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A Conditioned Place Preference Protocol for Measuring Incubation of Craving in Rats
Published on: November 6, 2018
The HMGB1-RAGE axis in nucleus accumbens facilitates cocaine-induced conditioned place preference via modulating
Jian Ye1, Shuang-Qi Gao1,2, Zi-Cun Liu1
1Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Introduction:
Repeated exposure to cocaine induces microglial activation. Cocaine exposure also induces a release of high mobility group box-1 (HMGB1) from neurons into the extracellular space in the nucleus accumbens (NAc). HMGB1 is an important late inflammatory mediator of microglial activation. However, whether the secretion of HMGB1 acts on microglia or contributes to cocaine addiction is largely unknown.
Methods:
Rats were trained by intraperitoneal cocaine administration and cocaine-induced conditioned place preference (CPP). Expression of HMGB1 was regulated by viral vectors. Activation of microglia was inhibited by minocycline. Interaction of HMGB1 and the receptor for advanced glycation end products (RAGE) was disrupted by peptide.
Results:
Cocaine injection facilitated HMGB1 signaling, together with the delayed activation of microglia concurrently in the NAc. Furthermore, the inhibition of HMGB1 or microglia activation attenuated cocaine-induced CPP. Box A, a specific antagonist to interrupt the interaction of HMGB1 and RAGE, abolished the expression of cocaine reward memory. Meanwhile, the inhibition of HMGB1-RAGE interaction suppressed cocaine-induced microglial activation, as well as the consolidation of cocaine-induced memory.
Conclusion:
All above results suggest that the neural HMGB1 induces activation of microglia through RAGE, which contributes to the consolidation of cocaine reward memory. These findings offer HMGB1-RAGE axis as a new target for the treatment of drug addiction.
Insights
Neural high mobility group box-1 (HMGB1) activates microglia via RAGE, contributing to cocaine reward memory. Targeting the HMGB1-RAGE axis may offer new treatments for cocaine addiction.
Area of Science:
- Neuroscience
- Neuroinflammation
- Addiction Research
Background:
- Repeated cocaine exposure activates microglia and releases high mobility group box-1 (HMGB1) from neurons in the nucleus accumbens (NAc).
- HMGB1 is a key inflammatory mediator, but its role in cocaine addiction and microglial activation remains unclear.
Purpose of the Study:
- To investigate the role of HMGB1-mediated microglial activation in the development of cocaine reward memory.
- To explore the HMGB1-RAGE axis as a potential therapeutic target for cocaine addiction.
Main Methods:
- Rats were trained using cocaine administration and conditioned place preference (CPP).
- HMGB1 expression was manipulated using viral vectors; microglial activation was inhibited with minocycline.
- The HMGB1-RAGE interaction was blocked using a specific peptide (Box A).
Main Results:
- Cocaine administration increased HMGB1 signaling and delayed microglial activation in the NAc.
- Inhibiting HMGB1 or microglia activation attenuated cocaine-induced CPP.
- Blocking the HMGB1-RAGE interaction abolished cocaine reward memory and suppressed cocaine-induced microglial activation.
Conclusions:
- Neural HMGB1 activates microglia through RAGE, playing a critical role in consolidating cocaine reward memory.
- The HMGB1-RAGE axis represents a novel therapeutic target for treating cocaine addiction.
