IRK mediated enhanced membrane excitability in accumbens neuronal ensembles promotes incubation of cocaine craving

The incubation phenomenon for cocaine craving, a poorly understood state with precipitated drug-seeking behaviors after prolonged abstinence, leads to a dilemma in treating cocaine addiction. The role of neuronal ensembles activated by cocaine experience in the incubation phenomenon was unclear. In this study, with cocaine self-administration (SA) models, we found that neuronal ensembles in the nucleus accumbens shell (NAcSh) showed increasing activation induced by drug-seeking test after 30-day withdrawal. Here, we explored the molecular dynamic of cocaine-ensembles in NAcSh during prolonged withdrawal by RiboTag, and discovered the specific translational regulation of genes and pathways in cocaine-ensembles before and after prolonged withdrawal. NAcSh cocaine-ensembles showed specifically increase of membrane excitability and downregulation of inward rectifier channels Kir2.1 currents after 30-day withdrawal. Overexpression of Kir2.1 in NAcSh cocaine-ensembles restored neuronal membrane excitability and suppressed drug-seeking behavior after 30-day withdrawal. Our results provide a cellular mechanism that the downregulation of Kir2.1 functions in NAcSh cocaine-ensembles induced by prolonged abstinence mediates the enhancement of ensemble membrane excitability, leading to incubation of cocaine craving.