A single dose of cocaine potentiates glutamatergic synaptic transmission onto locus coeruleus neurons

Abstract

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.