Enhanced expression of parvalbumin and perineuronal nets in the medial prefrontal cortex after extended-access cocaine self-administration in rats

The medial prefrontal cortex (mPFC) drives cocaine-seeking behaviour in rodent models of cocaine use disorder. Parvalbumin (PV)-containing GABAergic interneurons powerfully control the output of the mPFC, yet few studies have focused on how these neurons modulate cocaine-seeking behaviour. Most PV neurons are surrounded by perineuronal nets (PNNs), which regulate the firing of PV neurons. We examined staining intensity and number of PV and PNNs after long-access (6 h/day) cocaine self-administration in rats followed by either 8-10 days extinction +/- cue-induced reinstatement or short-term (1-2 days) or long-term (30-31 days) abstinence +/- cue-induced reinstatement. The intensity of PNNs was increased in the prelimbic and infralimbic PFC after long-term abstinence in the absence of cue reinstatement and after cue reinstatement following both daily extinction sessions and after a 30-day abstinence period. PV intensity was increased after 30 days of abstinence in the prelimbic but not infralimbic PFC. Enzymatic removal of PNNs with chondroitinase ABC (ABC) in the prelimbic PFC did not prevent incubation of cue-induced reinstatement but decreased cocaine-seeking behaviour at both 2 and 31 days of abstinence, and this decrease at 31 days was accompanied by reduced c-Fos levels in the prelimbic PFC. Increases in PNN intensity have generally been associated with the loss of plasticity, suggesting that the persistent and chronic nature of cocaine use disorder may in part be attributed to long-lasting increases in PNN intensity that reduce the ability of stimuli to alter synaptic input to underlying PV neurons. The medial prefrontal cortex (mPFC) contributes to cocaine seeking in rodent models of addiction and maintains cocaine memories. Perineuronal nets (PNNs) surround parvalbumin (PV) interneurons, which control mPFC output. PNNs regulate PV neuron firing and suppress plasticity. Extended access to cocaine self-administration increases PNN intensity in the mPFC, and PNN removal suppresses cue reinstatement after abstinence. These findings suggest that loss of plasticity after repeated cocaine may in part be due to an increase in PNN intensity in the mPFC.image