State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
Nanjing University of Chinese Medicine, Nanjing, 210029, China.
Acta Pharmacol Sin. 2022 Sep;43(9):2276-2288. doi: 10.1038/s41401-022-00866-x. Epub 2022 Feb 25.
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.
药物成瘾的特征是当成瘾者再次接触与药物相关的环境线索时会复发，但导致线索诱发复发的神经机制尚不清楚。在本研究中，我们研究了腹侧被盖区（VTA）到伏隔核核心（NAcore）的特定多巴胺能（DA）通路在小鼠线索诱发复发中的作用。在 DAT-Cre 转基因小鼠中建立了光控颅内自我刺激（oICSS）。我们表明，VTA 中 DA 神经元的光遗传学刺激或其投射末端在 NAshell 或边缘前脑皮层（PFC-IL）中的投射末端是令人愉悦的。此外，单独激活 VTA-NAcore 通路足以且有必要诱导 oICSS 的复燃。在可卡因自我给药模型中，通过细胞内 GCaMP 信号评估可卡因相关线索激活 VTA DA 神经元。通过光遗传学刺激 VTA-NAcore 通路触发可卡因寻求的线索复燃，并通过该通路的化学遗传抑制来抑制。总之，这些结果表明，线索诱发的奖励寻求的复燃部分是由 VTA-NAcore DA 通路的激活介导的。
