Neurobiological substrates of persistent working memory deficits and cocaine-seeking in the prelimbic cortex of rats with a history of extended access to cocaine self-administration

Cocaine use disorder (CUD) is associated with prefrontal cortex dysfunction and cognitive deficits that may contribute to persistent relapse susceptibility. As the relationship between cognitive deficits, cortical abnormalities and drug seeking is poorly understood, development of relevant animal models is of high clinical importance. Here, we used an animal model to characterize working memory and reversal learning in rats with a history of extended access cocaine self-administration and prolonged abstinence. We also investigated immediate and long-term functional changes within the prelimbic cortex (PrL) in relation to cognitive performance and drug-seeking. Adult male rats underwent 6 days of short-access (1 h/day) followed by 12 days of long-access (6 h/day) cocaine self-administration, or received passive saline infusions. Next, rats were tested in delayed match-to-sample (DMS) and (non)match-to-sample (NMS) tasks, and finally in a single context + cue relapse test on day 90 of abstinence. We found that a history of chronic cocaine self-administration impaired working memory, though sparing reversal learning, and that the components of these cognitive measures correlated with later drug-seeking. Further, we found that dysregulated metabolic activity and mGlu5 receptor signaling in the PrL of cocaine rats correlated with past working memory performance and/or drug-seeking, as indicated by the analysis of cytochrome oxidase reactivity, mGlu5 and Homer 1b/c protein expression, as well as Arc mRNA expression in mGlu5-positive cells. These findings advocate for a persistent post-cocaine PrL dysfunction, rooted in ineffective compensatory changes and manifested as impaired working memory performance and hyper-reactivity to cocaine cues. Considering the possible interplay between the neural correlates underlying post cocaine cognitive deficits and drug-seeking, cognitive function should be evaluated and considered when developing neurobiologically-based treatments of cocaine relapse.