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Brain cannabinoid CB2 receptors modulate cocaine's actions in mice

Nature Neuroscience volume 14, pages 11601166 (2011) | Download Citation

Abstract

The presence and function of cannabinoid CB2 receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB2 receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB1 receptor knockout (CB1−/−, also known as Cnr1−/−) mice, but not in CB2−/− (Cnr2−/−) mice. This inhibition was mimicked by GW405833, another CB2 receptor agonist with a different chemical structure, and was blocked by AM630, a selective CB2 receptor antagonist. Intra-accumbens administration of JWH133 alone dose-dependently decreased, whereas intra-accumbens administration of AM630 elevated, extracellular dopamine and locomotion in wild-type and CB1−/− mice, but not in CB2−/− mice. Intra-accumbens administration of AM630 also blocked the reduction in cocaine self-administration and extracellular dopamine produced by systemic administration of JWH133. These findings suggest that brain CB2 receptors modulate cocaine's rewarding and locomotor-stimulating effects, likely by a dopamine-dependent mechanism.

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Acknowledgements

We thank Y. Shaham and E.A. Stein of the Intramural Research Program of the National Institute on Drug Abuse, and K. Mackie of Indiana University for their helpful comments on this manuscript. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse.

Author information

Author notes

    • Xiao-Qing Peng
    • , Xia Li
    •  & Rui Song

    These authors contributed equally to this work.

Affiliations

  1. Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, USA.

    • Zheng-Xiong Xi
    • , Xiao-Qing Peng
    • , Xia Li
    • , Rui Song
    • , Hai-Ying Zhang
    • , Qing-Rong Liu
    • , Hong-Ju Yang
    • , Guo-Hua Bi
    • , Jie Li
    •  & Eliot L Gardner
  2. Beijing Institute of Pharmacology and Toxicology, Beijing, China.

    • Rui Song

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Contributions

Z.-X.X. developed the original research proposal, designed and supervised all of the experiments, analyzed all of the data and wrote the manuscript. X.-Q.P., X.L. and R.S. conducted the cocaine self-administration experiments. X.L., G.-H.B. and H.-Y.Z. conducted the in vivo microdialysis experiments. X.L., H.-J.Y., R.S. and J.L. conducted the locomotor behavioral experiments. X.-Q.P., R.S. and H.-J.Y. conducted the conditioned place preference/aversion experiments. Q.-R.L. contributed to the original research proposal. E.L.G. contributed to the original idea of this work and was responsible for overall supervision of the research and for revisions and modifications to the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Zheng-Xiong Xi.

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https://doi.org/10.1038/nn.2874