Abstract
Neurobiological alterations seen in addiction amplify during abstinence and compromise relapse prevention. Cocaine use disorder (CUD) exemplifies this phenomenon in which reward regions such as nucleus accumbens (NAc) undergo withdrawal-associated modifications. While genome-wide transcriptional changes in NAc are linked to specific addiction phases, these have not been examined in a context- and NAc-subregion-specific manner during withdrawal vs. extinction. We used cocaine self-administration in male rats combined with RNA-sequencing of NAc-core and -shell to transcriptionally profile withdrawal in the home-cage, in the previous drug context, or after extinction. As expected, home-cage withdrawal maintained seeking, whereas extinction reduced it. By contrast, withdrawal involving the drug context only increased seeking. Bioinformatic analyses revealed specific gene expression patterns and networks associated with these states. Comparing NAc datasets of CUD patients highlighted conserved transcriptomic signatures with rats experiencing withdrawal in the drug context. Together, this work reveals fundamental mechanisms that can be targeted to attenuate relapse.