The infralimbic and prelimbic cortices contribute to the inhibitory control of cocaine-seeking behavior during a discriminative stimulus task in rats.

The infralimbic and prelimbic (IL and PL, respectively) regions of the medial prefrontal cortex regulate the control of drug-seeking behavior. However, their roles in cocaine seeking in a discriminative stimulus (DS)-based self-administration task are unclear. To address this issue, male Sprague Dawley rats were trained on a DS task in which, on a trial-by-trial basis, a DS+ indicated that a lever press would produce a cocaine infusion, whereas a distinct DS- indicated that a lever press would produce nothing. IL and PL inactivation via GABA receptor activation decreased performance accuracy and disinhibited behavioral responding on DS- trials, resulting in greater lever pressing during the DS- presentation. This was accompanied by a decrease in cocaine infusions obtained, a finding confirmed in a subsequent experiment using a standard FR1 cocaine self-administration paradigm. We repeated the DS study using a food reward and found that inactivation of each region decreased performance accuracy but had no effect on the total number of food pellets earned. Additional experiments with the cocaine DS task found that dopamine receptor blockade in the IL, but not PL, reduced performance accuracy and disinhibited behavioral responding on DS- trials, whereas AMPA receptor blockade in the IL and PL had no effect on performance accuracy. These findings strongly suggest that, in a DS-based self-administration task in which rats must actively decide whether to engage in lever pressing (DS+) or withhold lever pressing (DS-) on a trial-by-trial basis, both the IL and PL contribute to the inhibitory control of drug-seeking behavior.