Nucleus accumbens D1/D2 circuits control opioid withdrawal symptoms in mice
Yongsheng Zhu, … , Jianghua Lai, Yunpeng Wang
Yongsheng Zhu, … , Jianghua Lai, Yunpeng Wang
Published August 10, 2023
Citation Information: J Clin Invest. 2023;133(18):e163266. https://doi.org/10.1172/JCI163266.
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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 5

The PVT→NAcD2 pathway modulates aversive withdrawal symptoms in Mor mice.

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The PVT→NAcD2 pathway modulates aversive withdrawal symptoms in Mor mice...
(A) Ex vivo oLFS-induced LTD in PVT→NAc D2 MSNs. The ChR2-expressing PVT→NAc pathway was stimulated by 1 Hz of oLFS to induce LTD. (B) Image of ChR2 expression in PVT terminals of D2-eGFP mice. Scale bar: 100 μm. (C) Normalized EPSC. oLFS induced a long-lasting reduction in EPSC in NAc D2 MSNs (n = 16 neurons from 4 mice) but not D1 MSNs (n = 9 neurons from 3 mice). ***P < 0.0001, by unpaired Student’s t test. (D) In vivo optogenetic depotentiation of PVT→NAcD2 pathway. Mice were implanted with optical fibers in dorsal to bilateral NAc and subjected to morphine treatment plus daily 1 Hz photo-stimulation for 15 minutes. (E) Naloxone-induced withdrawal symptoms in mice. n = 12–30 per group. ***P < 0.0001, by 2-way ANOVA followed by Šidák’s test. (F) Flowchart of CPP reinstatement test. Mor-D of D2-eGFP mice was subjected to daily 1 Hz photo-stimulations to induce oLFS in PVT→NAcD2 pathway. (G) Foot shock–induced CPP reinstatement. n = 6 per group. ***P < 0.0001, by mixed RM 2-way ANOVA followed by Šidák’s test. Data represent mean ± SEM.