1. Academic Validation
  2. Punishment-resistant alcohol intake is mediated by the nucleus accumbens shell in female rats

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

  • Neuropsychopharmacology. 2024 Jul 29. doi: 10.1038/s41386-024-01940-0.
Allison J McDonald 1 2 Panthea Nemat 1 2 Thijs van 't Hullenaar 1 2 Dustin Schetters 1 2 Yvar van Mourik 1 2 Isis Alonso-Lozares 1 2 Taco J De Vries 1 2 Nathan J Marchant 3 4
Affiliations

Affiliations

  • 1 Amsterdam UMC location Vrije Universiteit Amsterdam, Anatomy & Neurosciences, De Boelelaan 1117, 1081 HZ, Amsterdam, The Netherlands.
  • 2 Amsterdam Neuroscience, Compulsivity Impulsivity and Attention, Amsterdam, The Netherlands.
  • 3 Amsterdam UMC location Vrije Universiteit Amsterdam, Anatomy & Neurosciences, De Boelelaan 1117, 1081 HZ, Amsterdam, The Netherlands. n.marchant@amsterdamumc.nl.
  • 4 Amsterdam Neuroscience, Compulsivity Impulsivity and Attention, Amsterdam, The Netherlands. n.marchant@amsterdamumc.nl.
Abstract

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.

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