College of Forensic Science, Key Laboratory of National Health Commission for Forensic Science, National Biosafety Evidence Foundation, Xi'an Jiaotong University, Xi'an, China.
Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Xiamen Key Laboratory of Regeneration Medicine, Organ Transplantation Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
J Clin Invest. 2023 Sep 15;133(18):e163266. doi: 10.1172/JCI163266.
The nucleus accumbens (NAc) is the most promising target for drug use disorder treatment. Deep brain stimulation (DBS) of NAc is effective for drug use disorder treatment. However, the mechanisms by which DBS produces its therapeutic effects remain enigmatic. Here, we define a behavioral cutoff criterion to distinguish depressive-like behaviors and non-depressive-like behaviors in mice after morphine withdrawal. We identified a basolateral amygdala (BLA) to NAc D1 medium spiny neuron (MSN) pathway that controls depressive-like behaviors after morphine withdrawal. Furthermore, the paraventricular nucleus of thalamus (PVT) to NAc D2 MSN pathway controls naloxone-induced acute withdrawal symptoms. Optogenetically induced long-term potentiation with κ-opioid receptor (KOR) antagonism enhanced BLA to NAc D1 MSN signaling and also altered the excitation/inhibition balance of NAc D2 MSN signaling. We also verified that a new 50 Hz DBS protocol reversed morphine withdrawal-evoked abnormal plasticity in NAc. Importantly, this refined DBS treatment effectively alleviated naloxone-induced withdrawal symptoms and depressive-like behaviors and prevented stress-induced reinstatement. Taken together, the results demonstrated that input- and cell type-specific synaptic plasticity underlies morphine withdrawal, which may lead to novel targets for the treatment of opioid use disorder.
伏隔核（NAc）是治疗药物使用障碍最有前途的靶点。NAc 的深部脑刺激（DBS）对治疗药物使用障碍有效。然而，DBS 产生治疗效果的机制仍然是个谜。在这里，我们定义了一个行为截止标准，以区分吗啡戒断后小鼠的抑郁样行为和非抑郁样行为。我们确定了杏仁基底外侧核（BLA）到 NAc D1 中间神经元（MSN）通路，该通路控制吗啡戒断后的抑郁样行为。此外，丘脑室旁核（PVT）到 NAc D2 MSN 通路控制纳洛酮诱导的急性戒断症状。用光遗传学诱导κ-阿片受体（KOR）拮抗作用的长期增强作用增强了 BLA 到 NAc D1 MSN 的信号传递，并改变了 NAc D2 MSN 信号传递的兴奋/抑制平衡。我们还验证了一种新的 50 Hz DBS 方案可以逆转吗啡戒断引起的 NAc 异常可塑性。重要的是，这种改良的 DBS 治疗有效地缓解了纳洛酮诱导的戒断症状和抑郁样行为，并防止了应激引起的复吸。总之，这些结果表明，吗啡戒断时存在输入和细胞类型特异性突触可塑性，这可能为治疗阿片类药物使用障碍提供新的靶点。
