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 2

A subpopulation of morphine withdrawal mice with depressive-like phenotypes are vulnerable to stress-induced CPP reinstatement.

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A subpopulation of morphine withdrawal mice with depressive-like phenoty...
(A) Three-dimensional plot showing the variability in depressive-like behaviors of SPT, TST, and FST. (B) ROC algorithm to establish cutoff criteria based on SPT, TST, and FST. Orange line, cutoff value based on the maximum Youden index. AUC, area under the curve (0–1). n = 62 Sal, and n = 131 Mor. ***P < 0.0001, by unpaired Student’s t test. (C and D) Bimodal distribution of depression scores. Sal and Mor mice were considered positive for behavioral criteria 0 to 3 according to the cutoff value (orange line). (E) Separation of groups according to depression score. Mor mice that met all 3 positive criteria (D-3) were classified as the depressive-like phenotype (Mor-D). Mor mice with a D-0 or D-1 were classified as the non-depressive-like phenotype (Mor-nD). The Sal group only included mice with D-0 or D-1. (F) Correlation analysis between SPT sucrose preference, TST immobility time, and FST immobility time in Mor-nD and Mor-D group. *P < 0.05, **P < 0.01, by Pearson’s correlation test. (G) Flowchart of the CPP reinstatement test. (H) Left: Example traces of morphine CPP tests. The red chamber indicates the morphine-paired chamber. Right: CPP scores in pretest, post-test, and extinction test. (I) CPP reinstatement test. Left: CPP score before and after foot shock in different groups. n = 8 Sal, n = 21 Mor-nD, and n = 9 Mor-D. **P < 0.01, by mixed RM 2-way ANOVA followed by Šidák’s test. Right: A priming dose of morphine evoked CPP reinstatement in different groups. ***P < 0.0001, by 1-way ANOVA followed by Tukey’s test. Data are presented as mean ± SEM.