Species differences in cannabinoid receptor 2 and receptor responses to cocaine self-administration in mice and rats

Hai Ying Zhang, Guo Hua Bi, Xia Li, Jie Li, Hong Qu, Shi Jian Zhang, Chuan Yun Li, Emmanuel S. Onaivi, Eliot L. Gardner, Zheng Xiong Xi, Qing Rong Liu

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


The discovery of functional cannabinoid receptors 2 (CB2 Rs) in brain suggests a potential new therapeutic target for neurological and psychiatric disorders. However, recent findings in experimental animals appear controversial. Here we report that there are significant species differences in CB2 R mRNA splicing and expression, protein sequences, and receptor responses to CB2 R ligands in mice and rats. Systemic administration of JWH133, a highly selective CB2 R agonist, significantly and dose-dependently inhibited intravenous cocaine self-administration under a fixed ratio (FR) schedule of reinforcement in mice, but not in rats. However, under a progressive ratio (PR) schedule of reinforcement, JWH133 significantly increased breakpoint for cocaine self-administration in rats, but decreased it in mice. To explore the possible reasons for these conflicting findings, we examined CB2 R gene expression and receptor structure in the brain. We found novel rat-specific CB2C and CB2D mRNA isoforms in addition to CB2A and CB2B mRNA isoforms. In situ hybridization RNAscope assays found higher levels of CB2 R mRNA in different brain regions and cell types in mice than in rats. By comparing CB2 R-encoding regions, we observed a premature stop codon in the mouse CB2 R gene that truncated 13 amino-acid residues including a functional autophosphorylation site in the intracellular C-terminus. These findings suggest that species differences in the splicing and expression of CB2 R genes and receptor structures may in part explain the different effects of CB2 R-selective ligands on cocaine self-administration in mice and rats.

Original languageEnglish (US)
Pages (from-to)1037-1051
Number of pages15
Issue number4
StatePublished - Mar 2015
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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