The medial prefrontal cortex (mPFC) is a major contributor to relapse to cocaine in humans and to reinstatement behavior in rodent models of cocaine use disorder. Output from the mPFC is modulated by parvalbumin (PV)-containing fast-spiking interneurons, the majority of which are surrounded by perineuronal nets (PNNs). Here we tested whether chondroitinase ABC (ABC)- mediated removal of PNNs prevented the acquisition or reconsolidation of a cocaine self-administration memory. ABC injections into the dorsal mPFC prior to training attenuated the acquisition of cocaine self-administration. Also, ABC given 3 days prior to but not 1 hr after memory reactivation blocked cue-induced reinstatement. However, reduced reinstatement was present only in rats given a novel reactivation contingency, suggesting that PNNs are required for the updating of a familiar memory. In naive rats, ABC injections into mPFC did not alter excitatory or inhibitory puncta on PV cells but reduced PV intensity. Whole-cell recordings revealed a greater inter-spike interval 1 hr after ABC, but not 3 days later. In vivo recordings from the mPFC and dorsal hippocampus (dHIP) during novel memory reactivation revealed that ABC in the mPFC prevented reward-associated increases in beta and gamma activity as well as phase-amplitude coupling between the dHIP and mPFC. Together, our findings show that PNN removal attenuates the acquisition of cocaine self-administration memories and disrupts reconsolidation of the original memory when combined with a novel reactivation session. Further, reduced dHIP/mPFC coupling after PNN removal may serve as a key biomarker for how to disrupt reconsolidation of cocaine memories and reduce relapse.