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Drp1 mitochondrial fission in astrocyte modulates behavior and neuroinflammation during morphine addiction
Xiaotong Gu1, Wenjing Chen1, Zixin Li1
1State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Sanya, 572025, China.
Background:
Mitochondrial dynamics in neurons accompanied by neuroinflammation has been proved as pivotal events during repeated morphine exposure, however, the relationship between mitochondrial dynamics and neuroinflammation still remains unknown.
Methods:
This study was designed to investigate the potential role of astrocyte Drp1 in neuroinflammation during morphine addiction. Nucleus accumbens (NAc) tissues were collected for immunofluorescence, transmission electron microscopy (TEM) and quantitative real-time polymerase chain reaction (qRT-PCR) to detect the expression of pro-inflammatory cytokines and mitochondrial fission proteins. Morphine-induced conditioned place preference (CPP) and open field test (OFT) were used to determine the effects of Mdivi-1, a selective inhibitor of mitochondrial fission protein Drp1 in the rewarding properties of morphine. Astrocyte-specific knockdown experiments by an adeno-associated virus (AAV) vector containing shRNADrp1-EGFP infusion were performed to determine the effects of astrocyte Drp1 in NAc of mice with morphine treatment.
Results:
In this study, we found that repeated morphine exposure induced mitochondrial fragmentation in neurons, astrocytes, and microglia in NAc, correlating with increased inflammatory markers and addictive behaviors. The application of Mdivi-1 effectively mitigated mitochondrial fragmentation and astrocyte-mediated neuroinflammation within the NAc, thereby alleviating morphine-induced addictive behaviors. Crucially, the astrocyte-specific knockdown of Drp1 in NAc significantly curtailed drug-seeking behavior and substantially reduced neuroinflammation.
Conclusions:
Collectively, our findings suggest that alterations in mitochondrial dynamics, particularly within astrocytes, play an important role in regulating neuroinflammation associated with morphine addiction. This research offers novel insights into potential therapeutic strategies for addressing substance use disorder (SUD) by regulating mitochondrial dynamics within astrocyte.
Insights
Morphine addiction involves mitochondrial fragmentation and neuroinflammation, particularly in astrocytes. Inhibiting mitochondrial fission protein Drp1 in astrocytes alleviates addiction behaviors and reduces inflammation, offering new therapeutic targets for substance use disorder.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Mitochondrial dynamics and neuroinflammation are key in morphine exposure.
- The precise link between mitochondrial dynamics and neuroinflammation in morphine addiction remains unclear.
Purpose of the Study:
- To investigate the role of astrocyte dynamin-related protein 1 (Drp1) in neuroinflammation during morphine addiction.
- To explore the therapeutic potential of targeting mitochondrial dynamics in substance use disorder (SUD).
Main Methods:
- Analysis of nucleus accumbens (NAc) tissues using immunofluorescence, transmission electron microscopy (TEM), and qRT-PCR.
- Assessment of morphine-induced behaviors using conditioned place preference (CPP) and open field tests (OFT).
- Pharmacological inhibition of Drp1 using Mdivi-1 and genetic knockdown of astrocyte Drp1 via adeno-associated virus (AAV) vectors.
Main Results:
- Repeated morphine exposure caused mitochondrial fragmentation and increased inflammatory markers in NAc neurons, astrocytes, and microglia.
- Mdivi-1 treatment reduced mitochondrial fragmentation, astrocyte-mediated neuroinflammation, and morphine-induced addictive behaviors.
- Astrocyte-specific knockdown of Drp1 significantly decreased drug-seeking behavior and neuroinflammation.
Conclusions:
- Astrocyte mitochondrial dynamics, regulated by Drp1, are crucial in morphine addiction-related neuroinflammation.
- Targeting astrocyte mitochondrial dynamics presents a promising therapeutic strategy for SUD.
