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Brain cannabinoid CB2 receptors modulate cocaine's actions in mice


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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Figure 1: Effects of JWH133 on cocaine self-administration.
Figure 2: Effects of GW405833 or JWH133 on cocaine self-administration.
Figure 3: Systemic administration of JWH133 (10 and 20 mg per kg, intraperitoneal, 30 min before cocaine) dose-dependently inhibited cocaine-enhanced locomotion in wild-type (a, two-way ANOVA for repeated measures over time, F2,16 = 14.45, P < 0.001) and CB1−/− (b, F2,18 = 12.57, P < 0.001) mice, but not in CB2−/− (c, F2,12 = 0.17, P = 0.85) mice.
Figure 4: Effects of systemic or local intra-NAc administration of JWH133 or AM630 on locomotor activity.
Figure 5: Effects of systemic JWH133 and/or AM630 on NAc DA.
Figure 6: Effects of intranasal or intra-NAc local perfusion of JWH133 or AM630 on extracellular NAc DA.


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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




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.

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Correspondence to Zheng-Xiong Xi.

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The authors declare no competing financial interests.

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Xi, ZX., Peng, XQ., Li, X. et al. Brain cannabinoid CB2 receptors modulate cocaine's actions in mice. Nat Neurosci 14, 1160–1166 (2011).

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