Punishment-resistant alcohol intake is mediated by the nucleus accumbens shell in female rats

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2024-12, Vol.49 (13), p.2022-2031
• Main Authors: McDonald, Allison J., Nemat, Panthea, van ‘t Hullenaar, Thijs, Schetters, Dustin, van Mourik, Yvar, Alonso-Lozares, Isis, De Vries, Taco J., Marchant, Nathan J.
• Format: Article
• Language: English
• Subjects: 13/51; 631/378/1457/1936; 631/378/1595/1396; 631/378/1662; 631/378/1689/5; 631/378/1788; Alcohol Drinking - psychology; Alcohol use; Animals; Behavioral Sciences; Biological Psychology; Central Nervous System Depressants - administration & dosage; Central Nervous System Depressants - pharmacology; Drug addiction; Drug self-administration; Ethanol - administration & dosage; Ethanol - pharmacology; Female; Females; Footshock; Male; Medicine; Medicine & Public Health; Neurosciences; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Pharmacotherapy; Phenotypes; Psychiatry; Punishment; Rats; Rats, Long-Evans; Self Administration
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-024-01940-0

Alcohol use is widespread across many societies. While most people can control their alcohol use, a vulnerable sub-population develops alcohol use disorder, characterized by continued alcohol use despite negative consequences. We used a rat model of alcohol self-administration despite negative consequences to identify brain activity associated with this addiction-like behaviour. We and others have previously shown that response-contingent punishment of alcohol self-administration with mild footshock reliably identifies two sub-populations. One group substantially decreases alcohol self-administration in the face of punishment (punishment-sensitive, controlled) and another group continues alcohol self-administration despite negative consequences (punishment-resistant, addiction-like behaviour). In this study, we aimed to validate this model in females and identify associated brain regions. We trained Long-Evans outbred rats ( n  = 96) to self-administer 20% ethanol, and then introduced response-contingent footshock. We found that female rats consumed more alcohol in unpunished and punished sessions compared to male rats. In one group of rats ( n  = 24, m/f), we identified neuronal activity associated with punishment-resistant alcohol self-administration using the neurobiological marker of activity cFos. We found lower cFos expression in NAcSh associated with punishment-resistant alcohol self-administration. In another group of rats ( n  = 72, m/f), we used chemogenetic inhibition of NAcSh during punished alcohol self-administration. We found that chemogenetic NAcSh inhibition had no effect on unpunished alcohol self-administration but selectively increased punished alcohol self-administration in punishment-resistant female rats. These results indicate that more female rats develop punishment-resistant alcohol consumption, and that NAcSh hypofunction may underlie this phenotype.