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
View: Text | PDF
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

×

Figure 7

BLA→NAcD1 pathway bidirectionally modulates depressive-like behavior and stress-induced CPP reinstatement.

Options: View larger image (or click on image) Download as PowerPoint
BLA→NAcD1 pathway bidirectionally modulates depressive-like behavior and...
(A) Dual-channel ex vivo optogenetic LTP protocol in D1-Cre mice. Chronos and ChrimsonR were activated by 405 nm and 590 nm light, respectively. Scale bar: 100 μm. (B) Optogenetic high-frequency stimulation (oHFS; 405 nm, 50 Hz, 100 pulses, repeated 4 times with a 20-second interval) combined with optogenetic postsynaptic depression (oPSD; 2 seconds, 590 nm) induced a long-lasting elevation of EPSC in BLA→NAcD1 pathway. n = 15 neurons from 3 animals. ***P < 0.0001, by unpaired Student’s t test. Scale bars: 50 ms and 50 pA. (C) oHFS + oPSD + U69 or oHFS + oPSD + norBNI induced a long-lasting increase in EPSC in BLA→NAcD1 pathway. n = 15–22 neurons in 3–6 animals per group. ***P < 0.0001, by 1-way ANOVA followed by Tukey’s test. (D) Flowchart of the dual-channel in vivo optogenetic LTP protocol. Chronos and ChrimsonR were expressed in BLA→NAcD1 afferents of Mor-D mice. (E) Depressive-like behaviors in D1-oLTP treatment. n = 6 per group. *P < 0.05, ***P < 0.0001, by 2-way ANOVA followed by Šidák’s test. (F) Foot shock–induced CPP reinstatement. n = 6 per group. **P < 0.01, by 2-way ANOVA followed by Šidák’s test. (G) Schematic of the in vivo chemogenetic inhibition protocol. hM4Di was expressed in BLA→NAc afferents of Mor-nD mice. CNO was administered before foot shock. (H) Depressive-like behaviors after CNO administration. n = 12 per group. **P < 0.01, ***P < 0.0001, by unpaired Student’s t test. (I) Foot shock–induced CPP reinstatement. n = 12 per group. *P < 0.05, by unpaired Student’s t test. Data are presented as mean ± SEM.