethanol; Female; Inhalation; Male; Mice; Mice, Inbred C57BL; Rodents; Substance Withdrawal Syndrome - genetics; Substance Withdrawal Syndrome - psychology; Sucrose
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.14443

Background In alcohol‐dependent individuals, acute alcohol withdrawal results in severe physiological disruption, including potentially lethal central nervous system hyperexcitability. Although benzodiazepines successfully mitigate such symptoms, this treatment does not significantly reduce recidivism rates in postdependent individuals. Instead, persistent affective disturbances that often emerge weeks to months after initial detoxification appear to play a significant role in relapse risk; however, it remains unclear whether genetic predispositions contribute to their emergence, severity, and/or duration. Interestingly, significant genotypic and phenotypic differences have been observed among distinct C57BL/6 (B6) substrains, and, in particular, C57BL/6J (B6J) mice have been found to reliably exhibit higher voluntary ethanol (EtOH) intake and EtOH preference compared to several C57BL/6N (B6N)‐derived substrains. To date, however, B6 substrains have not been directly compared on measures of acute withdrawal severity or affective–behavioral disruption during extended abstinence. Methods Male and female B6J and B6NJ mice were exposed to either a 7‐day chronic intermittent EtOH vapor (CIE) protocol or to ordinary room air in inhalation chambers. Subsequently, blood EtOH concentrations and handling‐induced convulsions were evaluated during acute withdrawal, and mice were then tested weekly for affective behavior on the sucrose preference test, light–dark box test, and forced swim test throughout 4 weeks of (forced) abstinence. Results Despite documented differences in voluntary EtOH intake between these substrains, we found little evidence for substrain differences in either acute withdrawal or long‐term abstinence between B6J and B6NJ mice. Conclusions In B6J and B6NJ mice, both the acute and long‐term sequelae of EtOH withdrawal are dependent on largely nonoverlapping gene networks relative to those underlying voluntary EtOH drinking. C57BL/6NJ (B6NJ) mice display more persistent behavioral depression in the forced swim test following chronic‐intermittent ethanol (EtOH) vapor exposure compared to C57BL/6J (B6J) mice. However, this trend was not observed in the sucrose preference test, suggesting that substrain differences in abstinence‐induced behavioral depression are assay specific. Overall, these data support previous findings that the emergence of affective disturbances in postdependent mice follows distinct temporal trajectories which depend on several