Xie2-64, a novel CB2 receptor inverse agonist, reduces cocaine abuse-related behaviors in rodents

NEUROPHARMACOLOGY

卷:176

Article

Jordan, Chloe J.¹  Feng, Zhi-Wei^2,3,4  Galaj, Ewa¹  Bi, Guo-Hua¹  Xue, Ying^2,3,4  Liang, Ying¹  McGuire, Terence^2,3,4  Xie, Xiang-Qun^2,3,4,5,6,7  Xi, Zheng-Xiong¹ 

[1] NIDA, Addict Biol Unit, Mol Targets & Medicat Discovery Branch, Intramural Res Program, Baltimore, MD 21224 USA

[2] Univ Pittsburgh, Dept Pharmaceut Sci, Computat Chem Genom Screen CCGS Ctr, Pittsburgh, PA 15261 USA

[3] Univ Pittsburgh, Dept Pharmaceut Sci, Sch Pharm, Pittsburgh, PA 15261 USA

[4] Univ Pittsburgh, NIDA Natl Ctr Excellence Computat Drug Abuse Res, Pittsburgh, PA 15261 USA

[5] Univ Pittsburgh, Drug Discovery Inst, Pittsburgh, PA 15261 USA

[6] Univ Pittsburgh, Dept Computat Biol, Pittsburgh, PA 15261 USA

[7] Univ Pittsburgh, Dept Struct Biol, Pittsburgh, PA 15261 USA

关键词: Cannabinoid;    CB2 receptor;    Cocaine;    Xie2-64;    Dopamine;    Self-administration;    Optogenetics;   

DOI  :  10.1016/j.neuropharm.2020.108241

来源: Elsevier

【 摘 要 】

Cocaine abuse remains a public health threat around the world. There are no pharmacological treatments approved for cocaine use disorder. Cannabis has received growing attention as a treatment for many conditions, including addiction. Most cannabis-based medication development has focused on cannabinoid CB1 receptor (CB1R) antagonists (and also inverse agonists) such as rimonabant, but clinical trials with rimonabant have failed due to its significant side-effects. Here we sought to determine whether a novel and selective CB2R inverse agonist, Xie2-64, has similar therapeutic potential for cocaine use disorder. Computational modeling indicated that Xie2-64 binds to CB2R in a way similar to SR144528, another well-characterized but less selective CB2R antagonist/inverse agonist, suggesting that Xie2-64 may also have CB2R antagonist profiles. Unexpectedly, systemic administration of Xie2-64 or SR144528 dose-dependently inhibited intravenous cocaine self-administration and shifted cocaine dose-response curves downward in rats and wild-type, but not in CB2R-knockout, mice. Xie2-64 also dose-dependently attenuated cocaine-enhanced brain-stimulation reward maintained by optical stimulation of ventral segmental area dopamine (DA) neurons in DAT-Cre mice, while Xie2-64 or SR144528 alone inhibited optical brain-stimulation reward. In vivo microdialysis revealed that systemic or local administration of Xie2-64 into the nucleus accumbens reduced extracellular dopamine levels in a dose-dependent manner in rats. Together, these results suggest that Xie2-64 has significant anti-cocaine reward effects likely through a dopamine-dependent mechanism, and therefore, deserves further study as a new pharmacotherapy for cocaine use disorder.

【 授权许可】

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