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

Abstract

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.

Anti-relapse neurons in the infralimbic cortex of rats drive relapse-suppression by drug omission cues

“…These results extend previous reports 10,11,13,14,43 and establish the anti-relapse action of cocaine omission cues.…”

“…Disrupting neural activity in IL, using inhibitory GABA agonists, interferes not only with extinction (suppression) 12,35,36 (also see ref. 14 ), but also with reinstatement (promotion) 37,38 of drug seeking. Yet other reports indicate that GABA agonists in IL do not produce a significant effect on drug seeking 11,39 (also see ref.…”

Separate vmPFC Ensembles Control Cocaine Self-Administration Versus Extinction in Rats

“…However, our studies using Daun02 inactivation do not agree with this anatomical framework and demonstrate that neuronal ensembles in vmPFC and NAc shell promote rather than inhibit heroin or cocaine seeking, respectively (Bossert et al, 2011;Cruz et al, 2014). Other studies suggest that the mPFC subregions play more complex roles in drug seeking, via the efferent projections of individual neurons (Marchant et al, 2015;Moorman et al, 2015;McGlinchey et al, 2016;Gutman et al, 2017), rather than an anatomical divide between dorsal and ventral subregions.…”

Cocaine Self-Administration and Time-dependent Decreases in Prelimbic Activity

“…This study examined the effect of repeated cocaine self-administration (SA) on neuronal firing in the prelimbic (PL) cortex before, during, and immediately after SA. The PL cortex has an established involvement in drug-related behaviors: PL inactivation significantly reduces cocaine SA (Di Pietro et al, 2006;Gutman et al, 2016) whereas PL inactivation immediately prior to reinstatement suppresses context (Fuchs et al, 2005), cue (McLaughlin and See, 2003;Stefanik et al, 2016), cocaine-primed (Di Pietro et al, 2006;McFarland and Kalivas, 2001), and stress-induced (Capriles et al, 2003;McFarland et al, 2004) drug seeking. Corresponding changes take place in the PL cortex with continued cocaine use that contribute to relapse.…”