Dopaminergic neurons (DNs) from the Ventral Tegmental Area (VTA) are associated with addiction and are the first neurons to respond to a single dose of cocaine, leading to long-term potentiation. Gene expression and synaptic activity are reported to recover within the first 24 hours post cocaine exposure, but a memory of the first insult is thought to prevail, as a second exposure leads to more expansive activation. To gain mechanistic insights into the chromatin structure alterations seen by 24h and understand the cascade of events that disturbs networks of regulatory sequences and genes, we have generated single-cell RNA-ATAC datasets at different times after drug treatment. We found that a single cocaine administration induces long-lasting upregulation of a few genes up to 14 days, such as Cartpt, which has important roles in cocaine-induced behavior following abstinence. We identified dynamic regulatory regions over the time course that are enriched for distinct transcription factor binding sites such as AP-1 subunits, suggested to maintain de novo long-lasting chromatin states upon neuronal activation. We are also mining chromatin architecture maps obtained specifically for VTA-DNs after 24h or 14 days post single exposure. We found extensive rewiring of 3D chromatin structures at 24h many of which remain altered at 14d, and we currently explore their relationship to the cascades of gene activation and repressions post cocaine. Our work explores the dynamic changes in gene expression, regulatory landscape and 3D chromatin structure to discover the underlying mechanisms governing the protracted cellular recovery from a single cocaine administration.