Comparative analysis of the modulation of perineuronal nets in the prefrontal cortex of rats during protracted withdrawal from cocaine, heroin and sucrose self-administration

Abstract

Relapse into drug use is a significant problem for people recovering from addiction. The ability that conditioned cues have to reinstate and reinvigorate drug-seeking is potentiated over time (incubation of seeking), posing an additional difficulty for maintaining abstinence. While the prefrontal cortex has been involved in the incubation phenomenon and the extracellular matrix, perineuronal nets (PNN) in particular, may play a vital role in brain plasticity associated to drug relapse, there are no comparative analyses between different drug classes and natural reinforcers. Here, we compare the effects of early (1 day) and protracted (30 days) withdrawal from to cocaine, heroin and sucrose self-administration on the PNN content of different territories of the prefrontal cortex of male Lewis rats. Our results show that cocaine selfadministration and protracted withdrawal decreased PNN content in the prelimbic cortex. Also, heroin self-administration increased PNN content in the infralimbic cortex, but this effect was lost after 30 days of withdrawal. Heroin self-administration also decreased PNNs in the insula, an effect that remained even after protracted withdrawal from the drug. Finally, the self-administration of sucrose-sweetened water decreased PNN content in the dorsomedial prefrontal cortex and increased PNNs in the insular cortex, which was still evident after protracted withdrawal. Our results show that three different rewards with specific pharmacological and physiological actions differentially modulate PNNs in specific areas of the rodent prefrontal cortex with potential implications for the incubation of seeking phenomenon.