Cocaine and other addictive drugs are known to cause sensitization, a reinforced behavioral response to repeated exposures to the same drug, eventually contributing to compulsive use. The sensitized response is maintained for several weeks of abstinence, and outlasts transient transcription-dependent changes in neuronal physiology and plasticity. Due to its complex properties, the 3D structure of the genome may undergo long-lasting changes upon a single drug exposure, and serve as cellular memory in the path to addiction. Here, we show that a single exposure to cocaine induces extensive rewiring of 3D genome architecture of midbrain dopamine neurons (DNs) at particular synaptic and drug response genes that lasts up to 14 days post exposure. The effects of cocaine can trigger the extensive unfolding of neuronal genes with important synaptic and regulatory functions, which can become progressively stronger between 1 and 14 days after the exposure, such as at the post-transcriptional regulatory gene Rbfox1. Many of the genes with long-term altered topologies are most highly expressed in a specific sub-cluster of DNs known to project to secondary reward-pathway regions and have key features of highly cocaine-sensitive cells. These results reveal an unexpected role for 3D genome remodelling in the long-term memory of a single cocaine exposure, providing new insights about the inception of drug addiction and 3D genome plasticity.