The brainstem locus coeruleus (LC), the primary norepinephrinergic (NE) nucleus in the brain, has been implicated in the abuse of drugs such as opioids. However, whether and how the LC-NE system is involved in cocaine addiction remains elusive. Here, we demonstrated cocaine-evoked synaptic plasticity of glutamatergic transmission onto LC neurons as one of the earliest traces occurring after a single injection of cocaine. Twenty-four hours after mice were injected intraperitoneally with cocaine, the evoked α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated synaptic transmission onto LC neurons were strongly potentiated without major effect on N-methyl-d-aspartate receptor (NMDAR) mediated synaptic transmission. Compared with saline-pretreated mice, AMPAR-mediated excitatory postsynaptic currents (EPSCs) of cocaine-pretreated mice showed a marked inward rectification, demonstrating the insertion of GluR2-lacking AMPARs to plasma membrane. In addition, the single injection of cocaine did not affect presynaptic glutamate release probability measured by paired pulse ratio. Furthermore, we found that the cocaine-induced potentiation of AMPAR EPSCs could be blocked by prazosin, an inhibitor of α1-adrenoreceptor (AR), indicating that cocaine increases AMPAR transmission via α1-ARs. These results reveal that LC-NE serves as an initial target of drug intake.