Specialized aggregations of extracellular matrix called perineuronal nets (PNNs) appear during juvenile stages of development and surround primarily fast-spiking, parvalbumin (PV)-containing GABAergic interneurons in the central nervous system. These PNNs are an exciting structure to explore in drug abuse research because previous studies show that removing them in certain brain regions re-establishes juvenile-like states of plasticity; therefore, we may be able to alter the brain plasticity imposed by drugs of abuse. Our studies in rats show that removal of PNNs within the prelimbic region of the medial prefrontal cortex (mPFC) impairs the consolidation and reconsolidation of cocaine-associated memories in a cocaine-induced conditioned place preference (CPP) task. In addition, removal of PNNs blunts the acquisition of cocaine self-administration and appears to blunt the reconsolidation of the memory associated with cocaine cues. Conversely, cocaine exposure alters the intensity (thickness) of PNNs and the intensity of PV cells in the prelimbic mPFC. While acute cocaine injection decreases the intensity of PNNs and PV cells, repeated cocaine injection increases the intensity of PNNs and PV cells. Some of these changes observed after cocaine may be mediated by oxidative stress. Overall, our studies suggest that PNNs within the mPFC are highly dynamic and modulate cocaine-induced plasticity.