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

Man-yi Jing1, Xiao-yan Ding1,2, Xiao Han1, Tai-yun Zhao1, Min-min Luo3, Ning Wu1, Jin Li1, Rui Song1
1 tate Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
2 anjing University of Chinese Medicine, Nanjing 210029, China
3 ational Institute of Biological Sciences, Beijing 102206, China
Correspondence to: Ning Wu:, Jin Li:, Rui Song:,
DOI: 10.1038/s41401-022-00866-x
Received: 9 August 2021
Accepted: 13 January 2022
Advance online: 25 February 2022


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.
Keywords: drug addiction; dopamine; ventral tegmental area; nucleus accumbens; medial prefrontal cortex; optogenetic; optical intracranial self-stimulation; cocaine self-administration

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