Activation of mesocorticolimbic dopamine projections initiates cue-induced reinstatement of reward seeking in mice.

Drug addiction is characterized by relapse when addicts are re-exposed to drug-associated environmental cues, but the neural mechanisms underlying cue-induced relapse are unclear. In the present study we investigated the role of a specific dopaminergic (DA) pathway from ventral tegmental area (VTA) to nucleus accumbens core (NAcore) in mouse cue-induced relapse. Optical intracranial self-stimulation (oICSS) was established in DAT-Cre transgenic mice. We showed that optogenetic excitation of DA neurons in the VTA or their projection terminals in NAcore, NAshell or infralimbic prefrontal cortex (PFC-IL) was rewarding. Furthermore, activation of the VTA-NAcore pathway alone was sufficient and necessary to induce reinstatement of oICSS. In cocaine self-administration model, cocaine-associated cues activated VTA DA neurons as assessed by intracellular GCaMP signals. Cue-induced reinstatement of cocaine-seeking was triggered by optogenetic stimulation of the VTA-NAcore pathway, and inhibited by chemogenetic inhibition of this pathway. Together, these results demonstrate that cue-induced reinstatement of reward seeking is in part mediated by activation of the VTA-NAcore DA pathway.