Prelimbic cortex, but not its nucleus reuniens projections, regulates punished alcohol self-administration.

Alcohol use that persists despite negative consequences is observed in only a minority of those who drink alcohol and is a defining feature of alcohol use disorder (AUD). The neurobiological mechanisms underlying drinking despite negative outcomes are poorly understood. The medial prefrontal cortex (mPFC) is critical for decision-making and inhibitory control over behavior. Here, we employed a foot shock-punished alcohol self-administration procedure to examine the role of medial prefrontal subregions in drinking despite negative consequences in male Wistar rats. Introduction of response-contingent foot shock produced robust individual variability in suppression of responding, and rats were classified into shock-sensitive (SS) and shock-resistant (SR) subgroups. Using c-Fos immunohistochemistry, we showed that neuronal activation in the prelimbic (PrL) subdivision of the mPFC corresponds with suppression of responding during punished self-administration. To test the functional role of the PrL, we used chemogenetics to manipulate neuronal activity during punished sessions. Chemogenetic activation of the PrL enhanced responding during punished sessions in both SS and SR subgroups, while chemogenetic inhibition of the PrL reduced responding only in rats with an SR phenotype. We further explored how the PrL mediates punished drinking by assessing its outputs to the nucleus reuniens (Re), which plays a prominent role in aversive learning and memory. Chemogenetic activation and inhibition of PrL→Re projections had no effect on punished responding. Together, these data implicate the PrL in mediating individual differences in punished alcohol self-administration.