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.
ASJC Scopus subject areas
- Psychiatry and Mental health