Nucleus accumbens D1/D2 circuits control opioid withdrawal symptoms in mice
Yongsheng Zhu, Kejia Wang, Tengfei Ma, Yuanyuan Ji, Yin Lou, Xiaoyu Fu, Ye Lu, Yige Liu, Wei Dang, Qian Zhang, Fangyuan Yin, Kena Wang, Bing Yu, Hongbo Zhang, Jianghua Lai, Yunpeng Wang
Yongsheng Zhu, Kejia Wang, Tengfei Ma, Yuanyuan Ji, Yin Lou, Xiaoyu Fu, Ye Lu, Yige Liu, Wei Dang, Qian Zhang, Fangyuan Yin, Kena Wang, Bing Yu, Hongbo Zhang, Jianghua Lai, Yunpeng Wang
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Research Article Neuroscience

Nucleus accumbens D1/D2 circuits control opioid withdrawal symptoms in mice

Abstract

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.

Authors

Yongsheng Zhu, Kejia Wang, Tengfei Ma, Yuanyuan Ji, Yin Lou, Xiaoyu Fu, Ye Lu, Yige Liu, Wei Dang, Qian Zhang, Fangyuan Yin, Kena Wang, Bing Yu, Hongbo Zhang, Jianghua Lai, Yunpeng Wang

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Figure 4

Mor-D mice show increased PVT→NAcD2 and decreased BLA→NAcD1 synaptic efficiency.

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Mor-D mice show increased PVT→NAcD2 and decreased BLA→NAcD1 synaptic eff...
(A) Schematic of the in vivo recording of NAc D1/D2 MSNs. D1-tdTomato×D2-eGFP double transgenic mice were used to identify NAc D1/D2 MSNs. Scale bar: 100 μm. (B and C) Sample of optically evoked EPSC traces of NAc D1 MSNs and D2 MSNs from PVT or BLA inputs. The A/N ratio is shown in NAc D1 MSNs and D2 MSNs. n = 16–20 neurons from 4–5 animals per group. *P < 0.05, **P < 0.01, by 1-way ANOVA followed by Tukey’s test. (D) Flowchart of the classical high-frequency DBS treatment in bilateral NAc (130 Hz, 1 h/d for 5 days). (E) Depressive-like behaviors in mice treated with or without 130 Hz DBS. n = 16 per group Mor-nD, and n = 6 per group Mor-D. *P < 0.05, **P < 0.01, by mixed RM 2-way ANOVA followed by Šidák’s test. (F) Foot shock–induced CPP reinstatement. (G) A/N ratio in NAc of Mor-D mice. n = 18–22 neurons from 4–6 animals per group. ***P < 0.0001, by unpaired Student’s t test. Data are presented as mean ± SEM.