Background: Repeated cocaine exposure produces new spine formation in Striatal Projection Neurons (SPNs) of the Nucleus Accumbens (NAc). However, an acute exposure to cocaine can trigger long-lasting synaptic plasticity in SPN leading to behavioral alterations. This raises the intriguing question as to whether acute cocaine could modify enduringly striatal connectivity. Methods: A 3D morphometric analysis of presynaptic glutamatergic boutons and dendritic spines was performed on SPN one hour and one week after a single cocaine administration. Time-lapse two-photon microscopy in adult slices was used to determine the precise molecular events sequence responsible for the rapid spine formation. Results: A single injection triggered a rapid synaptogenesis and persistent increase in glutamatergic connectivity in SPN from the shell part of the NAc, specifically. Synapse formation occurred through clustered growth of active spines contacting pre-existing axonal boutons. Spine growth required ERK activation, while spine stabilization involved transcription-independent protein synthesis driven by MAP kinase interacting kinase-1 (MNK-1), downstream from ERK. The maintenance of new spines driven by MNK-1 was essential for long-term connectivity changes induced by cocaine in vivo. Conclusions: Our study originally demonstrates that an acute administration of cocaine is able to induce stable synaptic rewiring in the NAc, which will likely influence responses to subsequent drug exposure. It also unravels a new functional role for cocaine-induced ERK pathway independently of nuclear targets. Finally, it reveals that MNK-1 has a pivotal role in cocaine-induced connectivity.