Learned associations between the rewarding effects of drugs and the context in which they are experienced are decisive for precipitated drug-seeking and relapse in addiction. Such associative memories are stored in sparse and highly discriminative populations of concomitantly activated neurons defining drug-recruited ensembles. In this study, we explore the dynamics of recruitment of these ensembles through the encoding, strengthening and expression of cocaine-context associative memories. Additionally, we characterize the intrinsic (phenotypical) or acquired (plastic) cellular properties that would favor the allocation of specific cells to these functional ensembles and/or predict their further reactivation. Capitalizing on the activity-dependent labeling in Arc-CreERT2 mice, we captured and permanently tagged cocaine-activated cells in the Nucleus Accumbens. We show that distinct ensembles are recruited at early versus late stages of cocaine-context conditioning and that their reactivation during context re-exposure correlates with memory strength. Using optogenetic-mediated artificial reactivation, we found that these distinct populations had opposing roles in memory recall. We then isolated tagged nuclei with FACS and performed single nucleus RNA sequencing to analyze their transcriptional signature. We show that D1- and D2-dopamine receptor-expressing subtypes of medium spiny neurons are differentially recruited through the encoding and expression of drug-context associations. Using activity-dependent transcriptional programs as a marker of recent activation, we isolated a cluster of reactivated cells within the initially activated ensemble and identified gene programs predictive of context-dependent reactivation. Together, this ensemble-specific approach represents a pivotal step in identifying highly specific cellular processes involved in the encoding of pathological memories associated with drug addiction.