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Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal
Changyou Jiang, … , Lan Ma, Feifei Wang
Changyou Jiang, … , Lan Ma, Feifei Wang
Published January 18, 2024
Citation Information: J Clin Invest. 2024;134(5):e171995. https://doi.org/10.1172/JCI171995.
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Research Article Neuroscience

Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal

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Abstract

Converging studies demonstrate the dysfunction of the dopaminergic neurons following chronic opioid administration. However, the therapeutic strategies targeting opioid-responsive dopaminergic ensembles that contribute to the development of opioid withdrawal remain to be elucidated. Here, we used the neuronal activity-dependent Tet-Off system to label dopaminergic ensembles in response to initial morphine exposure (Mor-Ens) in the ventral tegmental area (VTA). Fiber optic photometry recording and transcriptome analysis revealed downregulated spontaneous activity and dysregulated mitochondrial respiratory, ultrastructure, and oxidoreductase signal pathways after chronic morphine administration in these dopaminergic ensembles. Mitochondrial fragmentation and the decreased mitochondrial fusion gene mitofusin 1 (Mfn1) were found in these ensembles after prolonged opioid withdrawal. Restoration of Mfn1 in the dopaminergic Mor-Ens attenuated excessive oxidative stress and the development of opioid withdrawal. Administration of Mdivi-1, a mitochondrial fission inhibitor, ameliorated the mitochondrial fragmentation and maladaptation of the neuronal plasticity in these Mor-Ens, accompanied by attenuated development of opioid withdrawal after chronic morphine administration, without affecting the analgesic effect of morphine. These findings highlighted the plastic architecture of mitochondria as a potential therapeutic target for opioid analgesic-induced substance use disorders.

Authors

Changyou Jiang, Han Huang, Xiao Yang, Qiumin Le, Xing Liu, Lan Ma, Feifei Wang

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Figure 6

Overexpression of MFN1 in dopaminergic Mor-Ens alleviates withdrawal symptoms after chronic morphine administration in both male and female mice.

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Overexpression of MFN1 in dopaminergic Mor-Ens alleviates withdrawal sym...
(A) Experimental scheme to assess the effect of MFN1 overexpression in dopaminergic Mor-Ens. (B) Representative smFISH images of Mfn1 mRNA expressed in the VTA Mor-Ens. Red, Mfn1; Green, Egfp; Blue, DAPI. Dashed white lines outline the Egfp+ cells. Scale bars: 20 μm; 5 μm. (C) Quantification of the Mfn1 mRNA in the Egfp+ cells from EGFP and MFN1-EGFP groups. 3–4 mice per group, Egfp, 121 cells; Mfn1, 91 cells. (D) Representative images of nitrotyrosine immunostaining in the VTA Mor-Ens expressing EGFP or MFN1-EGFP. Red, nitrotyrosine; Green, EGFP; Blue, DAPI. Dashed white lines outline the EGFP+ cell. Scale bars: 20 μm; 5 μm. (E) The normalized expression level of nitrotyrosine in the VTA EGFP+ Mor-Ens. 3 mice per group, EGFP, 381 cells; MFN1, 434 cells. Unpaired t test or Kolmogorov-Smirnov test. (F–O) The effect of MFN1 overexpression in the VTA dopaminergic Mor-Ens on naloxone-precipitated withdrawal symptoms in both male and female mice. Weight loss, diarrhea, jumps, wet dog shakes, and body tremors were analyzed in EGFP and MFN1-EGFP groups. Male: 12–13 mice per group; female: 13 mice per group. Unpaired t test or Mann-Whitney test. Data are presented as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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